Transvenous lead extraction: Experience of the Tandem approach.

AIMS: Transvenous lead extraction (TLE) is important in the management of cardiac implantable electronic devices but carries risk. It is most commonly completed from the superior access, often with 'bail-out' support via the femoral approach. Superior and inferior access may be used in tandem, which has been proposed as an advance in safety and efficacy. The aim of this study is to evaluate the safety and efficacy of the Tandem approach. METHOD: The 'Tandem' procedure entailed grasping of the targeted lead in the right atrium to provide countertraction as a rotational dissecting sheath was advanced over the lead from the subclavian access. Consecutive 'Tandem' procedures performed by a single operator between December 2020 and March 2023 in a single large-volume TLE centre were included and compared with the conventional superior approach (control) using 1:1 propensity score matching; patients were statistically matched for demographics. RESULTS: The Tandem in comparison with the conventional approach extracted leads of much greater dwell time (148.9 ± 79 vs. 108.6 ± 77 months, P < 0.01) in a shorter procedure duration (96 ± 36 vs. 127 ± 67 min, P < 0.01) but requiring more fluoroscopy (16.4 ± 10.9 vs. 10.8 ± 14.9 min, P < 0.01). The Tandem and control groups had similar clinical (100% vs. 94.7%, P = 0.07) and complete (94.8% vs. 92.8%, P = 0.42) success, with comparable minor (4% vs. 6.7%, P = 0.72) and major (0% vs. 4%, P = 0.25) complications; procedural (0% vs. 1.3%, P = 1) and 30-day (1.3% vs. 4%, P = 0.62) mortality were also similar. CONCLUSION: The Tandem procedure is as safe and effective as the conventional TLE. It can be applied to leads of a long dwell time with a potentially shorter procedure duration.

Comparison of non-laser and laser transvenous lead extraction: a systematic review and meta-analysis.

AIMS: Transvenous lead extraction (TLE) is performed using non-laser and laser techniques with overall high efficacy and safety. Variation in outcomes between the two approaches does exist with limited comparative evidence in the literature. We sought to compare non-laser and laser TLE in a meta-analysis. METHODS AND RESULTS: We searched Medline, Embase, Scopus, ClinicalTrials.gov, and CENTRAL databases for TLE studies published between 1991 and 2021. From the included 68 studies, safety and efficacy data were carefully evaluated and extracted. Aggregated cases of outcomes were used to calculate odds ratio (OR), and pooled rates were synthesized from eligible studies to compare non-laser and laser techniques. Subgroup comparison of rotational tool and laser extraction was also performed. Non-laser in comparison with laser had lower procedural mortality (pooled rate 0% vs. 0.1%, P < 0.01), major complications (pooled rate 0.7% vs. 1.7%, P < 0.01), and superior vena cava (SVC) injury (pooled rate 0% vs. 0.5%, P < 0.001), with higher complete success (pooled rate 96.5% vs. 93.8%, P < 0.01). Non-laser comparatively to laser was more likely to achieve clinical [OR 2.16 (1.77-2.63), P < 0.01] and complete [OR 1.87 (1.69-2.08), P < 0.01] success, with a lower procedural mortality risk [OR 1.6 (1.02-2.5), P < 0.05]. In the subgroup analysis, rotational tool compared with laser achieved greater complete success (pooled rate 97.4% vs. 95%, P < 0.01) with lower SVC injury (pooled rate 0% vs. 0.7%, P < 0.01). CONCLUSION: Non-laser TLE is associated with a better safety and efficacy profile when compared with laser methods. There is a greater risk of SVC injury associated with laser sheath extraction.

Anatomical variations in coronary venous drainage: Challenges and solutions in delivering cardiac resynchronization therapy.

AIMS: To investigate the abnormalities of the coronary venous system in candidates for cardiac resynchronization therapy (CRT) and describe methods for circumventing the resulting difficulties. METHODS: From four implanting institutes, data of all CRT implants between October 2008 and October 2020 were screened for abnormal cardiac venous anatomy, defined as an anatomical variation not conforming to the accepted 'normal' anatomy. Patient demographics, procedural detail, and subsequent left ventricle (LV) lead pacing indices were collected. RESULTS: From a total of 3548 CRT implants, 15 (0.42%) patients (80% male) of 72.2 ± 10.6 years in age with an LV ejection fraction of 34 ± 10.3% were identified to have had an abnormal cardiac venous anatomy over the study period. There were 13 cases of persistent left side superior vena cava (pLSVC), five of which had coronary sinus ostium atresia (CSOA) including two with an "unroofed" coronary sinus (CS); one patient had a unique anomalous origin of the CS and one patient had an isolated CSOA. In total 14 patients (60% repeat attempt) had successful percutaneous implant under general anesthesia (46.7%) via the cephalic vein (59.1%), using the femoral approach (53.3%) for levophase venography and/or pull-through, including one case of endocardial LV implant. Pacing follow-up over 37.64 ± 37.6 months demonstrated LV lead threshold between 0.62 and 2.9 volts (pulsewidth 0.4-1.5 ms) in all cases; five patients died within 2.92 ± 1.6 years of a successful implant. CONCLUSION: CRT devices can be implanted percutaneously even in the presence of substantial abnormalities of coronary venous anatomy. Alternative routes of venous access may be required.

A High-Cholesterol Diet Increases Toll-like Receptors and Other Harmful Factors in the Rabbit Myocardium: The Beneficial Effect of Statins.

BACKGROUND: A high-cholesterol diet (HCD) induces vascular atherosclerosis through vascular inflammatory and immunological processes via TLRs. The aim of this study is to investigate the mRNA expression of TLRs and other noxious biomarkers expressing inflammation, fibrosis, apoptosis, and cardiac dysfunction in the rabbit myocardium during (a) high-cholesterol diet (HCD), (b) normal diet resumption and (c) fluvastatin or rosuvastatin treatment. METHODS: Forty-eight male rabbits were randomly divided into eight groups (n = 6/group). In the first experiment, three groups were fed with HCD for 1, 2 and 3 months. In the second experiment, three groups were fed with HCD for 3 months, followed by normal chow for 1 month and administration of fluvastatin or rosuvastatin for 1 month. Control groups were fed with normal chow for 90 and 120 days. The whole myocardium was removed; total RNA was isolated from acquired samples, and polymerase chain reaction, reverse transcription PCR and quantitative real-time PCR were performed. RESULTS: mRNA of TLRs 2, 3, 4 and 8; interleukin-6; TNF-a; metalloproteinase-2; tissue inhibitor of metalloproteinase-1; tumor protein 53; cysteinyl aspartate specific proteinase-3; and brain natriuretic peptide (BNP) increased in HCD. Statins but not resumption of a normal diet decreased levels of these biomarkers and increased levels of antifibrotic factors. CONCLUSIONS: HCD increases the levels of TLRs; inflammatory, fibrotic and apoptotic factors; and BNP in the rabbit myocardium. Atherogenic diets adversely affect the myocardium at a molecular level and are reversed by statins.

Wenckebach cycle length: A novel predictor for AV block in AVNRT patients treated with ablation.

BACKGROUND: Radiofrequency catheter ablation remains the most effective management option for atrioventricular nodal reentry tachycardia (AVNRT). The risk of atrioventricular (AV) block requiring permanent pacemaker is substantial, but, currently, a reliable method to predict this complication is lacking. METHODS: The electrophysiologic studies (EPS) and baseline characteristics of patients who underwent catheter ablation for the treatment of AVNRT were retrospectively analyzed to investigate predisposing factors for AV block after treatment. Patients were followed for AV block at one month and one year after hospital discharge. RESULTS: Among 784 patients treated with catheter ablation for AVNRT between 1999 to 2019, 15 developed AV block. Patients with AV block were older (p = .001). Among the recorded EPS parameters, patients with AV block had significantly higher Atrial His interval (120 vs. 110 ms, p = .049), Wenckebach cycle length (WCL) (400 vs. 353 ms, p < .001) and tachycardia CL (400 vs. 387 ms, P = .01) during the ablation compared to their peers without AV block. Additionally, only WCL (OR = 1.1, 95% CI 1.02-1.19, p = .017) remained significant after adjustment for age, gender, ERP, AH interval, and HR. This association was confirmed by comparing patients with (n = 15) and without (n = 15) AV block using propensity score-matching. A WCL≥400ms was associated with a 4-fold higher incidence of AV block (4.79% vs. 1.25%). CONCLUSION: Increased pre-procedural WCL was associated with a high risk for AV block after catheter ablation treatment for AVNRT. These findings suggest that this readily available EPS-derived parameter may be a novel marker of risk for severe complications in these patients.

Prevalence of bradyarrhythmias needing pacing in COVID-19.

BACKGROUND: The Sars-Cov-2 infection is a multisystem illness that can affect the cardiovascular system. Tachyarrhythmias have been reported but the prevalence of bradyarrhythmia is unclear. Cases have been described of transient high-degree atrioventricular (AV) block in COVID-19 that were managed conservatively. METHOD: A database of all patients requiring temporary or permanent pacing in two linked cardiac centers was used to compare the number of procedures required during the first year of the pandemic compared to the corresponding period a year earlier. The database was cross-referenced with a database of all patients testing positive for Sars-Cov-2 infection in both institutions to identify patients who required temporary or permanent pacing during COVID-19. RESULTS: The number of novel pacemaker implants was lower during the COVID-19 pandemic than the same period the previous year (540 vs. 629, respectively), with a similar proportion of high-degree AV block (38.3% vs. 33.2%, respectively, p = .069). Four patients with the Sars-Cov-2 infection had a pacemaker implanted for high-degree AV block, two for sinus node dysfunction. Of this cohort of six patients, two succumbed to the COVID-19 illness and one from non-COVID sepsis. Device interrogation demonstrated a sustained pacing requirement in all cases. CONCLUSION: High-degree AV block remained unaltered in prevalence during the COVID-19 pandemic. There was no evidence of transient high-degree AV block in patients with the Sars-Cov-2 infection. Our experience suggests that all clinically significant bradyarrhythmia should be treated by pacing according to usual protocols regardless of the COVID status.

Tissue-specific relaxin-2 is differentially associated with the presence/size of an arterial aneurysm and the severity of atherosclerotic disease in humans.

Circulating or tissue-related biomarkers are of clinical value for risk stratification in patients with abdominal aortic aneurysms. Relaxin-2 (RL2) has been linked to the presence and size of arterial aneurysms, and to the extent of atherosclerosis in human subjects. Here, we assessed the expression levels of RL2 in aneurysmal (AA, n = 16) and atherosclerotic (ATH, n = 22) arteries, and established the correlation between RL2 levels and the presence/size of AA and the clinical severity of atherosclerosis. The expression levels of metalloproteinases (MMPs) and endothelial nitric oxide synthetase (eNOS) were also detected for correlations with different phenotypes of atherosclerosis and AA. Temporal artery biopsy specimens (n = 6) and abdominal aortic tissues harvested from accident victims during autopsy (n = 10) were used as controls. Quantitative tissue biomarker analysis revealed that tissue-specific RL2 was increased in patients with larger or symptomatic AA compared to subjects with atherosclerotic disease and healthy controls. In situ RL2 levels were proportional to the size and the severity of aneurysmatic disease, and were substantially elevated in patients with symptomatic aneurysm of any diameter or asymptomatic aneurysm of a diameter >350% of that of the normal artery. In contrast, tissue RL2 was inversely associated with the clinical severity of atherosclerotic lesions. Correlation between RL2 and MMP2 was different between ATH1 and ATH2, depending on atherosclerosis grade. Overall, tissue RL2 is differentially associated with discrete phenotypes of arterial disease and might exert multipotent biological effects on vascular wall integrity and remodeling in human subjects.

Differential expression patterns of Toll Like Receptors and Interleukin-37 between calcific aortic and mitral valve cusps in humans.

BACKGROUND: Significant differences are mentioned in the progress of calcification between aortic and mitral valve. Evidence of inflammation in calcific aortic and mitral valve disease suggests that pathways of Toll Like Receptors (TLR) and Interleukin (IL)-37 expression may contribute to this process. We sought to investigate the role of TLR-mediated inflammatory response and IL-37 pathway expression on aortic and mitral valve calcification. MATERIAL AND METHODS: One-hundred twenty stenotic valve cusps/leaflets (60 aortic, 60 mitral) were excised during surgery and were collected for histological, immunohistochemistry and morphometric analysis at our department. After total RNA isolation from a second part of valve cusps/leaflets, cDNA synthesis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) protocols were performed and relative mRNA levels of target genes were assessed. RESULTS: By histological analysis, the anti-inflammatory IL-37 levels were increased in mitral valve leaflets (MVL) compared to aortic valve cusps (AVCu) while all other biomarkers, including TLR, presented a reverse pattern with decreased levels as compared to AVCu. In terms of calcification biomarkers, only osteopontin differed between AVCu and MVL. mRNA analysis confirmed increased expression of IL-37 and decreased levels of TLR in MVL compared to AVCu. CONCLUSIONS: Stenotic cusps of aortic valves express lower IL-37 and increased TLRs levels than stenotic mitral valve leaflets, suggesting a differential pro-calcification and pro-inflammatory profile between the two valves. This may explain the higher incidence of calcification of AVCu than MVL and offer therapeutic considerations.

Stronger correlation with myocardial ischemia of high-sensitivity troponin T than other biomarkers.

BACKGROUND: Acute myocardial infarction (AMI) is considered a major cause of death and disability. Myocardial perfusion scintigraphy (MPS) as a non-invasive diagnostic imaging procedure and certain biomarkers associated with myocardial ischemia (ISCH), such as ischemia-modified albumin (IMA), neuropeptide Y (NPY), N-terminal pro b-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTnT) could probably aid in the detection of myocardial infarction. METHODS: Between December 2011 and June 2012, we prospectively analyzed patients who underwent a MPS study with the clinical question of myocardial ISCH. An exercise test was performed along with a MPS. Blood was drawn from the patients before exercise and the within 3 minutes from achieving maximum load and was analyzed for the aforementioned biomarkers. RESULTS: A total of 71 patients (56 men and 15 women) were enrolled with a mean age of 61 ± 12 years. Twenty-six patients (36.6%) showed reduced uptake on stress MPS images that normalized at rest, a finding consistent with ISCH. Between ISCH and non-ISCH groups, only hsTnT levels showed a significant difference with the highest levels pertaining to the former group both before (0.0075 ng/ml vs 0.0050 ng/ml, P = 0.023) and after stress exercise (0.0085 vs 0.0050, P = 0.015). The most prominent differences were seen in higher stages of the Bruce protocol (stress duration > 9.05 minutes - P < 0.017). None of the IMA, NPY, and NP-pro BNP showed significant differences in time between the two groups. CONCLUSIONS: Although IMA, NPY, and NT-pro BNP may not detect minor ischemic myocardial insults, serum hsTnT holds a greater ability of detecting not only myocardial infarction but also less severe ischemia. Further studies with larger cohorts of patients are warranted in order to better define the role of hsTnT as a screening tool for myocardial ischemia.

Electrical Storm: Current Evidence, Clinical Implications, and Future Perspectives.

PURPOSE OF REVIEW: Electrical storm (ES) is a life-threatening medical emergency of repetitive episodes of sustained ventricular arrhythmias within a short period. Its occurrence is associated with poor short- and long-term survival, even in patients with implantable cardioverter defibrillators (ICD). Management of ES is challenging and mainly based on retrospective studies. This article reviews the existing literature on ES, presents the available data regarding its management, and proposes a new algorithm based on current evidence. RECENT FINDINGS: Recent research could modify the management of ES supporting the role of non-selective ß1 and ß2 blockade and the early intervention with catheter ablation as well as strengthening the role of cardiac sympathetic denervation. A multipronged approach should be considered for the management of ES including identification and correction of reversible causes, ICD reprogramming, drug therapy (beta-blockers-especially non-selective ones-and other anti-arrhythmic drugs) and non-pharmacologic therapies such as catheter ablation and techniques of neuroaxial modulation. Although current data suggest early aggressive management, further research is required to clarify the optimal order and combination of therapies for the prevention of future events.

Repetitive-incessant electrical storm triggered by early repolarization.

Early repolarization syndrome (ERS) was originally considered a normal variant with benign outcome. However, recent studies have demonstrated that it can be linked to a considerable risk of life-threatening arrhythmias and sudden cardiac death. We report a case with an extraordinary, extremely malignant clinical expression of ERS refractory to all antiarrhythmic drugs including quinidine. This case demonstrates real-time changes of dynamic electrocardiogram (ECG) preceding a polymorphic ventricular tachycardia (VT)-ventricular fibrillation (VF) and possible external factors triggering arrhythmia onset. Implantable cardioverter-defibrillator (ICD) function was terminated 6 months after implantation due to multiple-incessant electrical storm (ES). Catheter ablation was the definite treatment of this malignant entity.

Endovascular Repair of Blunt Thoracic Aortic Trauma: Is Postimplant Hypertension an Incidental Finding?

BACKGROUND: Blunt thoracic aortic injury (BTAI) is the second most common cause of death in trauma patients. Nowadays, thoracic endovascular aortic repair (TEVAR) has become the treatment of choice because of lower rates of mortality, paraplegia, and stroke. However, concerns have been raised whether graft implantation is related to the development of hypertension in the postoperative period. The aim of this study was to report short- and long-term outcomes of patients undergoing TEVAR for BTAIs at a tertiary hospital and to investigate postimplant hypertension. METHODS: Between January 2005 and January 2016, 23 patients with blunt thoracic aortic trauma underwent TEVAR. Median age was 44 years (range, 18-73). Among them, 14 (60.9%) patients were diagnosed with aortic rupture, whereas 9 (39.1%) with pseudoaneurysm. Α single thoracic stent graft was deployed in 21 patients, and the rest 2 patients received 2 stent grafts. RESULTS: Complete exclusion of the injury was feasible in all subjects (100% primary success). The left subclavian artery (SCA) was intentionally covered in 6 patients (26%). Intraoperative complications included one nonfatal stroke managed conservatively and one external iliac artery rupture treated with iliofemoral bypass. One patient (4.3%) died on the first postoperative day in the intensive care unit (ICU) because of hemorrhagic shock. The overall 30-day mortality and morbidity were 4.3% and 8.7%, respectively. New-onset postimplantation arterial hypertension was observed in 8 (34.8%) previously nonhypertensive patients. Younger age (P = 0.027) and SCA coverage (P = 0.01) were identified as potential risk factors for the development of postimplant hypertension, whereas the presence of concomitant injuries (P = 0.3) and intraoperative complications (P = 0.1) were not. After a median follow-up of 100 months (range, 18-120), 6 of them still remain on antihypertensive therapy, whereas the other 2 did not require permanent treatment. CONCLUSIONS: TEVAR is a safe approach in the treatment of BTAI associated with low short- and long-term morbidity and mortality rates. Lower age and SCA coverage may contribute to the development of postimplant hypertension. Further larger cohort studies are warranted to elucidate the underlying mechanisms of postimplant hypertension.

Anticoagulation in Patients with Atrial High-rate Episodes Detected by Cardiac Implantable Electronic Devices.

Atrial high-rate episodes (AHRE) are atrial tachyarrhythmias that are identified by the use of continuous rhythm monitoring devices such as pacemakers, defibrillators, or implantable cardiac monitors. Nevertheless, the therapeutic implications of these rhythm disturbances remain uncertain. The presence of AHRE is associated with an increased risk of stroke as compared to patients who do not exhibit AHRE. The utilisation of oral anticoagulation has the ability to mitigate the likelihood of stroke occurrence in patients with AHRE. However, it is important to note that this treatment approach is also linked to a severe bleeding rate of approximately 2% per year. The stroke rate among individuals diagnosed with AHRE appears to be comparatively lower when compared to patients diagnosed with atrial fibrillation. The efficacy and safety of anticoagulation in patients with AHRE have yet to be definitively established. Further research is required to provide a comprehensive understanding of the effectiveness and safety of oral anticoagulation in individuals with AHRE.

Tissue and Serum Biomarkers in Degenerative Aortic Stenosis-Insights into Pathogenesis, Prevention and Therapy.

BACKGROUND AND AIM: Degenerative Aortic Stenosis (DAS) is a common disease that causes substantial morbidity and mortality worldwide, especially in the older population. Our aim was to further investigate novel serum and tissue biomarkers to elucidate biological processes involved in this entity. MATERIAL AND METHODS: We evaluated the expression of six biomarkers significantly involved in cardiovascular pathology, i.e., irisin, periostin, osteoglycin, interleukin 18, high mobility group box 1 and proprotein convertase subtilisin/kexin type 9 in the serum at the protein level, and in the tissue at both the protein and mRNA levels of patients with AS (N = 60). Five normal valves obtained after transplantation from hearts of patients with idiopathic dilated cardiomyopathy were also studied. Serum measurements were also performed in 22 individuals without valvular disease who served as controls (C). RESULTS: Higher levels of all factors were found in DAS patients' serum than in normal C. IHC and PCR mRNA tissue analysis showed the presence of all biomarkers in the aortic valve cusps with DAS, but no trace of PCR mRNA was found in the five transplantation valves. Moreover, periostin serum levels correlated significantly with IHC and mRNA tissue levels in AS patients. CONCLUSION: We showed that six widely prevalent biomarkers affecting the atherosclerotic process were also involved in DAS, suggesting a strong osteogenic and pro-inflammatory profile, indicating that aortic valve calcification is a multifactorial biological process.

Progress in Cardiac Resynchronisation Therapy and Optimisation.

Cardiac resynchronisation therapy (CRT) has become the cornerstone of heart failure (HF) treatment. Despite the obvious benefit from this therapy, an estimated 30% of CRT patients do not respond ("non-responders"). The cause of "non-response" is multi-factorial and includes suboptimal device settings. To optimise CRT settings, echocardiography has been considered the gold standard but has limitations: it is user dependent and consumes time and resources. CRT proprietary algorithms have been developed to perform device optimisation efficiently and with limited resources. In this review, we discuss CRT optimisation including the various adopted proprietary algorithms and conduction system pacing.

Coronary Caverns: Spontaneous Recanalized Chronic Total Occlusion With Multiple Microchannels.

Spontaneous chronic total occlusion recanalization is rare. It has scarcely been described previously and with minimal visual detail. Optical coherence tomography permitted comprehensive visualization of the microchannels in this case, seldom seen previously. With Thrombolysis in Myocardial Infarction 3 flow in the affected vessel via these patent channels, optimal medical therapy may be an appropriate strategy.

Arrhythmias in Chronic Kidney Disease.

Arrhythmias cause disability and an increased risk of premature death in the general population but far more so in patients with renal failure. The association between the cardiac and renal systems is complex and derives in part from common causality of renal and myocardial injury from conditions including hypertension and diabetes. In many cases, there is a causal relationship, with renal dysfunction promoting arrhythmias and arrhythmias exacerbating renal dysfunction. In this review, the authors expand on the challenges faced by cardiologists in treating common and uncommon arrhythmias in patients with renal failure using pharmacological interventions, ablation and cardiac implantable device therapies. They explore the most important interactions between heart rhythm disorders and renal dysfunction while evaluating the ways in which the coexistence of renal dysfunction and cardiac arrhythmia influences the management of both.

Economic Evaluation of Catheter Ablation Versus Medical Therapy for the Treatment of Atrial Fibrillation from the Perspective of the UK.

Randomised evidence supports an early rhythm control strategy as treatment for AF, and catheter ablation outperforms medical therapy in terms of effectiveness when studied as first- and second-line treatment. Despite evidence consistently showing that catheter ablation treatment is superior to medical therapy in most AF patients, only a small proportion receive ablation, in some cases after a prolonged trial of ineffective medical therapy. Health economics research in electrophysiology remains limited but is recognised as being important in influencing positive change to ensure early access to ablation services for all eligible patients. Such information has informed the updated recommendations from the recently published National Institute for Health and Care Excellence clinical guideline on the diagnosis and management of AF, but increased awareness is needed to drive real-world adoption and to ensure patients are quickly referred to specialists. In this article, economic evaluations of catheter ablation versus medical therapy are reviewed.

The Complex Relationship Between Diabetes and Cardiac Arrhythmias: Pathophysiology and Mechanisms.

Coronary artery disease, autonomic neuropathy, and diabetic cardiomyopathy are the most common cardiovascular complications of diabetes. However, emerging evidence demonstrates that diabetes also affects the heart's electrical conduction system, culminating in lethal arrhythmias and sudden cardiac death. Diabetes and rhythm disturbances have a complex relationship, and arrhythmias cannot only be attributed to ischemia and autonomic neuropathy. Hypoglycemia, hyperglycemia, and glucose fluctuations can potentially induce arrhythmias by activating various pathways. Structural remodeling can accelerate and exacerbate disease development. Mitochondrial dysfunction can also alter the structure and metabolism of cardiomyocytes and contribute to disease progression through oxidative stress and inflammation.