Assessment content of liver grafts.
\r\n\t
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During this period, China’s liver transplantation has experienced ups and downs and finally developed from immature to mature. Liver transplantation has been recognized as the only effective treatment for various end-stage liver diseases. The number of liver transplant cases in China ranks second in the world, ranking behind the United States. Its rapid development has attracted the attention of the world, and it has also exposed many problems that need to be solved [1].
\nThe development of liver transplantation in China has gone through the following stages:
The initial trial stage (1977–1983). In 1977, Shanghai Ruijin Hospital and Wuhan Tongji Hospital started the clinical liver transplantation in China. From 1977 to 1983, 57 liver transplants were carried out nationwide, but because the liver transplantation indications at that time were mainly advanced primary liver cancer, the curative effect was poor, and most patients died 3 months after surgery. Ten years later (1983–1993), China’s liver transplantation was basically at a standstill.
Re-development stage (1993–1997). With the continuous entry of new immunosuppressants into China, the continuous improvement of surgical techniques and perioperative management, and the continuous strengthening of international exchanges and cooperation, China’s liver transplantation finally re-emerged in the 1990s.
Rapid development stage (1997–2005). This is the main stage of liver transplantation development in China, and the main performance is as follows: (1) the number of liver transplants in mainland China has increased year by year. From 16 cases in 1997 to 100 cases in 1999, there were 200 cases of liver transplantation in 2000. By 2005, 3300 cases of liver transplantation were implemented. (2) The units and regions for liver transplantation have also increased year by year. More than 300 hospitals across the country have carried out liver transplantation. (3) Liver transplantation is diversified, from traditional classic liver transplantation to piggyback liver transplantation, ectopic liver transplantation, partial liver transplantation, split liver transplantation, and living donor liver transplantation. (4) The postoperative management level is continuously improved, the application of immunosuppressive agents is more individualized and diverse, and the survival rate of recipients is significantly improved. The 1-year survival rate after liver transplantation was 80.5%, and the 5-year survival rate was 65.9%. Liver transplantation technology and clinical efficacy are close to international standards [2]. In 2006, the Ministry of Health conducted an access work for organ transplant medical institutions, and China’s liver transplantation entered the stage of clinical normative development. Liver transplantation is gradually incorporated into the legal management. The medical institutions that are admitted are mainly strong medical institutions that have mature liver transplantation technology and talented echelons. Taking the service area and scope into account, the admitted liver transplant medical institutions are mainly concentrated in the affiliated hospitals of the provincial capital universities in the big cities, which further guarantee the quality, safety, and management of transplants [3]. In 2007, China’s first “Human Organ Transplantation Regulations” was officially implemented, and the Ministry of Health also issued relevant supporting regulations, marking a crucial step in the legalization and standardization of China’s organ transplantation [4]. In February 2005, the China Liver Transplant Registration Network was established. The system was supported by the University of Hong Kong with the support of the Ministry of Health. In May 2008, the China Liver Transplant Registration Network was officially authorized by the Ministry of Health to further cover the 80 admitted liver transplantation centers [5]. China Liver Transplant Registration Network has been upgraded from scientific voluntary registration to administrative mandatory registration, becoming the standardized management system for liver transplantation in China. China Liver Transplant Network has collected more than 12,000 cases of domestic liver transplant patients. By the end of 2008, China had implemented 14,600 liver transplants. By August 10, 2009, China had implemented 16,158 liver transplants until July 22, 2010. The Chinese transplant network registered 18,180 liver transplants [6].
DCD (organ donation after citizen’s death) Liver transplantation stage (2010–present) in 2010. China gradually began trial of DCD for liver transplantation, with 11 provinces including Zhejiang, Yunnan, Hubei, and Hunan as the first batch of pilots. The DCD was vigorously promoted and achieved good results. Summary after the completion of the pilot work: as of July 1, 2013, a total of 906 DCD donors donated nationwide, and 2469 organs were donated, including 746 livers. The above data show that although the Chinese DCD work started late, in the future it is the most potential source of organs [7]. Under the vigorous promotion of the Ministry of Health and the Red Cross Society, DCD work began to be promoted nationwide in 2012, and the construction of relevant laws and regulations also steadily advanced. In October 2012, in order to better implement the “Human Organ Transplant Regulations” and actively promote the Chinese organ donation work, the Ministry of Health formulated the “Management Methods for the Acquisition and Distribution of Human Organs in China” and established the “China Organ transplant response system” (OTRS). Through the application of this system, we wish to improve the matching degree of organs, reduce or prevent waste of resources, strive to achieve the traceability of each distributed organ, and eliminate the interference of human and subjective factors to ensure the principle of “fairness, openness, and justice” [8]. In 2010, DCD liver transplantation accounted for only 1.38% of the total, and in 2013, it has increased significantly to 26.02% [9], and by 2015, it has exceeded 80% [10]. China has completely banned the use of organs in the judicial channel since 2015. DCD donor China has become the main source of donors for organ transplantation in China. In 2017, 4732 cases of liver transplantation were performed in China, including 4138 cases of DCD liver transplantation, which was 26.43% higher than that of 2016 (3273 cases). The data show that the survival rates of liver transplantation in China at 1, 3, and 5 years are 84, 75, and 71%, respectively. The Chinese organ transplantation has entered the DCD era [11].
Although China’s organ transplants have developed rapidly, they have also achieved many achievements and showed the characteristics of China, but they also exposed some problems.
Problems faced by liver transplantation for liver cancer.
China is a big country with hepatitis B. The HBV carrying rate is about 10% in the national population. As the terminal end of the development chain of hepatitis-cirrhosis-hepatocarcinoma, the high incidence of liver cancer in China is inevitable. China’s liver cancer patients account for more than half of the world’s liver cancer patients, and 318,000 new liver cancer patients occur in China each year. With the continuous improvement of the medical insurance system, China has the world’s largest transplant recipient group, liver cancer liver transplantation once accounted for about 44% of China’s total liver transplant [5]. It is urgent to formulate the staging criteria and surgical adaptation of liver cancer liver transplantation in accordance with China’s national conditions as soon as possible. At the same time, how to combine immunosuppressive agents with antiliver disease and antihepatitis virus treatment is the main problem faced by Chinese transplant experts [12].
Problems faced by the DCD era.
The development of DCD donors has effectively alleviated the problem of donor shortages in China, and has also led to the complete abolition of judicial source donors. However, the current organ donation rate in China is still very low. In 2010, it was only 0.03 cases/million population. In 2015, it was 2.03 cases/million population, and in 2016, it was 2.98 cases/million population [13]. Although the growth is relatively fast, there is still a huge growth potential. This requires all levels of government in China to increase the propaganda of donations, and at the same time increase the staff of organ donation to find and report the information of potential donors in a timely manner. At the same time, a complete organ donation process must be developed to ensure the smooth implementation of the donation.
Basic and clinical research related to transplantation needs to be strengthened.
Organ transplantation is a multidisciplinary and interdisciplinary profession. Only by strengthening relevant basic and clinical research, can we better protect organ quality and provide better postoperative management and monitoring of patients [14].
The relevant laws and regulations on transplantation have yet to be perfected.
The current regulations on organ transplantation in China are mainly based on “the Interim Provisions on the Clinical Application Management of Human Organs Technology” issued in July 2006 and the “Human Organ Transplantation Regulations” promulgated by the State Council in March 2017. However, with the development of transplantation and the advent of the DCD era, more completed legal and ethical systems and management norms are needed to provide legal protection and policy support for the healthy and orderly development of organ transplantation in China.
China’s clinical liver transplantation has entered a critical period of simultaneous hopes and challenges, and Chinese liver transplant experts are constantly working hard to make liver transplantation a better way for patients with liver disease.
\nIn China, liver grafts used for transplantation are mainly from DCD (organ donation after citizen’s death), which includes DBD, DCD, DBCD, and living related donor. Here, we discuss the quality assessment of liver grafts from DCD. The quality of transplant liver is an important factor affecting the short-term and long-term effects of transplantation. Donated liver assessment mainly includes donor’s general information, medical history, general condition and intervention, laboratory results, etc. and specific items are listed in Table 1 [15]. Every case is evaluated dynamically, including at least one preliminary evaluation and final assessment prior to liver harvest. Donor age, hepatic steatosis, warm and cold ischemia time, the risk of infection and tumor, hypernatremia, etc. are risk factors affecting the quality of liver grafts.
\nCategory | \nItem | \nCategory | \nItem | \n
---|---|---|---|
General information of donor | \nGender | \nLaboratory tests | \nBlood routine | \n
Age | \nUrine routine | \n||
Blood type | \nFecal routine | \n||
Height | \nLiver function | \n||
BMI | \nBlood lipids | \n||
Medical history | \nPrimary disease (cause of death) | \nBlood sugar | \n|
ICU stay days | \nBlood electrolytes | \n||
Past history | \nCoagulation function | \n||
Family history | \nHIV | \n||
General condition and intervention | \nVital signs | \nHepatitis virus | \n|
Urine volume | \nSyphilis tests | \n||
Mechanical ventilation | \nTumor markers | \n||
Vasoactive drugs and other related drugs | \nInfection-related indicators | \n||
Other | \nJudgment during harvesting operation | \n\n | |
Warm and cold ischemia time | \n\n | \n | |
Pretransplant biopsies of livers | \n\n | \n |
Assessment content of liver grafts.
It is generally believed that elderly donors often have higher opportunity of getting arteriosclerosis, hepatic steatosis, and tumor, which are risk factors affecting the quality of liver. Therefore, age is an important factor in the evaluation of liver grafts, and usually, donor age > 50 years is considered a contraindication to the use for transplantation. However, as the progression of liver transplantation and the relatively expanded need for liver grafts, liver grafts from these elderly donors can also be used with rigorous assessment, especially in the case of ensuring a short warm and cold ischemia time [16, 17, 18].
\nHepatic steatosis is an important factor affecting liver function after transplantation; hence, the classification and the grading of hepatic steatosis are extremely pivotal. According to the histology classification, hepatic steatosis is mainly divided into macrovesicular steatosis, which is considered to be a more dangerous one, and microvesicular steatosis, which is generally regarded as being reversible. For microvesicular steatosis liver grafts, even though the lesion is severe, they can still be used. For macrovesicular steatosis liver grafts, if the lesion is more than 50%, it is considered to be a taboo for transplantation [19, 20]. At present, the methods for evaluating fatty liver graft mainly relies on the judgment of organ harvesting surgeon, and rapid frozen biopsy of liver grafts [21, 22]. The research toward the use of imaging methods such as ultrasound, CT, MRI, and metabonomics in the assessment of liver steatosis is launched and their efficiency still need to be verified [23].
\nWarm ischemic injury caused by hypotensive and hypoxic perfusion process is one of the most important features of liver grafts. Long-term ischemia can increase the risk of primary nonfunction and biliary complications; thus, the time of warm ischemia is an important factor in evaluating the quality of liver. In addition, cold ischemia time > 8 hours is also a risk factor of liver transplantation. It has been reported that the incidence of liver failure after transplantation increases by 8% for every 1 hour after cold ischemia time > 6 hours. Therefore, during the process of liver acquisition, in order to improve the quality of grafts, the operation and transportation time should be shortened as much as possible [18].
\nIt is mainly hepatitis B virus prevailing in China. The main route of HBV infection in liver transplant recipients is through liver grafts. Liver graft from the donor who is in active period of hepatitis virus infection or has developed hepatitis virus-related liver fibrosis should not be used. For HBV-positive grafts, they can still be used to recipients who are selected rationally, get prophylactic antiviral therapy and the treatment of HBV immunoglobulin [18, 19]. HCV infection is not common in China. HCV-positive liver grafts can be used to recipients who need transplantation urgently, and they need anti-HCV therapy after surgery.
\nFor donors who have malignant tumors or tumor history, whether the liver can be used for transplantation remains controversial, and the transfer risk of tumor cannot be properly assessed. It is generally believed that the incidence of donor-related tumor and the resulting mortality are very low. However, the current view is that the liver from donors who have malignant tumor history should be selected carefully because some malignant tumors have unpredictable possibilities of recurrence and metastasis [19].
\nHypernatremia (serum sodium >155 mmol/L) in donors is an important factor affecting the prognosis of liver transplantation. Studies have shown that hypernatremia affects the function of transplant organs and increases the risk of liver failure after transplantation, whose mechanism may be related to cell swelling, increased osmotic pressure, and reperfusion injury caused by hypernatremia. This adverse effect can be reduced by effectively correcting the blood sodium concentration [18].
\nThe effect of liver preservation affects the quality of grafts. At present, there are two methods of liver storage, which are static cold storage (SCS) and mechanical perfusion (MP). SCS is the most widely used method, and UW liquid, HTK liquid and Celsior liquid are the most popular preservation liquids. The ideal time for cold storage is less than 8 hours, and in clinical practice, the preservation time generally does not exceed 12–15 hours. MP can continuously infuse the organ’s intrinsic vascular system to deliver nutrient, achieve organ preservation, and repair simultaneously, having great value in prolonging the time of liver preservation and improving organ quality. Besides, MP can monitor liver function, bile secretion and other indicators dynamically during storage and transportation, and evaluate the quality of donated liver, showing important clinical application prospects [24, 25].
\nSince there is still no law about brain death, at the present stage in China, the sources of liver are DCD and living-related donation. Here, we only talk about the DCD donor liver procurement.
\nIt is recommended in most centers the “rapid cold perfusion and en-bloc liver-kidney procurement” technique [26]. Core temperature of the liver can be decreased rapidly to 0–4°C by double perfusion from the hepatic artery (aortic cannulation) and the portal vein (superior mesenteric vein cannulation). This technique also prevents accidental injuries to the hepatic hilar structures.
\nFollowing administration of 30,000 IU or 300 IU/Kg of heparin, expeditious access to the abdominal cavity is obtained through a midline incision from the xiphoid to the pubic symphysis. The abdominal aorta and inferior vena cava (IVC) are dissected and cannulated, and the cold flush (0–4°C normal saline) is initiated immediately. Superior mesenteric vein is isolated and cannulated at the root of small bowel mesentery followed with perfusion. Ice and slush are packed around the liver and kidneys, and subsequent dissection is carried out after completion of cold perfusion (Figure 1).
\nThe intubation perfusion of aorta and portal vein.
The liver is mobilized by dividing the round ligament, falciform, left triangular, and gastrohepatic ligaments. The hepatoduodenal ligament, posterior peritoneum nearby and the adhesions between the head of pancreas and duodenum are dissected with modified Kocher maneuver; the common bile duct is exposed and transected at the inferior margin of pancreas. The whole colon, stomach, and duodenum are isolated successively; then the bilateral peritoneum are cut open and the peritoneal attachments in the retroperitoneal space are divided until the spine. The ureters are isolated and transected at the common iliac artery level. After the procedure, only the liver, spleen, kidneys, and most part of pancreas are still left in the abdominal cavity. The pericardium and diaphragm are incised bilaterally: on the left, extending to the esophagus, and on the right, extending posterior the right lobe of the liver, adrenal gland, and IVC. The thoracic aorta and IVC are transected and the adhesions with the spine are divided until the common iliac artery level. The en-bloc liver-kidney-spleen organs cluster can be harvested with the aorta and IVC transection just below the cannulas.
\nOnce the multiple-organs cluster is taken out, it must be put into the sterile basin filled with 0–4°C organ preservation solution (usually UW solution) immediately. Additional perfusion usually is needed in order to eliminate the residual blood and sustain the low core temperature of the organs. The posterior wall of the aorta is longitudinal cut out, and the origins of celiac truck, superior mesenteric artery (SMA) and bilateral kidney arteries are exposed. The adhesions between the right kidney, adrenal gland, and the hepatic right lobe are divided until the inferior IVC exposed. IVC is transected just above the kidney veins level, and aorta is transected below the origin of SMA level; the liver and kidneys are separated and packaged respectively.
\nThe aim of bench surgery is to remove the unnecessary tissues attached to the liver and trim the main vessels and bile duct for a convenient anastomosis. The bench should be set up with a suitable sized bowl in which the graft is kept in sterile slush ice and UW at 4°C for the duration of the procedure to avoid rewarming.
\nFirstly, the diaphragm and remaining cardiac muscle are removed from the bare area of the liver and the vena cava. Then, the supra- and intrahepatic vena cava are skeletonized and all small branches are ligated with silk. The adrenal vein and the phrenic veins are tied or over sewn to prevent bleeding upon recirculation.
\nThe skeletonization of the hepatic artery is the most critical step in the bench surgery procedure. The dissection starts from the aorta and ends until the gastro duodenal artery (GDA) in order not to injure the hepatic lobar vessels. Care is taken to identify any aberrant arterial anatomy, which can be present in up to 20% of the population [27]. So, every artery and its branches should be isolated until it is identified that not entering the liver. The most common two variants are a replaced right hepatic artery emanating from superior mesenteric artery or a replaced left hepatic artery originating from the left gastric artery. Often the aberrant liver arteries need to be reconstructed for anastomosis.
\nThe portal vein is skeletonized up to 1–2 cm below the bifurcation point. Surrounding lymphatic tissue is removed, and care is taken not to injure the hepatic artery or bile duct.
\nThe pancreas tissues around the lower segment of the common bile duct are removed. Do not dissect excessively the tissues between the bile duct and the hepatic artery in order to preserve the blood supply of the bile duct.
\nA perfusion-giving set with cold UW should be set up to perfuse the liver and also to check the integrity of the portal vein and arterial tree, once the graft has been prepared for implantation (Figure 2).
\nThe trimmed and shaped donor liver.
Surgical methods of recipient liver transplantation include two main categories: orthotopic liver transplantation and ectopic liver transplantation [28]. At present, transplant centers in China basically use orthotopic liver transplantation. Orthotopic liver transplantation is divided into classic orthotopic liver transplantation, piggyback orthotopic liver transplantation, reduced-size liver transplantation, split liver transplantation, and auxiliary liver transplantation according to different surgical methods. The above procedures are applied in the Chinese transplant centers.
\nA curved cut under the regular costal edge or “Mercedes-Benz” logo shape incision has been made firstly, then dissecting the first hepatic portal dissecting the hepatic artery, separating the common bile duct, and finally separating the portal vein [29]. The inferior vena cava is then exposed. The posterior inferior vena cava can be quickly and safely separated from the posterior peritoneum [30].
\nThe nonhepatic venous bypass technique can reduce the congestion of the portal system and can solve the problem of blood return in the intestine and inferior vena cava during the nonhepatic period [31, 32]. As the surgical techniques become more and more skilled, the anastomosis time is shortened. At present, most transplant centers in China have adopted nontransfer liver transplantation technology [33]. However, for patients with severe hepatorenal syndrome, gastrointestinal bleeding, and cardiac insufficiency before surgery, extracorporeal portal bypass technology will still benefit.
\nThe portal vein and two inferior vena cava were clamped in turn, to avoid vascular torsion, and the blood vessels were cut off near the liver to remove the diseased liver. The suprahepatic inferior vena cava the infrahepatic inferior vena cava and the portal vein were sequentially anastomosed with 3-0, 4-0, and 5-0 Prolene sutures. The anastomosis was performed by two-point continuous valgus suture. Precautions of inferior vena cava anastomosis: A. The inferior vena cava of the recipient and the donor cannot be kept too long or too short; otherwise, the inferior vena cava will be folded or stretched, and the inferior vena cava hypertension or bleeding will be caused. B. The recipient’s suprahepatic inferior vena cava cannot be reversed; otherwise, it will cause poor blood flow in the inferior vena cava. C. The suture cannot be pulled too tightly to avoid damage to the intima form artificial stenosis, and even lead to Budd-Chiari syndrome. Precautions of hepatic portal vein anastomosis: A. Donor and recipient’s portal vein should be kept proper. B. The difference between the size of the portal vein of the donor and the recipient should not be too large, otherwise. C. The tension of the anastomosis needs to be appropriate. When the suture is completed, the “widening factor” of the portal vein should also be retained. The transplanted liver blood flow is then opened. The hepatic artery was reconstructed with a 7-0 Prolene suture, and the hepatic artery was opened. Successful hepatic artery reconstruction is critical to the function of the transplanted liver and the influence of bile duct. There is a variety of suturing methods: A. Separate the hepatic artery, the gastro duodenal artery and the common hepatic artery, and the three confluences were trimmed as a hornline, which was anastomosed with the donor’s common hepatic artery. B. When the gastroduodenal artery is relatively large, the donor’s celiac trunk artery can be anastomosed at the junction of the recipient’s gastroduodenal artery and the proper hepatic artery. C. If there is an anatomic abnormality in the hepatic artery of the donor, the hepatic artery should be trimmed, shaped, and then anastomosed with the recipient’s hepatic artery. D. When the recipient’s hepatic artery has an anatomic abnormality, the donor’s celiac trunk artery can be directly anastomosed to the abdominal aorta above the recipient’s celiac trunk artery. Finally, the bile duct was reconstructed with a 6-0 or 7-0 Prolene suture. T tube is drawn through the recipient’s common bile duct. If the recipient’s common bile duct is very small, it is recommended to perform bile duct jejunum Roux-en-Y anastomosis. The graft gallbladder was then removed [34, 35, 36] (Figure 3).
\nThe classical orthotopic liver transplantation.
Piggyback liver transplantation, different from the classical liver transplantation, is that the infrahepatic inferior vena cava is not necessary to be anastomosed, which thereby is clamped, and the suprahepatic inferior vena cava of the donor liver is anastomosed directly to the recipient’s hepatic vein or laterally to the recipient’s inferior vena cava [37, 38]. This procedure simplifies the operation of donor liver implantation, and only partially blocks the inferior vena cava during operation. It has little effect on hemodynamics in patients in nonhepatic phase, does not require venous bypass, and has less renal damage. However, this traditional piggyback liver transplantation procedure has a problem that the graft liver would swing in the abdominal cavity and cause vascular torsion, and the circulation return will be affected. At present, the modified piggyback procedure used in most mature transplant centers in China is below: inferior vena cava (VC) shaping: (1) recipient VC: according to the patient’s hepatic vein anatomy, the hepatic veins (left, middle and right) are split from the middle and trimmed into a continuous opening, and the front wall of inferior vena cava is also trimmed longitudinally, and all these together form an inverted triangular incision. (2) Donor VC: the posterior wall of the donor superior inferior vena cava was cut longitudinally with the two up angers of hepatic superior VC, also trimmed into an inverted triangular incision. Finally, these two inverted triangular incisions are anastomosed (Figure 4). The main purpose of this piggyback procedure is to enlarge the anastomosis of the outflow tract, avoid the anastomotic torsion, and reduce the incidence of postoperative outflow obstruction [39, 40].
\nThe two “inverted triangular” incisions of donor and recipient’s inferior CV.
In our clinical work, the whole liver transplantation cannot meet the needs of liver transplantation in children and some small-weight adults, because these patients cannot accommodate the large-size liver in the abdominal cavity, which is why the reduced-size liver transplantation came into being [41]. Reduced-size liver transplantation actually includes reduced-size cadaveric liver transplantation, split liver transplantation, and partial living liver transplantation. By 2010, 86 transplant centers in 30 provinces of Mainland China had undergone reduced-size liver transplantation. The donor liver for children with reduced-size liver transplantation is mainly the left liver. Split liver transplantation refers to the separation of an adult cadaveric donor liver into two transplanted livers with independent structures and functions by two-way technique, which is transplanted to two recipients. The conventional method is to detach the liver along the Cantlie line and obtain the intact right and left hepatic livers, respectively [42, 43].
\nAuxiliary liver transplantation refers to retaining the recipient’s liver or part of the liver, implanting the donor’s whole liver or part of the liver into the recipient, so that patients with liver failure can receive life support or compensate for the metabolism, detoxification, and other functions of the original liver deficiency [44]. It is divided into auxiliary ectopic liver transplantation and auxiliary orthotopic liver transplantation. The auxiliary liver transplantation has the following advantages: (1) patients with acute liver failure can pass the dangerous period, and (2) for congenital metabolic liver disease, implantation of a small amount of liver can meet the patient’s metabolic needs, (3) under surgical trauma, the recipient has no nonhepatic period, (4) the required liver volume is small, increase the donor liver source, and (5) for some patients within inability to tolerate the orthotopic whole liver transplantation, auxiliary liver transplantation should be performed first, and then the orthotopic liver transplantation should be considered after the recovery of the body function.
\nLiving donor liver transplantation has developed rapidly due to the severe lack of cadaver donor livers. In early years, the left half liver was used as the donor liver for living donor liver transplantation between adults, but for large-size recipients, the left half liver could not meet the demand of the recipient, so the right half liver was gradually used as the donor liver. The procedure of living donor liver transplantation is basically the same as that of orthotopic liver transplantation, but there are many differences in the reconstruction of hepatic vein, portal vein, hepatic artery, and bile duct.
\nIn living donor liver transplantation, the right half liver as donor liver is divided into two types, including the hepatic middle vein and not including the hepatic middle vein. Whether the branches of the hepatic middle vein in hepatic segment V and VIII should be reconstructed in living donor liver transplantation of right half liver is controversial. Different liver transplantation centers have proposed different reconstruction criteria.
\nIn the literature, B ultrasonography was used to assess congestion in the right half liver donation after temporary occlusion of the hepatic artery and the hepatic middle vein. Criteria for reconstruction of hepatic middle vein include: (1) after removing the area of the congestion, the remaining transplanted liver volume was less than 40% of recipient’s standard liver volume. (2) When hepatic artery and hepatic middle vein branches are blocked, the area of the donor liver congestion is more than half of the area of the right anterior lobe. (3) Noncongestive graft-to-recipient weight ratio (ncGRWR) < 0.65%.
\nThe diameter of the branches of the hepatic middle vein is also one of the criteria for reconstruction. The diameter of the branch of the hepatic middle vein in hepatic segments V and VIII was more than 7 mm, which was considered as the boundary of whether to reconstruct the branch of the hepatic middle vein. Kim et al. suggested that when the hepatic middle vein branches of segments V and VIII were larger than 5 mm in diameter, the hepatic middle vein branches needed to be reconstructed, and they tried to make the area of congestion less than 10% of the total graft volume [45].
\nIn living liver transplantation without hepatic middle vein, the grafts used for reconstruction of hepatic middle vein include the recipient’s own great saphenous vein, superficial femoral vein, umbilical vein, portal vein, artificial blood vessel, iliac vein or iliac artery cryopreserved from allogeneic tissue, and also venous patch to reconstruct the branch of hepatic umbilical vein. Liver transplantation center of the first Hospital of Zhejiang University carried out a preliminary study on 131 cases of living right donor liver transplantation without hepatic middle vein. The graft vessels were reconstructed by autologous portal vein, hepatic vein, great saphenous vein, or cryopreserved iliac artery to reconstruct the right hepatic vein branches V and VIII without hepatic middle vein [5].
\nAfter the portal veins of donor liver and recipient were in line with their caliber and length, they were performed with an end-to-end anastomosis. When the recipient of living donor liver transplantation has portal vein sclerosis or narrow problems, we anastomose the donor portal vein directly to the confluence of the recipient’s splenic vein and superior mesenteric vein. If the donor portal vein does not have enough length, portal vein transplantation can be performed.
\nThe reconstruction of hepatic artery in living donor liver transplantation is directly related to the success or failure of transplantation. The diameter of donor hepatic artery is only 2–3 mm. Arterial anastomosis under direct vision has been a difficult problem for many surgeons. Until the application of microsurgical vascular anastomosis under microscope, the incidence of hepatic artery thrombosis decreased from 25 to 0–3.8%. However, this technique is difficult to master and is influenced by arterial variations, donor-recipient caliber matching, and recipient hemodynamics. Therefore, it is important to establish a stable microsurgical team and mature arterial anastomosis methods in various transplantation centers.
\n\n
Bile duct shaping: within 3 mm, the combination of adjacent hepatic duct opening can be considered.
The principle of one-time suture insertion: in the so-called one-time suture process, the noninvasive suture needle from the recipient of the bile duct to the donor of the hepatic duct needle, must be completed at one time
The basic bile duct end to end anastomosis technique: the posterior wall is continuously sutured, and the anterior wall is discontinuously sutured.
With the improvement of liver transplantation anesthesia, surgical techniques and perioperative management, the efficacy and survival rate of liver transplant patients have been significantly improved. With the accumulation of surgical experience, we need promotion of our surgical techniques. However, in view of the current situation of organ shortage in China, how to choose the most suitable liver transplantation for different indications, preoperative status, and physiological and anatomical features still needs to continuously explore and summarize the experience.
\nIntraabdominal hemorrhage postliver transplantation is an early serious complication, and continues to be a prognostic factor for transplant success. Statistically, intraabdominal hemorrhage postliver transplantation occurs in 5–21% of recipients [46], while incidence rate of this complication in China is 5–15.3% [47, 48]. Reasons for intraabdominal bleeding after liver transplantation include coagulopathy, portal hypertension, massive transfusion of stored blood, primary graft non-function/poor graft function, anastomotic leakage, as well as blood vessel damage by abdominal infection. Coagulopathy is one of the most important risk factors for postoperative early hemorrhage. Diffuse hemorrhage postreperfusion often occurs in recipients with coagulopathy, especially in those with poor liver function or lack of clotting factors. In addition, massive transfusion of stored blood leads to circulatory overload, abnormal coagulation and acid-base imbalance, resulted with aggravated hemorrhage symptoms. Surgical bleeding is related with operation of liver resection or graft harvesting. Furthermore, early hemorrhage may also occur as a result of blood vessel damage caused by anastomotic leakage or abdominal infection. Therefore, keeping normal coagulation function perioperatively, reducing bleeding and achieving effective hemostasis during operation, accurate anastomosis of blood vessels with vascular patency, as well as preventing and controlling infection, can contribute to prevention of this complication.
\nTherapeutically, correcting the clotting problem via giving blood products and coagulants is usually effective. However, patients with persistent hemodynamic instability, which indicates active hemorrhage, usually require emergency exploratory laparotomy for hemostasis.
\nVascular complications represent one of the most critical complications, and contribute to a major source of morbidity and mortality after liver transplantation. Vascular complications, including hepatic arterial complications, portal vein complications and vena cava complications, threaten outcomes for liver transplant recipients and graft survival. Among the vascular complications, hepatic arterial complications following liver transplantation are the most threatening conditions, including hepatic arterial thrombosis (HAT), hepatic artery stenosis, hepatic artery aneurysm, and hepatic artery rupture.
\nHAT is a life-threatening complication, as it interrupts blood supply of the allograft and induces early graft loss, long-term graft dysfunction, or recipient death. As the most common hepatic arterial complication, HAT occurs in 2–9% of adult transplants with a higher incidence in pediatric recipients [49, 50]. Risk factors for the development of HAT include technical imperfection with the anastomosis, dissection of the hepatic arterial wall, celiac stenosis or compression by median arcuate ligament, aberrant arterial anatomy, complex back-table arterial reconstruction of the allograft, as well as high-resistance microvascular arterial outflow mediated by rejection or severe ischemic-reperfusion injury. According to the time of onset, HAT is divided into early HAT and late HAT. Early HAT, diagnosed less than 4 weeks after liver transplantation, shows various clinical manifestations, ranging from fulminant hepatic failure, recurrent biliary sepsis, or delayed biliary leaks to an asymptomatic presentation with abnormal liver function. Compared with early HAT, clinical presentation of late HAT is relatively reduced, varied from increased serum transaminase level with or without cholestasis to liver abscess and biliary complications such as ischemic biliary lesions, cholangitis, bile duct stenosis, or necrosis. Early diagnosis with emergent surgical intervention is lifesaving and contributes to graft survival. Diagnosis of HAT depends on imaging examinations, while surgical exploration can confirm diagnosis. In clinical setting, arteriography is recognized as gold standard for diagnosis of HAT following liver transplantation. Patients with early HAT and fulminant hepatic failure require resuscitation, broad-spectrum antibiotics, artificial liver, and expeditious retransplantation.
\nHepatic artery stenosis is one of the most common complications postliver transplantation, with incidence rate ranging from 4 to 11% [51, 52]. This stenosis most commonly occurs in anastomosis site or the kinking of reconstructed artery. Factors associated with hepatic artery stenosis include surgical injury, vasospasm, anastomotic stenosis, high-resistance hepatic artery blood flow mediated by rejection, and cold preservation injury. Clinical presentation varies from abnormal liver function to severe biliary complications. If unrecognized and managed appropriately, hepatic artery stenosis will lead to complete occlusion of hepatic artery or thrombosis, resulting in ischemic infarction and graft failure. Angiography is the gold standard for diagnosis of hepatic artery stenosis. Therapeutically, interventional vascular procedures are current major treatment.
\nHepatic artery aneurysm and hepatic artery rapture are rare complications after liver transplantation, with an incidence of 0.3–1% [53, 54]. However, these complications can also threaten patients and grafts.
\nThe incidence of biliary complications has decreased dramatically because of advances in liver transplantation; however, biliary complication remains the most frequent complications postliver transplantation, with an incidence of 26.92–53.8% [55, 56]. Biliary complication is no longer a major cause of mortality in experienced liver transplantation center, as these complications can be recognized early and revive timely effective management. But biliary complication exhibits impact on patients’ life quality, and sometimes it enables development of graft dysfunction. Therefore, biliary complication remains a challenging complication.
\nBiliary complications include bile leakage, anastomosis stenosis, bile duct ischemic injury, gall-stone formation, and sphincter dysfunction. Bile leakage, either anastomosis leakage or bile leakage after removal of T-tubes, usually occurs early postliver transplantation. Anastomosis stenosis is frequent. Endoscopic therapy and interventional radiology treatment are proven to be effective in treatment of anastomosis stenosis. Bile duct ischemic injury is a major cause of bile leakage, bile duct stenosis, or dilatation, followed by biliary sludge and cholelithiasis. Gall-stone formation is mainly found in donor liver bile duct, but can also be observed in recipient’s bile duct. Sphincter dysfunction is a complication hard to diagnose. Among the biliary complications after liver transplantation, bile duct ischemic injury is the most dangerous disease with high mortality. Patients with serious bile duct ischemic injury finally will need retransplantation. Surgical imperfection and bile duct ischemia are the major causes of biliary complication. Accurate bile duct anastomosis without distortion of the bile duct, proper use of T-tube, avoiding excessive trimming of vessels, and protecting blood supply of bile duct will promote reconstruction of bile duct and reduce bile duct complications after liver transplantation. Immunosuppressants can also contribute to this complication, such as CsA promotes cholestasis and gall-stone formation.
\nClinical presentation of biliary complication varies. Patients with bile leakage usually have mild or moderate abdominal pain, with bile drained out from drainage tube or biliary spillage from umbilical incision. Symptoms of serious bile duct stenosis include jaundice in a short time. Early symptoms of patients with bile duct ischemic injury are atypical, sometimes similar to bile leakage, but late symptoms of bile duct ischemic injury like bile duct stenosis. Gallstones may occur secondary to bile duct stenosis, and patients with serious bile duct obstruction usually will have abdominal pain and jaundice.
\nWith advances in imaging and endoscopic therapy, biliary complications can be diagnosed early and interventional treatment has become the first choice for patients with biliary complications after liver transplantation.
\nWith advances in transplant technique, liver transplant recipients achieve a longer life longevity and prolonged graft survival. Meanwhile, late complications postliver transplantation gradually become critical factors of their life quality and graft long-term survival.
\nDe novo diabetes after liver transplantation is critical for outcomes of patients, correlated with a higher incidence of infection or cardiovascular diseases postliver transplantation. And it contributes to graft dysfunction and lower recipients’ survival. According to definition of diabetes mellitus from WHO and ADA, de novo diabetes occurs in 9–63.3% patients with liver transplantation [57, 58]. Immunosuppressants, such as corticosteroid use and calcineurin inhibition, are risk factors for de novo diabetes. Appropriate use of immunosuppressant, including dose and duration, is of significance for preventing de novo diabetes postliver transplantation.
\nHyperlipidemia is a common complication is solid organ transplantation, which can significantly promote incidence of chronic cardiac diseases in organ recipients. The incidence rate of hyperlipidemia in liver recipients is 45–66% [48, 58, 59]. Elevations of serum cholesterol and triglyceride are common consequences of use of immunosuppressants. Particularly, steroids and cyclosporine are closely associated with higher levels of cholesterols and triglyceride, while sirolimus exerts a stronger impact on triglyceride levels. Life style modifications with diet, exercise, and weight loss are preferred treatments. Besides, HMG-CoA reductase inhibition requires caution, as it may cause hepatotoxicity.
\nHyperuricemia is common in patients with liver transplantation, which usually occurs in 17–60 months postliver transplantation. The incidence rate of hyperuricemia in patients received liver transplantation is 14–47% [60, 61]. Mechanically, long-term use of calcineurin inhibitors leads to kidney injury and impairs the capability to clear uric acid, resulted with elevated uric acid levels or gout.
\nAlthough huge advances have been made in liver transplantation, including biliary reconstruction, organ preservation and perioperative management, the incidence of biliary complications after liver transplantation remains high, up to 53.8% [56]. Biliary complications include biliary stenosis, bile leakage, ampulla dysfunction, biliary silt, and gallstone formation. However, biliary stenosis and gallstone formation are major late complications. As biliary reconstruction is recognized as Achilles’ heel of liver transplantation, biliary reconstruction technique is strongly correlated with biliary complications. Besides, poor blood supply of hepatic artery and injury caused by donor liver harvest, cold preservation, or reperfusion. Furthermore, infection is also an important cause of biliary complication.
\nRecurrent liver diseases after liver transplantation is a common late complication, including hepatitis B, nonalcoholic fatty liver disease, autoimmune hepatitis, primary biliary cirrhosis as well as primary sclerosing cholangitis; however, the risk and timing of recurrent liver diseases are variable. Of note, recurrent hepatitis B virus (HBV) infection can be prevented in compliant patients with hepatitis B immunoglobulin and anti-HBV drugs. However, poor therapy compliance with irregular immunosuppressants application allows recurrence of HBV infection. In addition, recurrent autoimmune hepatitis or primary biliary cirrhosis rarely cause graft dysfunction or require retransplantation, though there are no proven effective therapies for the treatment of these late complications.
\nLiver transplantation is an important option to treat the end-stage liver diseases and aims to prolong the life survival and to improve the quality of life for the patients. In principle, any acute or chronic liver disease, which has no other effective treatment or would cause the death of the patient in a short time, should be the indication to liver transplantation. With the increasing advance of liver transplantation, it can also be performed to improve the quality of life, although the primary liver disease might not be cured. The detail indications include the following:
Acute liver failure: infections, drug- or toxin-induced liver injury, circulatory disturbance, etc.
Liver cirrhosis: hepatitis cirrhosis, alcoholic cirrhosis, cholestatic cirrhosis, etc.
Liver neoplasms: hepatocellular carcinoma, cholangiocarcinoma, etc.
Metabolic disorders: Wilson disease, alpha-1 antitrypsin deficiency, hereditary tyrosinemia, glycogen storage disease, etc.
Others: autoimmune hepatitis, polycystic liver, trauma, etc.
The contraindications, although decreasing with the development of liver transplantation, generally include the following:
Malignancy outside of the liver and cannot be radical cured
Uncontrolled sepsis
Excessive drinking or drug abuse
Severe cardiopulmonary, encephalic or renal complications
Acquired immunodeficiency syndrome (AIDS)
Persistent nonadherence with medical care
Uncontrolled psychological or mental diseases
According to the China Liver Transplant Registry (CLTR), the most common disease leading to liver transplantation from DCD was liver neoplasms (42.98%), following by liver cirrhosis (41.05%) and acute liver failure (9.07%) from 2010 to 2017. The model for end-stage liver disease (MELD) or MELDNa score is applied to evaluate the status of the patients and to determine the priority of recipients and the allocation of organs by the CLTR.
\nIt was estimated that more than 300,000 patients died of hepatocellular carcinoma (HCC) in China, which accounted for half of the total deaths all over the world [62]. The main reason was the high rate of hepatitis B virus (HBV) infection. In recent years, liver transplantation has become an effective treatment to HCC, in which the en bloc resection of the tumor can be achieved and the cirrhotic liver can be replaced. According to the CLTR, HCC was one of the most common causes leading to liver transplantation from DCD in China, with the 1- and 5-year survival rate of 82.77 and 59.18%, respectively (CLTR, 2010–2017). With the large number of practices, the Chinese experience was summarized.
\nThe Milan criteria (a single lesion ≤5 cm, or up to three lesions, all ≤5 cm; no macrovascular invasion; no regional nodal or extrahepatic distant metastases) are the benchmark for selection of appropriate candidates for liver transplantation due to HCC. However, few patients in clinical practice could fully meet these strict criteria so that they might lose the opportunity of transplantation. Even expanded to the University of California at San Francisco (UCSF) criteria or Pittsburgh criteria, the number of candidates meeting the criteria is still limited in China. During the past decades, many Chinese scholars tried to expand the boundary of the indication, and concluded the criteria suitable for the Chinese situation.
Hangzhou Criteria.
The Hangzhou Criteria were proposed by Prof. Shu-Sen Zheng, etc. in 2008 [63]. The criteria contained one of the two following items: (a) total tumor diameter ≤8 cm; (b) total tumor diameter > 8 cm, with histopathologic grade I or II and preoperative alpha fetoprotein (AFP) level ≤ 400 ng/mL, simultaneously. Obviously, Hangzhou Criteria significantly expanded the candidate pool, and the reported 5-year survival rate was comparable to that of patients fulfilling Milan criteria (72.3 versus 78.3%, P > 0.05). More importantly, these criteria not only considered the tumor size, but also included the histopathologic grading and serum AFP level, which better reflected the biological characteristics of the tumor and predicted the prognosis. In Chinese guidelines of liver transplantation to HCC 2014, Hangzhou criteria were recommended [62].
Shanghai Fudan Criteria.
Compared to Milan criteria, Shanghai Fudan Criteria expanded the indications on the tumor size: single lesion ≤9 cm in diameter, or no more than three lesions, the largest ≤5 cm, with a total tumor diameter ≤ 9 cm. There was no significant difference in 1, 2, 3-year survival rates and recurrence-free survival rates between Milan criteria and Shanghai Fudan Criteria [64].
The early diagnosis of HCC in China is limited so that a large number of patients are diagnosed with advanced HCC. Even if the expanded criteria were applied, many patients still lose the opportunity of transplantation. For patients without macrovascular invasion or extrahepatic distant metastases but beyond the current indications, downgrade treatments are proved effective to make part of the patients available to liver transplantation [65, 66]. The main downgrade treatments include transcatheter hepatic arterial chemoembolization (TACE), and local ablation therapy (radiofrequency ablation, microwave ablation, cryoablation and percutaneous ethanol injection) [62]. The combination of multiple therapies may achieve better efficacy.
\nIt was reported that over 90% of the HCC patients in China were related to the HBV infection. The high HBV load would increase the risk of tumor recurrence so that antivirus treatment is recommended pre-, intra- and posttransplantation. Before transplantation, the candidate should receive the nucleotide analogues (NAs) like entecavir and tenofovir as soon as possible to reduce the HBV load. During the nonhepatic phase in operation, the hepatitis B immunoglobulin (HBIG) is administered to block the viral transmission. After transplantation, the combination of NAs and low-dose of HBIG is recommended. HBV vaccines are given to some recipients posttransplantation, but the effects are still controversial.
\nThe triple immunosuppressive regimens (CNI + MMF + corticosteroids) still consist the footstone of immunosuppression for HCC liver transplantation. Although CNI is reported as an independent risk factor for tumor recurrence, complete drug withdraw is not recommended. The mammalian target of rapamycin (mTOR) inhibitor like sirolimus or everolimus, which has the potential for the inhibition of tumor growth, has been applied with the induction of IL-2 receptor antagonist (IL-2RA) in some centers in China. What is advocated currently is the individualized regimen based on the individual’s immune status. The main regimens used in clinic include the followings: (1) CNI + MMF + corticosteroids, (2) IL-2RA + sirolimus/everolimus + MMF + corticosteroids, and (3) IL-2RA + sirolimus/everolimus + MMF [62].
\nThe recurrence of HCC is the main hinder for the long-term survival of these patients. Reportedly, the recurrence rate reached 20.0–57.8%; thus, it is critical to prevent the recurrence posttransplantation [67, 68]. The effective treatments include 131I-labeled metuximab, sorafenib, and chemotherapy. The choice depends on the morphological features, neoplasm staging, gene typing, histological grade, and biological characteristics of the tumor.
\nIn China, viral hepatitis is mostly caused by HBV infection, and the prevalence of HCV is low. National Hepatitis Serum Epidemiology Survey [69, 70] showed that the HBsAg carrier rate in China’s general population aged 1–59 years was 7.18%, while the anti-HCV prevalence rate was about 0.43% [71]. Based on this, there are about 93 million people with chronic HBV infection [72], and for HCV infection, this data are 5.6–10 million [73]. Patients with end-stage chronic hepatitis B have become the main population of liver transplant recipients in China. According to the China Liver Transplant Registry (CLTR) 2015 statistics, patients with viral hepatitis-associated liver disease accounted for 74.79%, and hepatitis B virus (HBV)-related liver disease patients accounted for 71.25%. Therefore, the following mainly describes the problems faced by liver transplantation in the treatment of hepatitis B virus-associated liver disease.
\nSimilar to other indications for liver transplantation in chronic liver disease, liver transplantation should be considered when the following conditions occur:
Patients undergoing systemic medical treatment, but the expected survival time is shorter than 2 years
Recurrent esophageal varices bleeding after endoscopic treatment
Refractory ascites
Chronic hepatic encephalopathy
Occasional bacterial peritonitis
Liver cancer that occurs on the basis of hepatitis B
The choice of patients with viral liver disease as recipients of liver transplantation was once controversial. The main reason is the high recurrence rate of viral hepatitis after transplantation. Although the liver transplantation completely removes the diseased liver, the extrahepatic tissue and blood are inevitably left with a small amount of residual virus, which causes the reinfection of HBV in liver. It was reported that the recurrence rate of hepatitis B after liver transplantation for hepatitis B-related liver disease is up to 70–80% in China [74, 75].
\nThe recurrence of hepatitis B is affected by a variety of factors. The use of immunosuppressive agents, preoperative HBV at high replication levels, and without other viral coinfections will increase the rate of postoperative hepatitis B recurrence. In addition, HBV genotypes can also affect the recurrence of hepatitis B after transplantation [76]. Among them, the gene D has the highest recurrence rate.
\nThe study found that patients with HBV reactivation after liver transplantation have more serious hepatocyte damage and faster fibrosis progression [77]. In the short term, it can rapidly develop into fibrous cholestatic hepatitis, cirrhosis, or acute liver failure, resulting in the death of the recipient. Therefore, prevention and treatment of recurrent hepatitis is particularly important.
\nThe practice guideline on prophylaxis and treatment of hepatitis B for liver transplantation in China recommended that HBV DNA should not be detected as much as possible or the HBV DNA level should be minimized before transplantation [78]. Therefore, antiviral drugs such as high-resistance gene barrier NAs (ETV or TDF) should be routinely applied before transplantation. In the liver transplantation, the fully use of HBIG to neutralize HBsAg is a key measure to prevent HBV infected the new liver. After transplantation, the “NAs combined with low-dose HBIG” regimen should be used, which could significantly reduce the risk of hepatitis B recurrence.
\nHBsAg, HBV DNA, and anti-HBs titers should be frequently detected within 6 months after HBV-related liver transplantation to monitor HBV replication and reinfection, and to determine the dose and frequency of HBIG use. During follow-up, the recipient’s anti-HBV titer, which suddenly decreased or wore off, often indicates the recurrence of HBV, so that the therapeutic regimen should be adjusted.
\nHBV reinfection/emerging infection after liver transplantation progresses relatively rapidly, which can lead to liver failure and even death of patients. It is necessary to carry out targeted evaluation and treatment as soon as possible, aiming to rapidly inhibit HBV replication in the short term and to avoid serious liver injury. After the HBV reinfection/emerging infection, HBIG should be discontinued and treated with high-resistance gene barrier NAs, and HBV-resistant mutant genes and regulatory drugs should be tested. Intensive monitoring of HBV DNA levels and liver injury indicators should be performed. When the liver injury indicators are abnormal, the pathological examination of the liver tissue should be considered, and the degree of liver injury and disease progression comprehensively determines whether the liver transplantation should be evaluated again.
\nIn the selection of NAs drugs, in addition to the resistance mutation factors, some scholars believe that HBV genotype should also be a reference factor. According to the difference of HBV gene sequence, it can be divided into 10 genotypes of A-J [79]. In China, HBV infection is mainly B/C type [70]. Numerous studies have shown that the antiviral efficacy of NAs is affected by the HBV genotype. Among them, Chinese literature reports that the antiviral efficacy of NAs is significantly different between HBV gene type B and type C [80, 81, 82, 83]. It is summarized in the following table.
\nAt present, the mechanism by which different genotypes of HBV react differently to antiviral drugs is still unclear. Moreover, some scholars have found that the genotype does not affect the antiviral efficacy of the drug, and may be related to the different genotype detection methods used by different researchers and the sample size. In conclusion, there is no consensus on the effect of HBV genotype on the antiviral efficacy of NAs. The specific mechanism and its correlation require further clinical observation and basic experimental research to guide clinical antiviral drug treatment and efficacy judgment (Table 2).
\nNA species | \nThe difference of the curative effect | \n
---|---|
ETV/entecavir | \nB > C | \n
LAM/lamivudine | \nB > C | \n
ADV/adefovir dipivoxil | \nNo significant difference | \n
TDF/tenofovir disoproxil fumarate | \nNo significant difference | \n
LdT/telbivudine | \nB > C | \n
NAs make a different curative effect in different HBV genotypes.
Alcoholic liver disease is caused by long-term heavy drinking. In the early stage, it usually manifests as fatty liver, which in turn can develop into alcoholic hepatitis, liver fibrosis, and cirrhosis. In severe alcohol abuse, extensive hepatocyte necrosis can be induced and even cause liver failure.
\nAccording to the 2014 World Health Organization report, the per capita alcohol consumption of Chinese people over the age of 15 is about 6.7 L/year, and 4.8% of the population has alcohol use disorders, including 9.1 and 0.2% for men and women, respectively. Overall, the proportion of Chinese drinkers and the prevalence of alcohol-related liver diseases are on the rise. According to epidemiological survey data of alcohol related liver disease in some provinces, the prevalence of alcohol-related liver disease is 0.50–8.55% [84, 85, 86]. From 2000 to 2004, the proportion of alcohol-related liver disease in hospitalized patients with liver disease had increased from 2.4 to 4.3% [87]. The proportion of patients with alcoholic cirrhosis in all patients with cirrhosis increased from 10.8% in 1999 to 24.0% in 2003 [88, 89]. Alcohol-related liver disease has become one of the most important chronic liver disease in China [90].
\nIt is generally believed that liver transplantation should be considered when patients with alcoholic liver disease meet the following conditions:
Fail to respond to medications.
Liver lesions are severe or end-stage liver disease manifests.
Suspected small liver cancer is present (single nodule <5 cm, 1–3 nodules <3 cm).
No serious alcohol damage in other organs.
After comprehensive factor evaluation, it is determined that there is a lower postoperative recovery of alcohol abuse.
Studies have shown that the 3-year survival rate of alcoholic patients after liver transplantation is significantly lower than that of nonalcoholic groups [91]. Therefore, in patients with alcoholic liver disease, whether or not successful alcohol withdrawal after liver transplantation becomes the key. Predictors of longer postoperative alcohol withdrawal include: (1) the patient recognizes the severity of alcoholism. (2) The patient has a stable residence. (3) The patient has a stable occupation. (4) The patient has at least one closely related patient to provide spiritual support.
\nThe following factors represent a higher risk of restocking. (1) The patient has had psychological or mental disorders. (2) The patient has unstable personality characteristics. (3) The patient has repeatedly failed to stop drinking. (4) The patient has the habit of drug abuse. (5) The patient’s social relationship is isolated. In practice, effective preventive education measures can significantly reduce the patient’s redrinking after surgery. At present, the Chinese guidelines are feasible for liver transplantation in patients with alcoholic liver disease who require alcohol withdrawal for 3–6 months before liver transplantation and no serious alcohol damage in liver.
\nLiver is an important metabolic organ of the human body. Therefore, congenital metabolic diseases caused by defects in certain key metabolic steps are often associated with the liver damage. Some genetic metabolic diseases are manifested in liver disease in infants or children. As the disease progresses, nerves, kidneys, heart, bones, vision, hearing, and skin mucosa are damaged. Liver diseases can also aggravated, leading to cirrhosis and liver failure. These diseases are collectively referred to as hereditary metabolic liver disease.
\nThere are many kinds of genetic metabolic diseases, and the etiology is complicated, 50–60% in childhood. At present, there are more than 600 kinds of hereditary metabolic liver diseases, including carbohydrate metabolism disease, amino acid metabolism disease, fatty acid metabolism disease, organic acid metabolism disease, mitochondrial liver disease, lysosomal disease, peroxisome disease, and metal. There are nine categories of metabolic disorders and 1-antitrypsin deficiency.
\nLiver disease progresses to advanced cirrhosis or liver failure and requires liver transplantation. According to CLTR, 0.69% of the liver transplantation from DCD is caused by hereditary metabolic liver diseases. In living donor liver transplantation, the rate is 4.13%.
\nThe clinical manifestations of genetic metabolic diseases are diverse, and the symptoms are often not limited to the liver. Since some hereditary metabolic liver diseases often involve multiple organ systems, liver transplantation cannot solve the lesions outside the liver, leading to a poor prognosis. There are certain limitations in liver transplantation in this respect. For example, the effect of simple liver transplantation on patients with progressive familial intrahepatic cholestasis type 1 is not ideal. For these diseases, it is often necessary to cooperate with other treatments. For example, for hyperglycinemia, liver transplantation can only improve the clinical symptoms, and patients can continue to excrete succinylacetone in the urine after surgery. Therefore, some cases need to be combined with liver and kidney transplantation to correct metabolic abnormalities.
\nWith the rapid development of liver transplantation technology, immunosuppressive drugs and drug regimens have emerged in endlessly, playing an increasingly important role. Looking back, medical pioneers had to use crude technical means such as whole-body x irradiation. Until the advent of cyclosporine, liver transplantation has gradually become the main stream of treatment for liver failure. Today, drugs like azathioprine have almost withdrawn from the stage of history. More and more novel immunosuppressants and different strategies are coming into view. Understanding each agent’s potency and deficiencies is an essential part of clinical practice. No immunosuppressant is universally applicable yet. Patients with renal impairment, malignancy, or autoimmune diseases may need specific agent or regimen. Therefore, individualized treatment is essential. Here, some commonly used immunosuppressants will be briefly introduced and discussed. Emphasis will be placed on the clinical application, rather than the mechanism of agents (Table 3 and Figure 5).
\nImmunosuppressants | \nAction | \nMerits | \nDemerits | \n|
---|---|---|---|---|
T cell activation inhibitors | \nCyclosporine | \nInhibits calcineurin via cyclophilin, blocking IL2 transcription | \n\n
| \n\n
| \n
Tacrolimus | \nInhibits calcineurin via FKBP12, blocking IL2 transcription | \n|||
T cell proliferation inhibitors | \nMPA prodrugs | \nIMPDH inhibitor: enzyme required for de novo synthesis of guanosine nucleotides, required for lymphocyte proliferation | \n\n
| \n\n
| \n
mTOR inhibitors | \nmTOR blockade prevents IL2-induced T cell proliferation | \n\n
| \n\n
| \n|
Azathioprine | \nInhibits purine synthesis, thereby blocking immune cell proliferation | \n\n
| \n\n
| \n
Comparison of common immunosuppressive agents.
Note: AZA: azathioprine.
The mechanism of common immunosuppressive agents.
Cyclosporine and tacrolimus are two well-known calcineurin inhibitors (CNIs). Both of them are discovered from the soil fungus and are mechanistically similar. They can suppress the immune system by inhibiting interleukin 2 (IL2) gene transcription. Cyclosporine’s effect is mediated by cyclosporine’s association with cyclophilin, while the tacrolimus’s effect is mediated by a specific interaction with FK-binding protein-12 (FKBP12), both of which can result in inhibition of the calcium/calmodulin-dependent phosphatase complex calcineurin, hence the designation “calcineurin inhibitor” (or CNI). An important distinction is that the immunosuppressive potency of tacrolimus is estimated to be 100-fold greater on a molar level. Due to their powerful capacity in reducing acute rejection, the CNIs have been playing an important role in immunosuppression regimens postliver transplantation. As it should be noted that most recent trials use tacrolimus monotherapy or tacrolimus-based therapy as the control group, suggesting that tacrolimus is considered the standard against, which other immunosuppressants are compared.
\nDespite the potency of CNIs, some serious problems remain. The CNIs may have close relationship with renal toxicity, HCV reinfection, hepatocellular carcinoma recurrence, and some other negative effects [92, 93, 94]. So how to use CNIs properly in liver transplantation is a conundrum. At present, to perform therapeutic drug monitoring to reduce the chance of overdosing is necessary, but not enough. The only reasonable step when facing those complicated cases is to minimize or eliminate CNI use.
\nAs for antimetabolites, what is popular now is mycophenolate mofetil (MMF; Hoffmann La Roche, Basel, Switzerland), which is a prodrug of mycophenolic acid (MPA). It takes effect through inhibiting inosine-59-monophosphate dehydrogenase (IMPDH), an important enzyme for de novo synthesis of guanosine nucleotides. Thanks to Sollinger, MMF was brought to the clinic in the early 1990s and used as an immunosuppressant from then on.
\nAnother prodrug of MPA being used clinically is referred to as enteric-coated mycophenolate sodium (ECMPS; Novartis, Basel, Switzerland). Different from MMF, EC-MPS is not rapidly absorbed in the stomach; it is a delayed-release drug formulation that allows release of MPA in the small intestine via a pH-dependent dissolution. The research and development of EC-MPS was trying to solve the well-known gastrointestinal side effects of MMF. However, things are not as smooth as imagined. Studies have not demonstrated fewer side effects with EC-MPS [95].
\nDue to the renal toxicity of CNI, MMF and EC-MPS are playing an increasing potential role in liver transplantation as they basically have no nephrotoxicity. Several studies have now shown that MMF and EC-MPS are superior to CNIs in terms of renal function, at the cost of a higher rejection rate [96]. For now, compromise is inevitable in such situation. Regimens like “MMF/EC-MPS +low dose CNIs” are acceptable [97].
\nAs mentioned above, MMF and EC-MPS are not without side effects. Both gastrointestinal disorders and hematological suppression are concerns that cannot be ignored.
\nBy the way, azathioprine (AZA) is another antimetabolite that has left an important part in the history of liver transplantation. Though its role for preventing rejection has been almost completely replaced by MMF/EC-MPS, some researches demonstrated that AZA may have some kind of anti-HCV effects [98, 99].
\nMammalian target of rapamycin (mTOR) inhibitors include sirolimus (rapamycin; Wyeth) and everolimus (a rapamycin derivative; Novartis). Rapamycin was first discovered in soil from Easter Island (Rapa Nui). Researchers were trying to find its fungi inhibiting ability while accidentally found its immunosuppressive effect. Rapamycin can bind to FKBP12 and form FKBP12 immunosuppressive complex, which can bind to and inhibit the activity of mTOR, thus inhibiting the development of G1 to S phase in cell cycle. Unlike the CNI effects, rapamycin allows T cell activation, but prevents cells from proliferating in response to IL2.
\nmTOR inhibitors have been approved for use in renal and heart transplantation in combination with CNIs, but not in liver transplantation so far. The use of mTOR inhibitors may cause several adverse reactions:
It may be related to the development of early posttransplant hepatic artery thrombosis, though not confirmed [100, 101].
It may elevate blood lipids (cholesterol).
It may cause wound-healing delays, leg edema and mouth ulcers.
However, this is not to say that mTOR inhibitors have no advantage in liver transplantation.
It may reduce early renal dysfunction compared to CNIs.
It may promote liver allograft tolerance compared to CNIs [102, 103].
It may have antifibrosis effect [106].
All in all, although mTOR inhibitors are not approved for use in liver transplantation yet, they have good reasons for further investigation.
\nNo doubt, steroids have made great contributions through the development of liver transplantation. For many years, they have been fighting against rejection. While as always the case, their utilization today is controversial. On one hand, corticosteroids have a wide range of immunosuppressive properties:
Inhibit arachidonic acid metabolism
Affect antigen presentation by dendritic cells
Inhibit IL1-dependent lymphocyte activation by decreasing IL1 transcription
Their broad spectrum of effects provides excellent anti-inflammatory activity that often reverses ongoing allograft rejection.
\nOf course, their side effects are also well known such as diabetes, hypertension, osteoporosis, obesity, etc. Besides, researches also suggested that high-dose steroids may exacerbate HCV infection and fibrosis, especially when used as pulse therapy for antirejection treatment [107]. Thus, how to use steroids in a proper way is still a pending problem. A variety of steroid-free/minimization immunosuppressive protocols in liver transplantation are under evaluation [108].
\nDue to space limitations, we did not talk about biologic agents like ATG and basiliximab, and will not discuss those promising agents such as belatacept, alemtuzumab and efalizumab, or cellular-based therapy, which may be widely used in liver transplantation in the future. For details, readers can refer to [109].
\nTacrolimus-based therapy: “Tac + MMF + steroids” or “Tac + steroids.”
\nDay 0 (the day of the operation): methylprednisolone 500 mg, intravenous, intraoperative; no Tac.
\nPostoperation: Tac 0.05 mg/(kg*d), twice, later adjust the dose according to blood concentration; methylprednisolone, gradually decrease the dosage, and on day 7 changed to prednisone 20 mg, oral administration; MMF 1.5–2 mg/d, twice.
\nAbout 24–48 hours after Tac administration, blood concentration should be tested, and together with other clinical results adjust the Tac dosage.
\nSteroids withdrawal strategy: day 0, methylprednisolone 500 mg, intravenous, intraoperative; day 1, 240 mg; then decrease 40 mg every day; day 7, change to prednisone 20 mg, oral administration. 1 month postoperation, start to decrease prednisone dosage, decrease 2.5 mg every 2 weeks. For hepatic cancer and hepatitis C recipients, the process of reducing the dosage should be fast. While for the primary biliary cirrhosis and combined liver kidney transplantation recipients, the process should be slower. In addition, gastric protective drugs should be used when steroids are used.
\nFor better-individualized medication, we have to understand the merits and demerits of each immunosuppressant available for liver transplantation, along with each patient’s condition. On this individualized basis, our ultimate goal is to minimize or even eliminate long-term pharmacological immunosuppression in liver transplantation recipients. Though difficult, it is worth the effort.
\nNowadays, with the improvement of the surgical techniques of liver transplantation and the update of immunosuppressive agents, liver transplantation in china is getting more and more mature, which has already been in line with the international standards, approximately 95% of patients can safely get through the perioperative period and discharge from hospital [110, 111]. With the increasing of cases of liver transplantation and the prolongation of life span, the patients’ long-term treatment and follow-up work have been paid more and more attention by experts and related scholars.
\nThe follow-up of liver transplantation is a long and complex work, which is mainly characterized by large data volume, individual differences, and long follow-up period (generally, lifelong follow-up). An efficient and reasonable follow-up system can not only improve the efficiency of the transplant center, but can also increase the rate of survival of patients. With the gradual standardization of liver transplantation, an ideal postoperative follow-up system has become an important indicator of a mature liver transplantation center.
\nThrough regular follow-up, the clinicians can dynamically observe the rehabilitation, mental state and medication situation of liver transplant recipients, and give necessary guidance and health education. In the follow-up, the clinicians can detect and deal with the complications after liver transplantation in time, improve the quality of life, prolong the survival period after the operation. Because the incidence of tumor after transplantation is higher than that of the general population, especially liver transplantation of HCC patients may lead to tumor recurrence and metastasis, follow-up regularly can promptly detect the tumor and give appropriate treatment. Moreover, follow-up is the need of medical model transformation, which makes up for the shortage of medical resources, is a tracking service and also an active service. In today’s China acute contradiction between doctors and patients, follow-up is a very good way of communication, which can make the relationship between doctors and patients more harmonious and understand each other more. Meanwhile, collection of information of the regular follow-up can accumulate valuable experience for clinical and scientific research [112].
\nLiver transplantation centers in China are in different stages of development, and each center should choose a suitable follow-up method according to its outpatient follow-up volume and staffing. With the increase of liver transplantation cases, our center has established the database for recipients’ management and follow-up since 2002, which is constantly updated and improved. In the early stage of liver transplantation, many centers in China lack a sound follow-up system, which is passive and sporadic. In 2008, China Liver Transplantation Registry (CLTR) came into use, the first liver transplantation scientific registration system in China, which is an intelligent data collection and management system in line with the characteristics of organ transplantation in China [48]. It sets up a good platform for clinical evidence-based medicine and the scientific research and provides patients with high-quality medical service at the same time. In our center, we set specialized transplant clinic and establish a complete follow-up procedure (Figure 6). The patients should follow the standard follow-up program in the absence of complications, including outpatient frequency and inspection items of follow-up (see Table 4) [113, 114]. Because exceeding or insufficient immunosuppressive agent has a negative effect on graft function, its concentration must be monitored regularly (see Table 5). In addition, there is a big problem in China now that all the candidates and recipients are lack of health education related with organ transplantation, which lead to many problems of long survival and better quality of life. Our center is aware of it and gives the patients regular health education during follow-up through PPT, video and handbook, etc. [115, 116].
\nFollow-up procedure after liver transplantation.
Inspection items | \n1–3 m post-LT | \n3–6 m post-LT | \n6–12 m post-LT | \n>12 m post-LT | \n
---|---|---|---|---|
Blood routine | \nOnce a week | \nOnce 2 weeks | \nOnce a month | \nOnce half year | \n
Liver function | \nOnce a week | \nOnce 2 weeks | \nOnce a month | \nOnce half year | \n
Renal function | \nOnce a week | \nOnce 2 weeks | \nOnce a month | \nOnce half year | \n
Blood glucose and lipids levels | \nOnce a week | \nOnce 2 weeks | \nOnce a month | \nOnce half year | \n
Blood coagulation function | \nOnce a week | \nOnce 2 weeks | \nOnce a month | \nOnce half year | \n
Immunosuppressive agent concentration | \nOnce a week | \nOnce 2 weeks | \nOnce a month | \nOnce half year | \n
HBsAg (for chronic hepatitis B patients) | \nOnce a month | \nOnce half year | \n||
HBV-DNA (for chronic hepatitis B patients) | \nOnce a month | \nOnce half year | \n||
HCV-DNA | \nOnce a month | \nOnce half year | \n||
AFP (for hepatocellular carcinoma patients) | \nOnce a month | \nOnce half year | \n||
Color ultrasound of transplanted liver | \nOnce a month | \nOnce half year | \n||
Chest film or lung CT | \nOnce a month | \nOnce half year | \n||
CT and MRCP | \nOnce 3 months | \nOnce half year | \n
Frequency and inspection items of follow-up.
Abbreviation: m, month; post-LT, post liver transplantation.
\n | 1 D–1 Mpost-LT | \n1–3 Mpost-LT | \n3–12 Mpost-LT | \n>12 Mpost-LT | \n
---|---|---|---|---|
Fk506 C0 (ng/mL) | \n8–10 | \n6–8 | \n6–8 | \n5–7 | \n
CSA C0 (ng/mL) | \n200–350 | \n150–300 | \n100–250 | \n>50 | \n
CSA C2 (ng/mL) | \n1000–1500 | \n800–1200 | \n600–1000 | \n>400 | \n
SIR C0 (ng/mL) | \n5–8 | \n4–8 | \n4–8 | \n3–6 | \n
Immunosuppressive agents concentration based on postoperative time.
Abbreviation: C0, the minimal concentration; C2, peak plasma concentration.
As is well known, the success of liver transplant surgery only means the beginning of a new life for patients. The long-term survival of liver transplant recipients depends not only on the surgical skills of surgeons, but also on the high quality and efficient follow-up after liver transplantation. With the increase in the number of liver transplantation and the application of CLTR, the experts and scholars in China will have more experience to help the patients benefit from liver transplantation.
\nAfter decades of efforts, the liver transplantation in Mainland China has made many achievements. The number of cases has ranked second in the world, and the quality and survival rate are no different from those of advanced countries; since 2010, China’s organ donation work has been gradually carried out, and the source of liver transplant donors has transitioned from relying on judicial channels to DCDs and relative living donors. Before 2015, DCD work has not been widely carried out in the country. For some time, due to the shortage of donors, the proportion of living relatives has increased significantly (Figures 7 and 8), but with the development of DCD work, DCD has become the main source of liver, which better alleviated the problem of organ shortage, meanwhile many shortcoming and problems have been exposed in the DCD era.
The main primary disease of liver transplantation in current China is still HBV-related disease. China is a large HBV country, and patients requiring liver transplantation are increasing year by year. Although DCD donors alleviate the shortage of donors to a certain extent, it is necessary for Chinese health management departments to pay more attention to the prevention and treatment of HBV and related research work. For transplant experts, more work and research is needed on HBV treatment and prevention of recurrence before and after transplantation.
The proportion of liver cancer liver transplants in China is high (Figures 9 and 10). How to develop a liver transplantation standard suitable for liver cancer in China, how to reduce the recurrence of liver cancer after transplantation, prolong the survival time, and how to effectively combine with immunosuppressant are also problems faced by Chinese physicians.
Legal regulations are not yet complete. China has not established a brain death law, and the relevant transplant laws and regulations are also quite lacking. The corresponding management system is still not perfect. The Chinese government and transplant experts are also constantly exploring and working hard on these issues.
DCD-related work needs to be strengthened. China’s contribution rate per million populations is very low, only about three cases per million people. In order to better carry out DCD work, it is necessary to increase the positive publicity of organ donation, further improve the donation, acquisition and distribution system, and establish effective services for transplant-related institutions. These are issues that China still needs to solve.
Proportion of living donor liver transplantation (data from CLTR).
The categories of living donors (data from CLTR).
2010–2017 Primary disease statistics of DCD liver transplant recipients (data from CLTR).
2010–2017 Primary disease statistics of living donor liver transplant recipients (data from CLTR).
China’s liver transplantation is facing enormous challenges and opportunities. It not only faces legal issues, sociology, ethics, and many other issues in donor donation, but also requires surgeons to refine and continuously improve surgical methods. More related researches needed to be done by transplant scholars. The entry criteria for liver transplant recipients and the induction of human immune tolerance in accordance with China’s national conditions also depend on further research by domestic transplant workers, and the solution to these problems will be tortuous and difficult. We believe that through the long-term joint efforts of the Chinese transplanting colleagues, China’s liver transplantation will have a brighter future.
\nWe thank Prof. Zheng Shu-sen from liver transplantation center of the first hospital of Zhejiang University and workers from China Liver Transplantation Register (CLTR) for their technique support and data providing. This work was supported by grants from the National Natural Science Foundation of China (no. 81771722) to YZM and (no. 81700658) to QZ, and the Natural Science Foundation of Hunan Province (no. 2016JJ4105) to QZ.
\nNo conflict of interest.
Cardiac problems are one of the most important problems across the globe. According to autopsy studies, heart disease has increased since the 1960s due to a rise in the frequency of coronary atherosclerosis with resultant coronary heart disease. The number of CVD deaths in India each year is anticipated to increase from 2.26 to 4.77 million between the years 1990 and 2020. The coronary heart disease frequency rates in India have fluctuated from 1.6 to 7.4% in rural populations whereas from 1 to 13.2% in urban populations during the last several decades [1]. Heart disease claims the lives of about 17 lakh individuals in India each year, and the number is estimated to rise to 2.3 crores by 2030. This rise is linked to an increase in smoking and dietary changes, resulting in higher blood cholesterol levels. The symptoms like angina, chest pain, difficulty breathing, edema, fatigue, and lightheadedness may indicate a heart problem or heart attack. Heart attack can lead to cardiac arrest, which occurs when the heart’s rhythm is disrupted, or the heart stops beating, and the body can no longer function [2].
Any disorder that affects the cardiovascular system is alluded to as heart disease [3]. Heart disease comes in various forms, each of which affects the heart and blood arteries in distinct ways. The most typical kinds of heart disease are coronary artery disease, arrhythmia, heart valve disease, and heart failure [4]. Coronary artery disease is the most noticeable type of heart disease. It happens when plaque accumulates in the arteries that deliver blood to the heart. It can cause a reduction in blood flow to your heart muscle, preventing it from receiving the oxygen it requires. Atherosclerosis, often known as artery hardening, is the most common cause of the illness. Arrhythmia refers to an improper beating of the heart [5]. It happens when the electrical impulses that regulate the heartbeat do not even function properly. As a result, the heart may beat excessively fast, too slowly, or in an irregular pattern. Heart valve disease occurs when a heart valve is damaged [6]. Infectious diseases such as rheumatic fever, congenital heart disease, excessive blood pressure, coronary artery disease are all causes of heart valve disorders. Heart failure does not imply that the heart has ceased to beat. A condition in which the heart is not pumping blood as efficiently as it should be to satisfy the body’s demands. There are some more heart diseases like pericardial disease, myocardial infarction [7], cardiomyopathy, mitral valve regurgitation, congenital heart disease, etc.
Over the last several decades, the rapid advancement of cardiology has profoundly changed the natural course of cardiac patients. Cardiac care has evolved, with technology playing an increasingly significant role. With the appropriate technology and artificial intelligence (AI) and machine learning, cardiac care providers have been motivated to improve treatment methods [8]. Then there’s remote care that enables electrocardiogram (ECG) diagnosis [9], which uses cloud technology and Bluetooth-enabled cardiac devices to test the parameters and send them back to healthcare practitioners without attending the clinic. Some emerging technologies used every day in cardiology are transcatheter mitral and tricuspid valve interventions, artificial intelligence, wearable devices, big data, structured reporting, robots in the cath lab, virtual and augmented reality, FFR technologies, holographic procedural navigation in the Cath Lab, etc. [10].
There are many cardiac implantable electronic devices like pacemakers, implanted cardioverter defibrillators (ICDs), biventricular pacemakers, and cardiac loop recorders, which are used to control or monitor irregular heartbeats in persons with specific heart rhythm problems and heart failure. An implanted cardioverter-defibrillator is a device that can do cardioversion, defibrillation, and cardiac pacing. ICD is capable of rectifying the majority of life-threatening cardiac arrhythmias. A pacemaker is a device that is implanted beneath the skin and communicates with the heart through electrical leads. Pacemakers are used to treat bradycardia, a condition where the heart beats too slowly (less than 60 times per minute). The pacemaker sends electrical pulses to the heart to maintain it beating normally. A biventricular pacemaker is a compact, battery-operated device and light. This gadget aids with the proper pumping of your heart. It also protects from harmful cardiac arrhythmias. An implantable loop recorder is a heart-monitoring device implanted beneath the chest skin. It has a variety of applications. Searching for reasons of fainting, palpitations, very rapid or slow heartbeats, and hidden rhythms that might cause strokes are among the most prevalent. Computer-aided diagnosis (CAD) [11] refers to software that helps clinicians understand medical images. The radiologist or other medical expert must assess and evaluate a large amount of data in a short amount of time using imaging modalities such as X-ray, MRI, and ultrasound diagnostics. The Kurt Rossmann Laboratories for Radiologic Image Research in the Department of Radiology at the University of Chicago began large-scale systematic research and development of several CAD methods in the early 1980s. The idea of computer-aided design was established in 1966 and has been completely implemented since 1980.
Nowadays, computer-aided diagnosis has become a contentious research topic in medical imaging and diagnostic radiology research. CAD technology aids in the improvement of the performance of radiologists in increasing productivity by cost-effectively enhancing sensitivity rate. CAD can improve image diagnostic accuracy by detecting illnesses that are too premature to be detected by naked eyes. It enables early detection, which can lead to better treatment results. Computer-aided detection is a relatively new advancement in the area of breast imaging that aims to increase the throughput of radiologists to identify diseases like breast cancer [12] even at an early stage. In recent times, computer-aided diagnosis is used to diagnose acute lymphoblastic leukemia, which suggested a solution to the flaws in manual diagnosis techniques. Even ECG-based computer-aided diagnosis [13] is also used for cardiovascular diseases which have the potential to improve diagnosis accuracy while also lowering costs.
Medical images nowadays play a crucial role in the identification and diagnosis of awide range of disorders. To aid in the interpretation of medical images, a variety of computer-aided detection and diagnosis technologies have recently been developed in order to achieve a more reliable and accurate diagnosis. CT, MR imaging, digital radiography, biomagnetism, and optical range sensing are examples of imaging systems that take advantage of sophisticated computer technology.
The real-life problem with manual experimentation is that manual diagnostic procedures are time-consuming, less accurate, and prone to mistakes due to different human variables such as stress, exhaustion, fatigue, and so forth. As a result, many automated techniques have been developed to combat the flaws in manual diagnostic approaches. When compared to manual diagnosis procedures, these computer-aided technologies are faster, more dependable, more efficient, more standardization and more accurate. Computer-aided diagnosis (CAD) aids in the calculation of computational and statistical features that people cannot gather visually or intuitively. Computer-assisted diagnosis also reduces the reliance on the operator in ultrasonic imaging and makes the diagnosis procedure reproducible. Interference testing and 3D animations are simple to accomplish in computer-aided diagnosis [14].
Machine learning has been applied in a variety of fields all over the world and the health industry is no exception. On the other hand, deep learning is part of the family of machine learning algorithms relying on representation and artificial neural networks are being utilized for the analysis of medical data. For quite some time, these algorithms were used to assess patients’ status with respect to the image or non-image-based medical data acquired using new generation medical equipment. These developments are attributable to the emergence of new CAD systems known as knowledge-based systems, including expertise or knowledge. As a result, the modern CAD systems include some intelligence [15]. The major job of the software related to these systems nowadays is to automate the analytical phases. To ensure that components and assemblies achieve design standards, CAD software is used to make computer modeling, fit them together, and simulate their performance. Because design reviews, conducted by specialists, evaluate if changes should be made, the analytical phases of the design process are repeated (design synthesis). Design synthesis may be done immediately with AI-based technologies without the need for a separate design review, and they are correctly implemented.
Based on the recent advancements, computer-aided diagnosis is used to diagnose heart abnormalities such as arrhythmias and heart blockages using electrocardiogram (ECG) signal analysis [16]. Although electrocardiography (ECG) is affordable and commonly available, ECG abnormalities are not specific for the diagnosis of congestive heart failure (CHF) which is the inability of the heart to efficiently circulate blood throughout the body without a rise in intracardiac pressure. Based on the ECG, a well-designed computer-aided detection (CAD) system for CHF might possibly eliminate subjectivity and give a quantitative evaluation for better decision-making.
Cardiologists and medical practitioners frequently utilize ECG to assess heart health. The difficulty in identifying and classifying distinct waveforms and morphologies in ECG signals is the major issue with manual analysis. This task is both time-consuming and error-prone for a human. Cardiovascular illnesses are the leading cause of mortality worldwide, accounting for around one-third of all fatalities. Millions of individuals, for example, suffer from irregular heartbeats, which can be fatal in some circumstances. As a result, precise and low-cost arrhythmic heartbeat diagnosis is extremely desirable.
Many research in the literature investigated the utilization of machine learning approaches to reliably detect abnormalities in ECG data to solve the drawbacks present in human analysis. Pre-processing, like passing through bandpass or high pass filter, is used in most of these methods to prepare the signal to be compatible for machine-based analysis. The handcrafted features, which are typically statistical summarizations of signal windows, are then retrieved from these signals and employed in subsequent processing. For the last categorization task, conduct an analysis.
In terms of the conclusion, for ECG, traditional machine learning algorithms [2] like support vector machines, multi-layer perceptrons, decision trees, and other methods of analysis were used previously. Automated feature extraction and representation approaches have been shown to be more scalable and capable of producing more accurate predictions, according to current machine learning research. In this study, we are going to elaborate on a few of the new emerging and compatible technologies and their applications.
The rest of the article has been organized in the following manner. First, Section 2 provides a brief theoretical and mathematical background related to this domain of study which is followed by the problem statement in Section 3. Next, Section 4 discusses about the significance of noise removal with stages of data processing. Section 5 gives a brief survey about the recent state-of-the-art techniques related to automated signal processing of ECG signals that is followed by the promising experimental results reported in the recent literature. Finally, Section 7 concludes this chapter.
In signal processing [17], several mathematical methods like sampling frequency, Nyquist filtering, Fourier analysis series and transform,
The reduction of a continuous-time signal to a discrete-time signal is known as sampling and the sampling frequency represents the number of samples per second collected from a continuous signal to create a discrete or digital signal. There are few applications of the sampling process. The sampling process is utilized in music recordings to ensure sound quality. The sampling technique is also used to convert analog to discrete data. It is also used in speech recognition systems, radar and radio navigation, sensor data evaluation, modulation and demodulation, and pattern recognition systems.
The sampling frequency [18] or sampling rate
If a continuous-time signal has no frequency components greater than a sampling rate of
A Nyquist filter is an electrical filter that equalizes the visual characteristics of TV receivers. In receivers, a Nyquist filter is utilized to equalize the low and high-frequency components of the VF signal. It plays an essential role in the creation of n bandlimited pulses in wired and wireless communication systems to ensure minimal inter symbol interference. Its principal application is as a pulse-shaping filter. Nyquist filters are a form of multi-rate finite impulse response filter that is also known as
The following equation indicates the impulse response of a Nyquist filter
where,
The following equation satisfies the
where,
The frequency responses of all
The Fourier series is a periodic function made up of harmonically compatible sinusoids that are integrated together using a weighted summation. The Fourier series is an infinite series that can be used to solve several forms of differential equations. It’s mainly composed of an infinite sum of sines and cosines, and it’s valuable for evaluating periodic functions since it’s periodic. The Fourier series is widely utilized in telecommunications systems for voice signal modulation and demodulation.
The Fourier transform is a technique for transforming time-domain signals to frequency-domain signals. The Fourier transform is a useful image processing method for decomposing an image into sine and cosine components. The image in the Fourier or frequency domain is represented by the output of the transformation, whereas the spatial domain equivalent is represented by the input image. It’s utilized in electrical circuit design, solving differential equations, signal processing, signal analysis, image processing, and filtering, among other things.
The Fourier transform is a mathematical approach for converting a time function,
The Fourier transform of a sequence is represented as:
where
It can also be written as:
As
The analysis equation of forward Fourier transform is:
On the other hand, the synthesis equation of inverse Fourier transform is:
The bilateral
The unilateral
Fourier transform and
A system’s Fourier transform and
The pole-zero plot is a valuable tool for relating a system’s Frequency domain and
Pole-zero plot can be expressed as the following equation:
where the numerator and denominator are both polynomials in
The electrocardiogram (ECG) signal is a representation of the electrical impulses of the heart that can be seen from the strategic points of the human body. It can be visually depicted by a quasi-periodic voltage signal. ECG refers to a 12-lead ECG recorded while laying down and electrodes or sticky patches are put on the body surface and often over the chest and limbs to record a standard surface ECG. These electrode wires are linked to a 12-lead ECG machine which records data from 12 distinct locations on the body’s surface. The aggregate amplitude of the heart’s electrical potential is then monitored and recorded over a period of time from those distinct angles (“leads”).
The graphical representation of the heart’s electrical activity is formed by analyzing numerous electrodes in Figure 1(a). There are three types of leads: limb augmented limb, and precordial or chest. Three limb leads and three augmented limb leads are organized in the coronal plane like the spokes of a wheel, and six precordial leads or chest leads are organized in the perpendicular transverse plane. In three-dimensional space, each of the 12 ECG leads represents a distinct direction of cardiac activation. The conventional ECG leads are denoted as lead I, II, III, aVF, aVR, aVL, V1, V2, V3, V4, V5, and V6. The limb leads are I, II, III, aVR, aVL, and aVF whereas the precordial leads are V1, V2, V3, V4, V5, and V6.
12 leads ECG. a) Signals from 12 Leads ECG [
The 12-lead ECG is typically made up of 10 electrodes linked to the body, each monitoring a distinct electrical potential difference. The 10 electrodes in a 12-lead ECG are RA, RL, LA, LL, V1, V2, V3, V4, V5, and V6. Each of the 10 electrodes has a different placement as shown in Figure 1(b). RA is used to place on the right arm and similarly, LA is used to place on the left arm. RL is located in the lower end of the inner portion of the calf muscle on the right leg, similarly, LL is placed in the same standard position but on the left leg. V1 is placed in the fourth intercostal space (between ribs 4 and 5) immediate right of the sternum. V2 is placed in the fourth intercostal space (between ribs 4 and 5) immediate left of the sternum. V3 is placed between leads V2 and V4 where V4 is placed in the fifth intercostal space (between ribs 5 and 6) in the midclavicular line. On the other hand, V5 and V6 are placed in the left anterior axillary line and midaxillary line, respectively. The electrodes which are located on the limbs are called limb leads which are leads I, II, and III. Lead I refer to the voltage difference between LA and RA, that is, Lead I = LA-RA. Similarly, Lead II denotes the voltage difference between LL and RA, that is, Lead II = LL-RA. And Lead III denotes the voltage between LL and LA, that is, Lead III = LL-LA.
Lastly, a PQRST complex is part of an ECG complex which is shown in Figure 2. The P wave is produced by the sinoatrial node which is the heart’s pacemaker and implies atrial depolarization in an ECG complex. The atrioventricular node generates the QRS wave. Ventricular depolarization is represented by the QRS, while ventricular repolarization is indicated by the T wave.
PQRST waveform [
In biology, neural networks develop the structure of animal brains, where the phrase “artificial neural networks” comes from. It is widely used in deep learning algorithms. An artificial neural network (ANN) [23] generally consists of three layers, namely, the input layer, hidden layer, and output layer. The hidden layers are present in-between input and output layers. It executes all the calculations to find hidden features and patterns. A shallow neural network consists of only one hidden layer and a deep neural network consists of multiple hidden layers. Generally, each node in one layer is linked to every other node in the next layer. By increasing the number of hidden layers, the network becomes deeper. This architecture is demonstrated in Figure 3.
Architecture of a general ANN [
Based on the concept of ANNs, a convolutional neural network (CNN) [25] was formulated which is a deep learning method that can take an image as input and learn some filters that can be used to extract essential features from those images. The brain is the source of inspiration for convolutional neural networks. CNN performs a linear mathematical procedure known as a convolution in the several hidden layers between an input and output layer. The general mathematical expression of convolution operation is provided in the following equation:
where
CNN’s have the benefit of being able to construct an internal demonstration of a two-dimensional image. This enables the model to learn position and scale in different data formats, which is essential when working with images.
A recurrent neural network (RNN) [26] is a form of artificial neural network which is designed to operate with time series, analyzing temporal and sequential data. It’s one of the algorithms responsible for the incredible advances in deep learning over the last few years. RNN can handle inputs/outputs of varying lengths. The idea of “memory” in RNNs is used to store the states or information of earlier inputs in order to generate the sequence’s next output. It has the ability to store or memorize historical information.
Long short term memory (LSTM) [27] is a type of recurrent neural network and LSTM networks are well-suited to categorize, processing, and generating predictions based on time series data as there might be delays of undetermined duration between critical occurrences in a time series. LSTMs were designed to explode gradients and solve the problem of vanishing gradients that can occur while training standard RNNs.
LSTM uses the concept of gates. It has three gates which are input gate, forget gate, and output gate. The input gate determines what new information will be stored in the cell state. The forget gate determines what information to throw away from the cell state whereas the output gate is used to activate the LSTM block’s final output. In LSTM, output of the gates are operated with sigmoid activation functions, which calculates a value between 0 and 1, which is usually rounded to either 0 or 1 depending upon a predetermined threshold. “0” indicates that the gates are blocking everything and “1” denotes gates that enable everything to pass through it. The LSTM gates have the following equations:
where,
The cell state, candidate cell state, and final output equations are given as follows:
where,
The architecture of LSTM at any timestamp
Graphical representation of LSTM unit [
Bidirectional LSTMs [29] are a kind of LSTM that can be used to increase model performance on sequence classification issues. Bidirectional long-short term memory is the process of allowing any neural network to store sequence information in both backward (future to past) and forward (forward to future) directions. BI-LSTM is typically used when sequence to sequence activities are required. Text classification, speech recognition, and forecasting models can all benefit from using this type of network. Figure 5 shows the architecture of a BI-LSTM.
Graphical representation of bi-directional LSTM unit [
Before the invention of CAD, diagnosis used to be done manually and manual diagnostic procedures were time-consuming, less accurate. In the manual diagnostic procedures, there might be errors in the calculation of computational and statistical features. To counteract the faults in manual diagnostic procedures, deep learning has been introduced to diagnosis. CAD application has heightened the diagnostic performance of non-expert radiologists. Regardless of radiologist expertise, the fundamental benefit of CAD is the minimum false-negative rate and enhanced sensitivity. CAD technologies are faster, more dependable, more accurate and also help to improve in the calculation of computational and statistical features [31]. In this regard, this study focuses on speculating about some of the valuable technologies and trying to approach a conventional solution.
Noise is an undesirable signal which disrupts the original message signal and causes the message signal’s parameters to be altered. Noise distorts the message and hinders it from being understood in an intended manner. When there is loud, distracting noise that disrupts the communication assimilation process, comprehension suffers.
There is no signal without noise. The signal strength may be affected or aided by noise. Noise can cause signal distortion, which is most noticeable in agitated receivers. Both analog and digital systems suffer from noise, which diminishes their performance. Noise degrades the quality of the received signal in analog systems. Noise reduces the overall performance of a digital system because it necessitates retransmission of data packets or additional coding to recover data in the event of an error. The most prevalent and evident issue produced by signal noise is the distortion of the processed signal, which causes inaccurate interpretation or display of a process state by the equipment. Unusual signal noise can cause an apparent signal loss. Noise filtering is incorporated into most current electrical devices. However, in excessively loud circumstances, this filter may not be sufficient, resulting in the device getting no signal and no connection.
The presence of noise can make it difficult or impossible to identify a representative ECG signal. Noises in the ECG signal can lead to incorrect interpretation. In the ECG signal, there are primarily two kinds of noise. Electromyogram noise, additive white Gaussian noise, and power line interference are examples of high-frequency noises. Power line interference distorts the amplitude, duration, and shape of low-amplitude local waves of the ECG signal. Baseline wandering is an example of low-frequency noise. Baseline wandering alters the ECG signal’s ST-segment and LF components.
Noise can be reduced by keeping the signal wires as short as possible or by keeping the wires away from electrical machinery. By using differential inputs, noise can be reduced from both wires. Noise also can be reduced by filtering the signal or by using an integrating A-D converter to reduce mains frequency interference.
There are various ECG denoising techniques [32] that are being used to reduce the noise from signals. Some ECG denoising techniques are EMD-based models, deep-learning-based models, wavelet-based models, sparsity-based models, Bayesian-filter-based models, hybrid models, discrete wavelet transform, etc.
The discrete wavelet transform is a digital processing computational technique that allows for electrical noise with a higher signal-to-noise ratio than lock-in amplifier equipment. A discrete wavelet transform decomposes a signal into a number of sets, each set including a time series of coefficients that describe the signal’s time evolution in the associated frequency band.
The process of converting raw data into a comprehensible format is known as data preprocessing. Dealing with raw data is not suitable, thus this is a key stage in data mining. Before using machine learning or data mining methods, make sure the data is of high quality. In every brain-computer interface-based application, preprocessing data is a necessary and significant step. It checks the accuracy, completeness, believability, consistency, interpretability, timeliness of the data. It assists with the removal of undesirable artifacts from the data and prepares it for subsequent processing.
Peimankar et al. [33] proposed a deep learning model for real-time segmentation of heartbeats which might be utilized in real-time telehealth diagnostic systems. The proposed technique integrates a CNN and an LSTM model to predict and analyze the onset, peak, and offset of various heartbeat waveforms such as the P-wave, QRS complex, T-wave, and no wave. The proposed model is also known as DENS-ECG model. Using 5-fold cross-validation, this model is trained and evaluated on a dataset of 105 ECGs with a length of 15 min each. It attains an average sensitivity and accuracy of 97.95 and 95.68%, respectively. In addition, the method is calibrated on an unknown dataset to assess how robust it is at detecting QRS with a sensitivity of 99.61% and accuracy of 99.52%. This model illustrates the combined CNN-LSTM model’s adaptability and accuracy in delineating ECG signals. The accuracy of the proposed DENS-ECG model in recognizing ECG waveforms leaves the door open for cardiologists to apply this algorithm in-house to evaluate ECG recordings and diagnose cardiac arrhythmias. This model is provided in Figure 6.
Flowchart of the proposed DENS-ECG model [
In Figure 6, noise reduction refers to the filtering of the ECG signals to reduce noise and remove baseline wanders. In the segmentation, the ECG signals are divided into 1000-sample chunks and sent into the model as input. Then the segmented ECG signals are split into two sets to separate the testing set from a non-testing set. This model used a 5-fold cross-validation technique to provide a more trustworthy performance in terms of interpretability. The model consists of eight layers, including an input layer, three 1D convolution layers, two BiLSTM layers, and a dropout layer. And the Adam optimization algorithm is used to validate the algorithm, which is radically different from the steepest gradient descent (SGD) optimization technique and achieved higher performance on the validation. The trained model is tested on 26 unseen test records from the QTDB dataset to assess the classifier’s performance. Furthermore, the model is evaluated for QRS detection on the unexplored MITDB dataset.
Jambukia et al. [34] represented an overview of ECG classification into arrhythmia categories and stated that classification of electrocardiogram (ECG) signals plays a crucial role in the monitoring heart diseases as early and precise diagnosis of arrhythmia types is essential for monitoring cardiac disorders and selecting the best treatment option for a patient. The survey outlines the challenges of ECG classification and provides a comprehensive overview of preprocessing approaches, ECG databases, feature extraction techniques, ANN-based classifiers, and performance measures for evaluating the classifiers’ accuracy. According to the survey, many researchers have worked on ECG signal classification. They have used different pre-processing techniques, various feature extraction techniques, and classifiers. For ECG categorization, the majority of the researchers used the MIT-BIH arrhythmia database. A. Dallali et al. used DWT to extract the RR interval and then used Z score to normalize it. They classified ECG beats using FCM. They achieved a 99.05% accuracy rate. RR interval and R point position are two characteristics retrieved using DWT. FCM was used for pre-classification, while 3-layer MLPNN was used for final classification. They were able to reach a 99.99% accuracy rate.
Saadatnejad et al. [35] proposed an ECG classification model, which was suggested for continuous cardiac detection on wearable devices with limited processing resources. This model is demonstrated in Figure 7 in detail. The model works in such a way that the incoming computerized ECG data were first split into heartbeats and their RR interval while wavelet characteristics were extracted. The ECG signal as well as the extracted characteristics were then put into two RNN-based models that categorized every heartbeat. After that, the two outputs were combined to create the final categorization for every pulse. The suggested method fits the temporal criteria for continuous and real-time execution on wearable devices. Unlike many compute-intensive deep-learning-based techniques, the proposed methodology is accurate and lightweight, allowing wearable devices to have continuous monitoring with accurate LSTM-based ECG categorization having negligible computing expenses while running indefinitely on wearable devices with modest processing capability.
The proposed algorithm of LSTM-based ECG classification model [
Ribeiro et al. [36] had proposed an end-to-end DNN competent of accurately identifying six ECG abnormalities in S12L-ECG examinations, with diagnostic performance comparable to that of medical residents and students. This DNN model trained on data from the Clinical Outcomes in Digital Electrocardiology research which included over 2 million labeled tests analyzed by the Telehealth Network of Minas Gerais. The DNN surpassed cardiology resident medical practitioners in detecting six different types of abnormalities in 12-lead ECG recordings with F1 scores over 80% and specificity exceeding 95%. These results suggest that DNN-based ECG analysis, which was previously tested in a single-lead scenario, generalizes well to 12-lead examinations, bringing the technology closer to practical use. This model has the potential to lead to more accurate automated diagnosis and better clinical practice. Even professional assessment of complex and borderline cases appears to be essential in this future scenario, the implementation of such automatic interpretation by a DNN algorithm may increase the population’s access to this fundamental and valuable diagnostic test. Figure 8 shows the deep learning model used in this work.
The DNN architecture used for ECG classification [
In Figure 8, the Conv, BN, and dense imply the convolution, batch normalization, and the fully connected layers whereas the ReLU and
Figure 9a and b demonstrate the DENS-ECG model’s confusion matrices for the 5-fold CV and test set, respectively. The no wave class has the majority of incorrect cases in all three classes which are P-wave, QRS, and T-wave or it can be said that the model does not make significant errors in classifying the three major classes (P-wave, QRS, and T-wave). The minimal discrepancy between the 5-fold CV and test outcomes indicates that the model has been effectively trained and does not have an overfitting problem.
Confusion matrix [
As demonstrated in Figure 10 the performance plot, the DENS-ECG model performs similarly to other models in QRS detection with 99.61% of sensitivity and 99.52% of precision. The wavelet-based model proposed by Martinez et al. has the best performance in terms of sensitivity and accuracy of 99.8 and 99.86%, respectively followed by Kim and Shin’s proposed model. The postulated DENS-ECG model performed similarly to the well-known Pan and Tompkins’s QRS detection model but it outperformed the QRS detection methods proposed by Poll et al.
Comparison of DENS-ECG and various deep model architectures’ classification performance on the test set [
In [35], the classification ECG signals from heartbeat were classified into both 7 and 5 arrhythmia classes, respectively. For 5-classification problems, the heartbeats are divided into five categories by the Association for Advancement of Medical Instrumentation (AAMI). normal (N), supraventricular (S) ectopic, ventricular (V) ectopic, fusion (F), and unknown (Q) beats are the four types of an ectopic heartbeat. Further, the class N is divided into three more classes in the 7-classification to improve resolution by isolating the two conduction anomalies known as left bundle branch block (L) and right bundle branch block (R). Figure 11 represent the confusion matrix of 7 and 5-class classification problem, respectively where the former model is capable of effectively distinguishing L and R from N.
Confusion matrix [
As shown in Figure 12, Ribeiro et al. [36] has compared DNN’s performance indexes to the average performance of 4th-year cardiology residents, 3rd-year emergency residents, and 5th-year medical students. The performance of the DNN on the test set is demonstrated in the above accuracy plot. The above-shown figure shows that the performance of DNN which exceeds human performance. In most cases, the accuracy of DNN on the data set is more than 95%.
Comparison of performance indexes of DNN and the average performance of cardiology students on the test set [
Finally, the work of Jambukia et al. [34] presents a survey on the performance of various works present in the literature which are based on ECG signal categorization utilizing different pre-processing approaches, feature extraction techniques, and classifiers. Figure 13 presents the plot of the accuracy of different ECG classification techniques which have used the MIT-BIH arrhythmia database over time.
Comparison of the accuracy of the different ECG classification techniques [
Health issues in the human race are increasing day by day and cardiac issues are one of the most common diseases which has been noticed in the past few decades. Therefore, many technologies have been introduced and CAD is the most emerging technology to diagnose cardiac issues or solve heart-related diseases. Furthermore, deep learning has played an important role in the area of computer-aided diagnosis (CAD). From the above discussion, it can be observed that various algorithms or methods have performed pretty well in the field of cardiovascular disease detection. This indicates that deep learning in cardiac signal processing has an unbounded scope in the research field for enhancing CAD and getting more accurate and cost-effective and fast output.
The authors declare no conflict of interest or delete this entire section.
ECG | electrocardiogram |
CVD | cardiovascular disease |
AI | artificial intelligence |
ICD | International Classification of Diseases |
CAD | computer-aided design |
CT | computed tomography |
CHF | congestive heart failure |
ANN | artificial neural network |
CNN | convolutional neural network |
RNN | recurrent neural network |
LSTM | long short-term memory |
BI-LSTM | bi-directional long short-term memory |
DNN | deep neural networks |
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\n\nIntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Noteworthy, the stroke — related brain tissue metabolic damages involve an essential ATP deplete clash along with a suppression of brain specific nucleotide — associated kinases and ATP synthase, both Mg2+ — dependent complex enzyme “machineries”. This itself makes the latter’s a legitimate target for some advanced pharmaceuticals as long as the drug — induced overstimulation of corresponding enzymatic activity is the case. Thus, magnetic isotope effects (MIE) of the nuclear spin possessing paramagnetic 25Mg2+ ions might modulate the brain creatine kinase, alfa-glycerophosphate kinase and pyruvate kinase catalytic activities in a way of a remarkable ATP hyperproduction required to compensate the hypoxia caused acute metabolic breakdown. To realize the Magnesium-25 pharmacological potential, a low-toxic amphiphilic cationite nanoparticles were introduced lately. 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Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:43,paginationItems:[{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82212",title:"Protein Prenylation and Their Applications",doi:"10.5772/intechopen.104700",signatures:"Khemchand R. 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Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"93",type:"subseries",title:"Inclusivity and Social Equity",keywords:"Social contract, SDG, Human rights, Inclusiveness, Equity, Democracy, Personal learning, Collaboration, Glocalization",scope:"
\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices"},{id:"38",title:"Pollution",scope:"\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment"},{id:"41",title:"Water Science",scope:"