The Use of Calcium Dobesilate in the Treatment of the Early Stage of Non-Proliferative Diabetic Retinopathy

Introduction

Etiological Contributors

According to INTERNATIONAL DIABETES FEDERATION (IDF), more than 400 million people in the world suffer, and half of the cases of the diabetes mellitus type 2 (DM 2) is not diagnosed. Changes in the body developing in patients with DM 2 lead to a violation of all types of metabolism, angiopathy, polyneuropathy, as well as to violation of the function of almost all organs and tissues [1-3]. One of the vascular complications of DM 2 is Diabetic Retinopathy (DR), which is the main cause of weakness and blindness [4,5]. The prevalence of the DM 2 and the severity of its complications, in particular, DR determine the enormous medical and social significance of this disease. Early detection of foci of lesion and maintaining the normal functioning of the retinal tissue and the optic nerve at the initial stages of DR is considered an extremely important step of its secondary prophylaxis [4,6]. In this case, conservative treatment of DR using a number of angioprotective and antioxidant drugs is published [5,7]. At the same time, the progression of DR leads to hypoxic and morphological damage to neuroepithelial cells, which makes it appropriate for the inclusion of neuroprotective drugs into a complex of conservative therapy [8,9]. One of the pieces of interest is the doxy-hem - (calcium docking) angioprotector, the drug that improves the retinal microcirculation capable of preventing and corrected biochemical changes in the nerve tissues that has an endothelo protective effect.

It is also proven that the therapeutic dosage of the drug leads to a significant decrease in the volume of edema arising from a pronounced lymphatic drainage effect. The drug shows a variety of pharmacological effects in relation to the main pathophysiological processes at DR, as well as other vascular changes in patients with diabetes. The medicine Dox-Hem® reduces the increased permeability of the vessels, increases the resistance of the capillar stakes, moderately reduces the aggregation of platelets and blood viscosity, increases the elasticity of the erythrocyte membrane. The action is associated to a certain extent with an increase in the activity of plasma kinines, as well as with its chemical structure, which allows you to interact with free radicals, suppressing peroxidation oxidation of lipids. In clinical and experimental studies, the angioprotective effect of the Dox-Hem® as a result of the suppression of apoptosis, which occurs due to the prevention of changes in the permeability of the membrane and DNA fragmentation. The use of Dox-Hem® orally in the experiment made it possible to protect the retina from damage to free radicals, the Dox-Hem® stabilizes the GRS, reduces the output of the albumin, thereby contributing to the preservation of the normal retinal thickness. Dox-Hem® affects NO-dependent vasodilation, inhibiting endothelin-1. Thus, the use of Dox-Hem® contributes not only to optimizing endothelialdependent vasodilation, but also to reduce the intensity of retinal neurodegeneration. Another most important effect of the Dox-Hem® is its effect on angiogenesis, which is a key point in the development of the proliferative stage of other experimental studies, proved the powerful dose-dependent anti-angiogenic effect of Dox-Hem®, associated both inhibition of fibroblast growth factor and the VEGF factor that promotes the proliferation of endothelial cells and an increase in vascular permeability. The purpose of the study is to evaluate the effectiveness of the application of “doxy-chem” in patients with preclinical and early stages of diabetic retinopathy.

Materials and Methods

Surveyed 60 patients (120 eyes), the average age of which amounted to 59.4 ± 6.2 years. The study included patients with preclinical and early stages of non-proliferative diabetic retinopathy without any other eye pathology. All patients were divided into 2 homogeneous groups depending on the treatment carried out: patients in the main group (n = 60), in addition to the standard treatment on the main disease, was appointed Dox-Hem® according to the scheme (in the first 3 weeks - 1 capsule in time or after meals, further use the drug per day for 10 months); In the control group (n = 60), only a standard treatment for the main disease was carried out. Ophthalmic examination of patients, in addition to basic research methods, such as: visual acuity with optimal optical correction, bio microscopy, ophthalmoscopy and tonometry, also included static perimetry with the definition of medium sensitivity of the retina and fowolar photosensitivity, Optical Coherent Tomography (OCT) with an estimate of the thickness of the central fox and Makula in 4 meridians and color Doppler mapping of vessels. All patients were used by the Color Doppler Ultrasound method for estimating the peak systolic velocity of blood flow (PSV), the final diastolic velocity of blood flow (FDV) and the Resistance Index (RI) in the following arteries: Eye Artery (EA), Central Artery Retinal (CAR), Central Vienna Retina (CVR), Short Back Cylinder Artery (SBCA). The survey included an integrated ultrasound study of the eye and orbits in EA CAR, CVR and SBCA on the VOLUSONE 8 device (GE, Healt Ere) to using a linear sensor with a frequency of 10 to 16 MHz. The spectrum of the doppler shift of the frequencies was recorded and the main quantitative indicators of blood flow were determined: VSYST, VDiaSti Ri.

Results and Discussion

In the primary inspection of patients, a decrease in visual acuity was revealed on average to 0.61 ± 0.03 in 72.5% of cases (44 eyes). At an ophthalmoscopy in 84.3% of cases (50 eyes), the microaneurysms of the rear area of the eye, localized mainly in the macular region, in 80.1% (48 eyes) are point hemorrhages in 20.1% (12 eyes), small solid (30 %, 18 eyes) Exudates .. At OCT of the Fovea Center, a non-uniform thickening of the neuroepithelium of the retina was revealed in 23% of cases (14 eyes), which, apparently, is associated with hypoxia phenomena and microcirculation disorders in patients with diabetic retinopathy. The results of analyzing the thickness of the Macula in patients of the main and control groups remained within the age norm. As a result of the treatment, a significant increase in visual acuity was noted in the main group - on average by 0.20 ± 0.02 (p <0.05), with 84.5% of cases (50 eyes) there was a positive trend. In the control group, the visual acuity has not changed significantly, and its increase was not statistically significant (p> 0.05). According to the results of the optical coherent tomography of patients of the main group, a decrease in the thickness of the retina in the Fovea is found by an average of 1.60μm (p <0.05), as well as a decrease in thickness in other parts of the central zone. In general, the positive dynamics was marked in 75% of cases (44 eyes). In the control group, when comparing the results of the thickness of the retina before and after the treatment of statistically significant changes, (P> 0.05) is noted (Table 1).

Table 1: The retina before and after the treatment of statistically significant changes.

Analysis of changes in the eye picture pattern (microaneurism, the number and dynamics of hemorrhage, solid and soft exudates, retinal edema) indicated statistically significant changes in the main group, starting with 3 months of observations. In the control group, the statistical authenticity of the positive dynamics of the process in the specified period was absent. An analysis of the remote results of the study showed that 3 months after treatment, the patients with the main group showed a slight decrease in visual acuity compared with the results obtained immediately after treatment, but this figure remained reliably higher than the initial results by an average of 20.78% (p <0 05). In the control group, in 3 months, visual acuity was similar to the initial values. After 6 months after treatment, a decrease in visual acuity was noted in all studied groups, while in the main group this indicator remained above the initial results on average by 18.67% (p <0.05), and in the control group decreased compared to the initial Indicators on average by 4.9% (p> 0.05). OCT-scanning of the central retinal zone in patients of the main group after 3 months revealed a further minor decrease in the thickness of the central fox and the makeup with a tendency to increase by 6 months after treatment, though the values were preserved significantly below the source data (p <0.05). Statistically significant changes in patients of the control group were not (P> 0.05).

Table 2 shows a progressive reduction of blood flow at the second stage of IB and the third IC NDR in the central artery of the retina (CAК) in the initial state [8,9]. The progressive phased decrease in blood flow in the short rear ciliary artery (SRCA) was also revealed. Peak Systolic Speed (PSS) in the Central Vein of The Retina (CVR) changed from 6.48cm / s at stage Ia to 3.97cm / s at stage IC, which indicates dilatation of veins increasing as retinopathy progression. Ultrasound studies of the condition of blood flow in the vessels of the eye were performed in 12 patients (24 eyes) with various stages of the Central Tshold Group II and in 14 patients (28 eyes) of the III group, of which 10 eyes with the non-acudative stage of TsDD in the group II group and 12 eyes in the group III, 8 Eye with an exudative stage of TsDD in group II and 8 eyes in the third group, with a scar stage of TsDD in the group II 6 eyes, in the third eye group. When analyzing hemodynamic indicators in persons with non-assessive stage of TsDD in the II and III group of patients, TCDDs revealed increased microcirculation in the CAR and the WCCC system, which manifest itself with an increase in the systolic velocity of blood flow: in patients with group II 1.2 times and III groups 1.5 times and decrease Resistance index, respectively. These parameters in patients of the Group III significantly correlated with indicators of visual acuity (Table 3).

Table 2: Results of ultrasonic doppler vascular vessels by groups. (abs. Numbers and%).

Note: *NPDR = Non-Proliferative Diabetic Retinopathy, PSV = Peak Systolic Rate of Blood Flow, CRA = Central Artery Retina, CVR = Central Vein Retina, SPCA = Short Rear Cylinder Artery, EA = Eye Artery, ri = Resistant Index; *p <0.05; **p <0.01 - from healthy, #p <0.05 - from the NDR IA, ^P <0.05- from the NDRR IB; SD = Standard deviation.

Table 3: Comparative assessment of the results of treatment on the dynamics of CDC indicators in patients with NDPR.

Note: *P <0.05 The accuracy of differences in relation to the data before treatment. **p <0.05 accuracy differences between groups.

Thus, the analysis of the results, showed that in the group of patients who received “doxy-hem” after treatment, there was a reliable positive dynamics of a number of studied functional and doppler indicators, which is associated with the effect of the drug on the microcirculation of the retina and its protection against the effects of metabolic and hypoxic defeats in patients dr. These clinical and functional studies have shown the effectiveness of the drug “Doxy - Hem” in the treatment of non-proliferative DR. The use of this drug contributes to an increase in visual acuity, a decrease in the thickness of the retina, improving the hemodynamics indicators. Positive changes in visual functions obtained as a result of treatment are preserved for up to 6 months. All this makes it possible to recommend the specified method for the secondary prevention of the development of diabetic retinopathy and the rehabilitation treatment of patients with early stages of nonproliferative DR [10-12].

Conclusion

1) This study showed that the treatment with the drug “Doxy- Hem” helps to improve eye blood flow in retrobulbar vessels, especially in the central artery of the retina and the short rear ciliary artery.

2) psV and RI in CRA and SPCA can be potentially useful for early diagnosis and subsequent observation of others.

3) The places of increased resistance or reduced blood flow velocity can be used to predict a higher risk of developing heavy DR, which is important to determine the further patient’s tactics.

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Efficacy Analysis of Trans-Vaginal Cystocele Repair with Transobturator Four-Arm Mesh: A Mid-Term Follow-Up

Introduction

Pelvic organ prolapse (POP) refers to a female pelvic organ (vagina, uterus, bladder and/or rectum) that enters or protrudes beyond the vagina. POP is a common disease involving women’s pelvic floor, which has a negative impact on women’s quality of life, sex life and body image [1]. The prevalence of POP varies depending on the diagnostic criteria, from 3% to 50%, based on symptoms and vaginal examination findings [2]. Cystocele (also known as anterior vaginal wall prolapse) is the most common type of POP caused by the relaxation of the anterior vaginal wall. According to statistics, the incidence of posterior vaginal wall prolapse (rectocele) is twice that of uterine prolapse. Hysterectomy (or vaginal vault prolapse during hysterectomy) three times [3]. Various surgical methods are available to treat anterior vaginal wall prolapse (Cystocele), possibly reflecting lack of consensus regarding the optimum approach [4]. The current treatment methods are divided into traditional non-mesh anterior pelvic repair surgery and mesh repair surgery [5]. In 2002, the FDA approved the first surgical mesh product for POP disease. The introduction of surgical mesh makes transvaginal POP repair easier to learn and operate, and mesh shows better anatomical repair advantages in the treatment of cystocele [6]. In the past two decades, transvaginal polypropylene mesh (transvaginal mesh repair, TVM) has made great progress in the treatment of cystocele [7]. However, compared with traditional meshless repair surgery, mesh surgery is still controversial in terms of symptom relief rate, surgical complications, and recurrence of prolapse. The purpose of this study is to evaluate the effectiveness and safety of transvaginal transobturator polypropylene pelvic floor mesh in the treatment of cystocele.

Clinical Characteristics Surgical Steps and Follow- Up

A retrospective analysis of the clinical data of patients with cystocele in the Department of Urology, Shanghai Changhai Hospital from September 2016 to April 2018. The surgeries were performed by a single surgeon with extensive experience in urology and pelvic organ prolapsed (POP) repair. According to the classification of pelvic Organ prolapse quantification (POP-Q), patients who are diagnosed as ≥ II degree [8] and have no history of POP surgery. The surgical method is transvaginal transobturator bladder prolapse repair with four-arm polypropylene mesh. If patients combined with III-degree or IV-degree posterior vaginal wall prolapse, the vaginal posterior wall repair (autologous tissue repair) will be performed simultaneously with transvaginal transobturator bladder prolapse repair. Obtain the patient’s informed consent. Collect the patient’s clinical data, operation time, blood loss, hospital stay and complications and other information. Using TiLOOP Total 4 four-arm pelvic floor prolapse repair mesh, prepare two sets of puncture needles.

The patient takes the lithotomy position, an indwelling F18 catheter to empty the bladder, injects normal saline under the vaginal wall, and takes 2cm from the lower edge of the urethra vagina to the fornix of the anterior vagina tomake a longitudinal incision as shown in (Figure 1) to fully separate the vagina and bladder The fascia on both sides of the serosal layer, the anterior branch puncture point is at the height of the urethral orifice and the base of thigh. The posterior branch is 2cm outside and 2cm below the anterior branch (Figure 2). The upper edge of the mesh is fixed at the bladder neck and the lower edge is fixed at the cervix. The mesh is in an expanded state. Cut off the excess anterior vaginal wall (Figure 3). The extra sling is cutted off. Put iodophor gauze into the vagina and take it out after 48 hours (Figure 4). Follow-ups were conducted at 12 and 24 months after surgery. A POP-Q of 0 or I was defined as an objective cure. Intraoperative complications, early complications and late complications were counted. Complications less than 30 days after surgery were defined as early complications, and complications greater than 30 days after surgery were defined as late complications. The statistical method uses SPSS 13.0 software, the measurement data is represented by the mean, median, standard deviation, minimum and maximum value, and the count data is represented by frequency and percentage.

Figure 1: Longitudinal incision of the front wall of the vagina.

Figure 2: Marking the puncture points of the anterior and posterior branches.

Figure 3: Cut off the excess anterior vaginal wall.

Figure 4: Cut off the extra sling and put iodophor gauze into the vagina.

Outcome

A total of 21 patients were included in this study. The clinical characteristics and demographic features are shown in Table 1. Among them, 15 cases (71.4%%) were stage III prolapse, 6 cases (28.6%) were stage IV prolapse; the average age was 68.2 (±9.0) years, 42.9% of them were overweight or obesity, and 52.4% had multiple births ( ≥2 times), 28.6% had a history of gynecological surgery. Among them, 5 cases were combined with posterior vaginal wall prolapse (rectocele), and all were stage III or IV, and underwent repair of posterior vaginal wall at the same time. The operation time was 66.0±13.7 (50-105) min, the blood loss was 26.2±13.2 (10-50) ml, the total hospital stay was 8.5±1.5 (6-12) days, and 20 cases (95.2%) were cured objectively after 12 months. 1 case had recurrence of posterior vaginal wall prolapse. One case was lost to follow-up 24 months after the operation, and 19 cases (95%) were cured objectively (showed Table 2). The complication statistics are shown in Table 3. All 21 patients had no early complications. In terms of late complications, 4 cases (19.0%) had occult stress urinary incontinence 2 months after the operation, of which 2 cases underwent TVT-O (Tension-free vaginal tape obturator)surgery; 1 case (4.8%) had recurrence of posterior vaginal wall prolapse (stage III) at 10 month after surgery who was cystocele combined with posterior vaginal, and underwent repair of posterior vaginal wall once again; 1 case (4.8%) had a feeling of inexhaustible urine, but the residual urine of ultrasound was negative, and the symptom improved after oral tamsulosin treatment; 1 case (4.8%) complained of dyspareunia and pain relief in 10 months after surgery. In this study, there were no complications of mesh erosion and scar hyperplasia.

Table 1: Demographic features and clinical characteristics.

Note: Value* defined as median (mean ± SD, range), or number (percentage)

Table 2: Follow-up at 12 and 24 months after surgery.

Note: Data are expressed as absolute number or percentage.

Table 3: Complications rate associated with operations at 12-months follow-up.

Note: Values are presented as number (%).

Discussion

POP seriously disturbs women’s quality of life and increases the medical burden. In the United States, about 22,500 surgical operations are performed each year due to pelvic organ prolapse, and cystocele and posterior vaginal wall prolapse account for 80% [9]. In the UK, POP accounts for about 20% of gynecological operations and is the main reason for hysterectomy in postmenopausal women [10]. An epidemiological survey of urban population in China shows that 9.67% of women suffer from POP of varying degrees, and the prevalence increases with age. The prevalence of women over 70 years old is about 26.11% [11]. The risk factors for POP vary among patients. A recent systematic review of studies found that parity, vaginal delivery, age, and body mass index were pivotal risk factors for primary POP in developed Western countries [12]. The 21 cases in this study were all postmenopausal women, and the proportion of elderly women was high. Among them, 42.9% were overweight or obesity and 52.4% had more than 2 births. POP surgery has two methods, transvaginal or transabdominal, which can be divided into autologous tissue (non-mesh) and polypropylene mesh repair. At present, 80-90% of operations choose the transvaginal surgery [13]. Anterior colporrhaphy, known as traditional repair of anterior vaginal wall prolapse including cystocele, alone has a high failure rate and can lead to vaginal shortening and/or constriction and is useful only for the midline defects [14, 15]. The transvaginal route of mesh procedure for anterior prolapse, first described by Julian, has reported good success rates in various non-randomized trials, ranging from 75% to 100% [16-18].

Palma introduced the transobturator four-arm mesh for the treatment of cystocele for the first time in 2004, and more and more relevant studies and cases have been reported since then [19]. In this study, the cure rate was 95.2% and 90% at 12 and 24 months after surgery, which was similar to the mid-term follow-up study of Yonguc and other double sling surgery [20]. In this study, there were no intraoperative complications such as bladder perforation or urethral injury; similarly, there was no need for blood transfusion caused by massive bleeding during the operation, and the average blood loss was only 26.2 (±13.2) ml, which is consistent with the results of the Kdous and Zhioua study [21]. There was no early complications such as fever, hematuria, urinary tract infection, and deep venous thrombosis. 4 cases (19.0%) developed occult stress urinary incontinence (SUI) during follow-up, of which 2 cases underwent Transobturator Tension-free Vaginal tape (TVT-O) in our hospital, and 2 cases did not receive surgery because of moderate symptoms. Occult SUI refers to the new SUI that appears after the POP is cured or relieved. About 50% of SUI women with no symptoms may develop SUI after the prolapse is repaired. Women with symptoms of urinary incontinence or a history of SUI have a higher risk of developing SUI. [22]. In this study, there were no cases of recurrence of cystocele. One case who was cystocele with posterior vaginal wall prolapse was found recurrence of posterior vaginal wall prolapse at 10 months and received posterior vaginal wall prolapse repair operation again.

Eboue et al. reported that the recurrence rate of cystocele was 2.4% after 123 women underwent transobturator four-arm mesh repair for 1 year [23]. We believe that the recurrence of cystocele is related to the displacement of the mesh, surgeon experience and the material of the mesh. The mesh and histocompatibility are critical. This process takes several weeks. We recommend that patients stay in bed within 2 weeks after surgery and avoid strenuous activities within 4 weeks, which may also be one of the reasons for no recurrence. One case (4.8%) had dyspareunia. We believe that dyspareunia has nothing to do with the mesh itself, but may be related to some other aspects of the operation. In order to reduce the risk of dyspareunia after surgery, the surgeon must ensure that the mesh placement is tension-free and the mesh arm is not stretched too tightly, so as to In order to relieve the pain of postoperative painful sexual intercourse [24]. Mesh erosion is one of the most common and serious complications after POP repair, with an incidence of 4% to 30% [25].

The size and location of the vaginal incision, the depth of the incision, sexual intercourse, and younger women are considered to be risk factors for mesh erosion. In addition, insufficient surgeon experience is also a factor in the high incidence of mesh erosion [26, 27]. In this study, the occurrence of no mesh erosion complications may be related to the surgeon professional training in urology and the guidance and supervision of experienced superior doctors. The main limitations of this study are single center, small number of cases, short follow-up time, and no quantitative subjective evaluation of surgical satisfaction. In summary, the transobturator four-arm polypropylene mesh is safe and effective in the treatment of cystocele, and the complications are controllable. The strength of the present study is relatively comprehensive long follow up and uniformity of this procedure as it is a single-center, single-surgeon study using the same technique. However, more randomized controlled, multi-center, long-term follow-up, and large-sample studies are still needed to further evaluate the safety and effectiveness of the transobturator four-arm pelvic floor mesh.

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Pathophysiology and Management of Atrial Fibrillation

Introduction

Atrial fibrillation is characterized by irregular and often very fast contractions of the atrial cardiomyocytes, resulting in an irregular heart rate, palpitations, dizziness, shortness of breath, and tiredness in the patient. AF can occur when abnormal electrical impulses suddenly start firing in the atria and override the heart’s natural pacemaker, which can no longer control the rhythm of the heart. Importantly, AF is associated with severe complications, such as thromboembolic events, heart failure, cognitive impairment, and increased mortality [1,2]. The progressive stages of AF are associated with structural changes that promote contractile dysfunction and the impairment of electrical conduction in the atrial myocardium [3]. Atrial Fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with considerable morbidity and mortality [4]. Biomarkers of inflammation (C-reactive protein and fibrinogen), myocardial injury (high sensitivity troponin I), renal dysfunction (fibroblast growth factor-23), and hemodynamic stress (NT-proBNP [N-terminal pro-B-type natriuretic peptide]) have been reported to be independently associated with prevalent and incident AF [5]. The prevalence of AF ranges from 2% in the general population to 10–12% in those aged 80 and older. Patients with AF are five times more likely to have a stroke and three times more likely to experience heart failure compared to healthy individuals. AF may also increase an individual’s socioeconomic burden through increased healthcare costs [6-8].

Etiological Contributors

A variety of etiological factors contribute to AF occurrence. In most patients, AF results from interactions among multiple factors operating simultaneously. Over 70% of AF cases have associated heart disease. Aging is a major risk factor, largely via structural remodeling. Congestive Heart Failure (CHF), hypertension, valvular heart disease, and Coronary Artery Disease (CAD) are common contributors. Less common predisposing conditions include pericarditis or myocarditis, atrial myxomas, and hypertrophic cardiomyopathy. Extracardiac conditions also promote AF occurrence. Sufficiently powered studies suggest that heavy alcohol consumption promotes AF. Hyperthyroidism is a wellrecognized contributor, and the roles of sleep apnea and obesity are increasingly recognized [9,10]. Modifiable risk factors associated with atrial fibrillation are hypertension; diabetes mellitus; coronary artery disease; heart failure; valvular heart disease; chronic kidney disease; obesity; obstructive sleep apnoea; hyperthyroidism; smoking; chronic obstructive pulmonary disease; excessive alcohol intake and excessive exercise [11].

Pathophysiology

Immunothrombosis refers to the complex participation of the innate immune system in the formation of intravascular thrombus through distinct cellular and molecular interaction. This local coagulation can promote more inflammatory processes, initiating atrial remodeling through direct and indirect tissue damage. Fibrinogen, Von Willebrand Factor (vWF), and A Disintegrin and Metalloprotease with ThromboSpondin motif repeats 13 (ADAMTS13), a vWF-cleaving protease, are biomarkers that play key roles in coagulation and inflammatory pathways, and perhaps therefore be associated with AF. However, prospective research on this is scarce. Activation of the innate immunity can cause neutrophils to release neutrophil extracellular traps (NETs). Besides their important role in actively killing pathogens by releasing chromatin and DNA, NETs also stimulate coagulation processes by recruiting and activating platelets, binding to tissue factor, and stimulating fibrinogen and vWF. This way, NETs are at the intersection between inflammation and thrombosis, both potentially major players in AF pathophysiology [12,13]. AF is initiated by focal ectopic firing and is maintained by re-entry mechanisms in a vulnerable atrial substrate. The ectopic firing seems to arise from myocyte sleeves within the pulmonary veins and is triggered by a diastolic leak of Ca2+ from the sarcoplasmic reticulum that in turn determines myocyte depolarization due to an inward Na+ current via Na+ -Ca2+ exchanger. The re-entry mechanism is promoted by slow conduction velocity of the depolarizing wave front and a shortened refractory period of cardiac myocytes. The presence of structural and electrophysiological atrial abnormalities favors the selfperpetuation of AF by promoting re-entry [14].

Focal Ectopic Activity

Delayed after depolarization’s (DADs) constitute the most important mechanism of focal atrial arrhythmias. They result from abnormal diastolic leak of Ca2+from the main cardiomyocyte Ca2+ storage organelle, the sarcoplasmic reticulum (SR Ca2+ enters cardiomyocytes through voltage dependent Ca2+ channels during the action potential plateau, triggering Ca2+ release from the SR via Ca2+ release channels known as ryanodine receptors (RyRs; RyR2 is the cardiac form). This systolic Ca2+ release is responsible for cardiac contraction. Following action potential repolarization, diastolic cardiac relaxation occurs when Ca2+ is removed from the cytosol back into the SR by a Ca2+ uptake pump, the SR Ca2+ ATPase (SERCA). DADs result from abnormal diastolic Ca2+ leak through RyR2 from the SR to the cytoplasm. Excess diastolic Ca2+ is handled by the cell membrane Na+, Ca2+-exchanger (NCX), which transports three Na+ ions into the cell per single Ca2+ ion extruded, creating a net depolarizing current (called transient inward current, or Iti) that produces DADs. DADs that are large enough to reach threshold cause ectopic firing. Repetitive DADs cause focal atrial tachycardias (tachycardia is a heart rhythm >100 bpm). RyR2s are Ca2+ sensitive, and RyR2 leak results from SR Ca2+ overload or intrinsic RyR2 dysfunction. RyR2 function is modulated by channel phosphorylation: hyperphosphorylation makes RyRs leaky and arrhythmogenic [15-17].

Reentry

Reentry requires appropriate tissue properties, a vulnerable “substrate.” Reentry substrates can be caused by altered electrical properties or by fixed structural changes. Cardiac tissue exhibits a discrete refractory period (inexcitable interval following the last firing, governed by APD). Reentry initiation usually requires a premature ectopic beat that acts as a trigger. The resulting impulse conducts through the pathway leading to recording point ii, which is no longer refractory, but blocks in the pathway leading to recording point iii because of its longer refractory period. The premature impulse arrives at the distal end of previously refractory site iii and attempts to reenter [18] (Figure 1).

Figure 1: Tissue mechanisms leading to AF and clinical forms.

(A) Ectopic activity can act as a driver maintaining AF or as a trigger on a vulnerable substrate resulting in reentry (singleor multiple-circuit). Local driver mechanisms (ectopic or single-circuit reentrant) produce irregular fibrillatory activity via fibrillatory conduction. Rapid atrial activity (tachycardia) causes atrial remodeling, promoting multiple-circuit reentry.

(B) Clinical AF can manifest as paroxysmal AF (self-terminating), persistent AF (requires drug therapy or electrical cardioversion to terminate), and permanent AF (non-terminating). Focal ectopic drivers are principally associated with paroxysmal forms, functional reentrant substrates with persistent AF, and increasingly fixed substrates with permanent forms [51].

Aldosterone

Figure 2: Potential pathogenetic mechanism linking aldosterone excess with atrial fibrillation.

Aldosterone itself has been shown to up regulate MR expression in cultured HL-1 cardiomyocytes, thus reinforcing its effects on the heart. Since the MR not only binds aldosterone, but also cortisol, it can be argued that some effects mediated by MR activation may be attributable to cortisol. 11â-hydroxysteroid dehydrogenase type 2, an enzyme which converts cortisol to inactive metabolites allowing aldosterone binding to the MR, is up regulated in the left atrial myocardium of patients with AF, thereby suggesting that MR activation in this setting is mainly due to aldosterone [19,20]. As regards to the potential physiopathological mechanism linking aldosterone excess to FA, aldosterone is thought to be involved in the genesis and perpetuation of AF not only by causing AH and electrolyte imbalance, but also by inducing inflammation, oxidative stress, fibrosis and electrophysiological changes; all these mechanisms contribute to structural and electrical atrial remodeling that are known to predispose to AF [21] (Figure 2). Oxidative Stress Over recent years, oxidative stress has been investigated as a potential essential mechanism in the development of AF. Reactive Oxygen Species (ROS) constitute the normal byproducts generated through the metabolism of oxygen. These molecules have been proven to have a multifaceted effect on the cells present in the heart tissue. The prevalence and incidence of AF were related to the redox potentials of glutathione (EhGSH) and cysteine, markers of oxidative stress. The study concluded that the prevalence of AF was 30% higher for each 10% increase in EhGSH, while the same alteration resulted in a 40% increase in the risk of incident AF [22]. Iron accumulation causes AF is increased oxidative stress [23].

Inflammation

Inflammation has been linked to the onset and maintenance of atrial fibrillation, according to accumulating evidence. Inflammation contributes to the atrial remodelling involving both structural and electrophysiological alterations that form the basis for the disease. A large-scale prospective study involving 24,734 women participants investigated the association of inflammatory markers such as CRP, fibrinogen, and intercellular adhesion molecule 1 (sICAM-1) with the incidence of AF. The results suggested that inflammation is a strong indicator for the incidence of AF with the median plasma levels of the biomarkers being independently correlated with the development of the disease in patients [24]. Inflammation has been implicated in the pathophysiology of various cardiac, as well as non-cardiac, diseases that are comorbid with AF. HF and cardiomyopathy are associated with a 4–6-fold increase in AF prevalence. Inflammation has been implicated in the pathophysiology of HF and modulates the cell signaling activation patterns associated with fibrosis, apoptosis and hypertrophy; these are all forms of cardiac remodeling that, when they occur at the atrial level, predispose to AF. CAD is a systemic, lipid-driven condition with immune inflammatory components. AF frequently occurs in acute myocardial infarction, especially in the early stages when the myocardial inflammatory reaction is at its maximal. Serum levels of interleukin-6 (IL-6), an inflammatory biomarker, were independently associated with AF risk in a cohort of subjects with known CAD [25,26].

Tumour Necrosis Factor A

TNF-α stimulates an acute immune cell reaction and induces inflammation. TNF-α is synthesized by various immune cells, including macrophages and lymphocytes [27].

C-Reactive Protein

C-Reactive Protein (CRP) is a highly reproducible but nonspecific inflammatory biomarker, synthesized primarily in the liver in response to inflammatory cytokines. The circulating level of CRP is increased in patients with AF compared with those without an AF history, and persistent-AF patients have higher CRP levels than do those with paroxysmal-AF [28].

Interleukin-6

IL-6 is produced by lymphocytes and stimulates inflammatory responses. IL-6 also has anti-inflammatory effects, via the inhibition of TNF-α signaling and the activation of IL-10, an anti-inflammatory cytokine [29].

Treatment

Lifestyle and dietary modifications including weight loss, alcohol reduction, and cardiometabolic risk factor management would be a cornerstone for AF prevention. In patients with short paroxysms of AF, therapeutic strategies should generally concentrate on providing control of the arrhythmia itself. Regardless of the arrhythmia pattern or the therapeutic strategy chosen, and in the absence of contraindications, patients should be considered for anticoagulation if they have one or more risk factors for thromboembolism. Patients at low or intermediate risk, and higher risk patients in whom warfarin is contraindicated, may benefit from antiplatelet treatment [30,31]. The medical prescription of medications other than anti-inflammatory agents, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists, can all help to reduce LA enlargement, atrial fibrosis, and TGF-β indicators, as well as atrial dysfunction. These are the most widely used drugs for AF and have to be considered for patients with a history of heart failure. The novel SGLT-2 inhibitors reveal beneficial effects in systolic heart failure included improved cardiac energy metabolism, the prevention of inflammation, oxidative stress, adverse cardiac remodelling, less LA enlargement, fibrosis, atrial mitochondrial dysfunction, inflammation, and AF inducibility [32-34].

Rhythm Control Strategy

Chelation Therapy: Effective in preventing both arrhythmic recurrences and iron overload;

Deferoxamine: this was the first iron chelator introduced in clinical practice. It has a short plasma life and is not absorbed in the gastrointestinal tract, so it must be administered parenterally. Deferoxamine can also be administered in continuous intravenous infusion when intensive chelation is needed [35].

Amiodarone: Effective safe in the short term; Amiodarone is often both effective in the control of arrhythmic recurrences and safe in the short term. However, its multiple adverse effects when taken chronically, associated with the frequent coexistence of organ damage from iron accumulation, suggest avoiding prolonged use. Long-term therapy, in fact, is often complicated by thyroid and hepatic dysfunction, as these organs are also targets of iron-mediated damage. Other antiarrhythmic drugs (flecainide, propafenone, sotalol).

Fewer Side Effects in the Long Term and Catheter Ablation: Avoiding side effects of antiarrhythmic drugs [36,37]. Catheter ablation has been shown to be a safe and effective option for rhythm control in patients with AF. Current international guidelines recommend ablation for patients with symptomatic AF, both paroxysmal and persistent, who have failed an antiarrhythmic drug therapy (class I of evidence). However, they also add that ablation may be used in selected patients even before a trial of antiarrhythmic drugs (class IIa) [38,39]. Flecainide and propafenone have been shown to be similarly effective at suppressing symptomatic paroxysms of AF and, in the absence of structural heart disease, neither drug appears to cause significant proarrhythmia. In general, these class Ic agents tend to be better tolerated and more effective than class Ia agents, such as quinidine and disopyramide [40].

Rate Control Strategy

Rhythm control strategy should be preferred in symptomatic patients due to paroxysmal pattern of AF and the presence of a hyperdynamic circulation [41]. β-blockers is effective in reducing symptoms when rhythm control is not possible Indicated also for HF; Calcium channel blockers (verapamil, diltiazem): Effective in reducing symptoms when rhythm control is not possible and Digoxin: Second line therapy when β-blockers or calcium channel blockers are not tolerated [42].

Anticoagulation

Warfarin: Frequent monitoring of coagulation state (INR) and DOACs (apixaban, dabigatran, edoxaban, rivaroxaban): More manageable and safer than warfarin [43].

Anti-Inflammatory Drugs

Statins: Statins have pleiotropic actions beyond cholesterol reduction, including improved endothelial function, reduced thrombogenesis, and suppression of oxidative stress and inflammation. In animal AF models, statins decreased AF vulnerability [44].

Colchicine: Colchicine suppresses leukocyte activation, endothelial cell adhesion and migration. Postoperatively initiated adjusted dose colchicine prevented POAF and shortened hospital stay without significant adverse effects in a double-blind randomized trial [45-47].

Corticosteroids: In an experimental study, tachycardiainduced atrial remodeling and AF vulnerability were attenuated by prednisone treatment; circulating CRP levels were also decrease [48-51].

Conclusion

AF is characterized by irregular and often very fast contractions of the atrial cardiomyocytes, resulting in an irregular heart rate, palpitations, dizziness, shortness of breath, and tiredness in the patient. Immunothrombosis refers to the complex participation of the innate immune system in the formation of intravascular thrombus through distinct cellular and molecular interaction. Inflammation contributes to the atrial remodelling involving both structural and electrophysiological alterations that form the basis for the disease. The medical prescription of medications other than anti-inflammatory agents, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists, can all help to reduce LA enlargement, atrial fibrosis, and TGF-β indicators, as well as atrial dysfunction.

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