Stress-Mediated Abnormalities in Regional Myocardial Wall Motion in Young Women with a History of Psychological Trauma.

BACKGROUND: Psychosocial stress has been associated with the development and progression of atherosclerotic cardiovascular disease (CVD). Previously, we reported subtle differences in global longitudinal strain in somatically healthy women with a psychiatric diagnosis of borderline personality disorder (BPD). This study aimed to investigate the impact of BPD on segmental myocardial wall motion using speckle tracking echocardiography (STE) analysis. METHODS: A total of 100 women aged between 18 and 38 years were included in this study. Fifty patients meeting the diagnostic criteria for BPD were recruited from the Department of Psychiatry (LWL-University Hospital Bochum) and compared with fifty age-matched healthy control subjects without previous cardiac disease. Laboratory tests and STE were performed with segmental wall motion analysis. RESULTS: The BPD group had a higher prevalence of risk factors for CVD, with smoking and obesity being predominant, when compared with the control group. Other cardiovascular parameters such as blood pressure, glucose, and cholesterol levels were also elevated, even though not to pathological values. Moreover, in the STE analysis, the BPD group consistently exhibited decreased deformation in nine myocardial wall regions compared with the control group, along with a shift toward higher values in the distribution of peak pathological segments. Additionally, significantly higher values of free thyroxine concentration and thyroid's secretory capacity were observed in the BPD group, despite falling within the (high-) normal range. CONCLUSIONS: BPD is associated with chronic stress, classical risk factors, and myocardial wall motion abnormalities. Further exploration is warranted to investigate the relationship between high-normal thyroid metabolism, these risk factors, and myocardial function in BPD patients. Long-term follow-up studies would be valuable in confirming the potential for predicting adverse events.

[Echocardiography in cardiac arrhythmias]. / Echokardiographie in der Rhythmologie.

Echocardiography plays a key role in planning and guidance of electrophysiological procedures. After exclusion of structural heart disease, echocardiography provides insight into the extent of left atrial remodeling by determining left atrial metrics. This "biomarker" is associated with the risk of new-onset atrial fibrillation and predictive of atrial fibrillation recurrence after ablation. Transesophageal echocardiography is necessary to exclude left atrial thrombi and is able to guide a transseptal puncture. In case of a rare but life-threatening cardiac tamponade, an echocardiographic-guided pericardiocentesis ensures quick and effective treatment. Left ventricular ejection fraction and deformation analysis determined by echocardiography are established methods for risk stratification in patients with systolic dysfunction and used to guide pharmacological and device therapy.

Mortality rates of severe COVID-19-related respiratory failure with and without extracorporeal membrane oxygenation in the Middle Ruhr Region of Germany.

The use of extracorporeal membrane oxygenation (ECMO) is discussed to improve patients' outcome in severe COVID-19 with respiratory failure, but data on ECMO remains controversial. The aim of the study was to determine the characteristics of patients under invasive mechanical ventilation (IMV) with or without veno-venous ECMO support and to evaluate outcome parameters. Ventilated patients with COVID-19 with and without additional ECMO support were analyzed in a retrospective multicenter study regarding clinical characteristics, respiratory and laboratory parameters in day-to-day follow-up. Recruitment of patients was conducted during the first three COVID-19 waves at four German university hospitals of the Ruhr University Bochum, located in the Middle Ruhr Region. From March 1, 2020 to August 31, 2021, the charts of 149 patients who were ventilated for COVID-19 infection, were included (63.8% male, median age 67 years). Fifty patients (33.6%) received additional ECMO support. On average, ECMO therapy was initiated 15.6 ± 9.4 days after symptom onset, 10.6 ± 7.1 days after hospital admission, and 4.8 ± 6.4 days after the start of IMV. Male sex and higher SOFA and RESP scores were observed significantly more often in the high-volume ECMO center. Pre-medication with antidepressants was more often detected in survivors (22.0% vs. 6.5%; p = 0.006). ECMO patients were 14 years younger and presented a lower rate of concomitant cardiovascular diseases (18.0% vs. 47.5%; p = 0.0004). Additionally, cytokine-adsorption (46.0% vs. 13.1%; p < 0.0001) and renal replacement therapy (76.0% vs. 43.4%; p = 0.0001) were carried out more frequently; in ECMO patients thrombocytes were transfused 12-fold more often related to more than fourfold higher bleeding complications. Undulating C-reactive protein (CRP) and massive increase in bilirubin levels (at terminal stage) could be observed in deceased ECMO patients. In-hospital mortality was high (Overall: 72.5%, ECMO: 80.0%, ns). Regardless of ECMO therapy half of the study population deceased within 30 days after hospital admission. Despite being younger and with less comorbidities ECMO therapy did not improve survival in severely ill COVID-19 patients. Undulating CRP levels, a massive increase of bilirubin level and a high use of cytokine-adsorption were associated with worse outcomes. In conclusion, ECMO support might be helpful in selected severe cases of COVID-19.

Altered Left Ventricular Myocardial Deformation in Young Women With Borderline Personality Disorder: An Echocardiographic Study.

OBJECTIVE: Borderline personality disorder (BPD) is characterized by intense mood swings, impulsivity, self-injurious behavior, poor anger control, fear of abandonment, and unstable interpersonal relationships. BPD is also associated with a heightened risk of cardiovascular disease, whereby the underlying mechanisms are insufficiently understood. Accordingly, the present study set out to examine whether individuals with BPD would show abnormal myocardial deformation and to explore the role of potential risk factors, including maladaptive stress responsivity, childhood trauma, and current stress exposure. METHODS: Fifty female patients diagnosed with BPD and 50 controls matched for sex and age underwent echocardiography to determine the global longitudinal strain (GLS) of the left ventricle. In addition, childhood trauma, chronic stress, and "allostatic load" were determined, as well as borderline symptom severity and common risk factors for cardiovascular disease. RESULTS: Aside from a significantly greater GLS in BPD patients, a multivariable regression analysis revealed that allostatic load (ß = 0.225, p = .048) was significantly associated with GLS, with childhood trauma (ß = 0.279, p = .062) approaching significance. Conversely, smoking (p = .867), chronic stress (p = .193), and borderline symptom severity (p = .342) were not associated with GLS, even though bivariate correlations were significant. CONCLUSIONS: Somatically healthy women with BPD display subtle signs of increased GLS, which is associated with allostatic load as an indicator of the "wear-and-tear" of the body. The association between childhood trauma with GLS was of similar strength but did not reach the threshold for statistical significance. This finding may support the need for primary prevention of somatic consequences of maladaptive stress responsivity in psychiatric patients.

Outcomes after transcatheter aortic valve replacement in older patients.

BACKGROUND: The prevalence of aortic valve stenosis is increasing due to the continuously growing geriatric population. Data on procedural success and mortality of very old patients are sparse, raising the question of when this population may be deemed as "too old even for transcatheter aortic valve replacement (TAVR)." We, therefore, sought to evaluate the influence of age on outcome after TAVR and the impact of direct implantation. METHODS: The data of 394 consecutive patients undergoing TF-TAVR were analyzed. Patients were divided into four age groups: ≤75 (group 1, n = 28), 76-80 (group 2, n = 107), 81-85 (group 3, n = 148), and >85 (group 4, n = 111) years. Direct implantation was performed when possible according to current recommendations. Survival was evaluated by Kaplan-Meier analysis. RESULTS: Mortality at 30 days and 1 year was not significantly different between the four age groups (3.6 vs. 6.7 vs. 5.4 vs. 2.7% and 7.6 vs. 17 vs. 14.5 vs. 13%m respectively, log-rank p = 0.59). Direct implantation without balloon aortic valvuloplasty was more frequently performed on patients aged >85 vs. ≤85 years (33.3 vs. 14.1%, p < 0.001). the incidence of procedural complications frequently associated with advanced age (stroke, vascular complications) was not significantly increased in group 4. CONCLUSION: Outcome after TF-TAVR is comparable among different age cohorts, even in very old patients. Direct implantation simplifies the procedure and could therefore play a role in reducing the incidence of peri-interventional complications in patients of advanced age.

Multipoint left ventricular pacing with large anatomical separation improves reverse remodeling and response to cardiac resynchronization therapy in responders and non-responders to conventional biventricular pacing.

BACKGROUND: Multipoint pacing [Multipoint™ Pacing (MPP), Abbott] via a single left ventricular lead (Quartet™ LV lead, Abbott) improves acute left ventricular (LV) function and response to cardiac resynchronization therapy (CRT). Aim of this study was to examine additional benefits in terms of LV reverse remodeling and CRT response by activating MPP in responders and non-responders to conventional biventricular pacing (CONV). METHODS: 43 consecutive patients receiving CRT (Quadra Assura MP™, Abbott) received LV dP/dtmax optimized CONV programming for 6 months. MPP programming with large anatomical electrode separation (> 30 mm) and basal LV1 pacing location was activated afterwards. Echocardiographic and clinical parameters were obtained at baseline, 6- and 12-month follow-up (FU). The response was defined as an improvement of LVESV ≥ 15% and super-response as improvement ≥ 30% relative to baseline. RESULTS: 41 patients completed FU (one died of non-cardiac cause and one was lost to FU) and after 6 months CONV, 26 patients (63%) were classified as CRT responders. With MPP, the response rate increased to 90% (p < 0.001). Super-response also improved significantly with MPP compared to CONV (71% vs. 22%; p < 0.005). LV reverse remodeling in terms of LVESV improved significantly with MPP compared to CONV (79 ± 45 ml vs. 103 ± 64 ml; p < 0.001). NYHA-class only improved significantly with CONV relative to baseline (1,8 ± 0,7 vs. 2,7 ± 0,5; p < 0.001), but not further with MPP (1,7 ± 0,6 vs. 1,8 ± 0,7; p = 0.49). CONCLUSION: Multipoint pacing significantly improves response and super-response to CRT as well as LV reverse remodeling compared to conventional biventricular pacing.

One-year outcome of percutaneous mitral valve repair in patients with severe symptomatic mitral valve regurgitation.

AIM: To investigate one-year outcomes after percutaneous mitral valve repair with MitraClip® in patients with severe mitral regurgitation (MR). METHODS Our study investigated consecutive patients with symptomatic severe MR who underwent MitraClip® implantation at the University Hospital Bergmannsheil from 2012 to 2014. The primary study end-point was all-cause mortality. Secondary end-points were degree of MR and functional status after percutaneous mitral valve repair. RESULTS: The study population consisted of 46 consecutive patients (mean logistic EuroSCORE 32% ± 21%). The degree of MR decreased significantly (severe MR before MitraClip® 100% vs after MitraClip® 13%; P < 0.001), and the NYHA functional classes improved (NYHA III/IV before MitraClip® 98% vs after MitraClip® 35%; P < 0.001). The mortality rates 30 d and one year after percutaneous mitral valve repair were 4.3% and 19.5%, respectively. During the follow-up of 473 ± 274 d, 11 patients died (90% due to cardiovascular death). A pre-procedural plasma B-type natriuretic peptide level > 817 pg/mL was associated with all-cause mortality (hazard ratio, 6.074; 95%CI: 1.257-29.239; P = 0.012). CONCLUSION: Percutaneous mitral valve repair with MitraClip® has positive effects on hemodynamics and symptoms. Despite the study patients' multiple comorbidities and extremely high operative risk, one-year outcomes after MitraClip® are favorable. Elevated B-type natriuretic peptide levels indicate poorer mid-term survival.

Initial Experience With Novel Oral Anticoagulants During the First 45 Days After Left Atrial Appendage Closure With the Watchman Device.

BACKGROUND: The use of oral anticoagulation or dual antiplatelet therapy (DAPT) is recommended within the first 45 days after left atrial appendage (LAA) closure using the Watchman device because of incomplete device endothelialization. This study reports for the first time the feasibility of novel oral anticoagulants (NOAC) in these patients. HYPOTHESIS: NOAC therapy is safe and effective after LAA closure. METHODS: Interventional LAA closure was performed successfully in 45 patients. Of these, 18 patients received NOAC during the first 45 days after implantation and 27 patients received DAPT. Transesophageal echocardiography was conducted 45 days after implantation. The primary study endpoint was abnormal thrombus apposition 45 days after implantation. Secondary study endpoints were death from any cause, major adverse cardiac and cerebrovascular events (MACCE), and major bleedings. RESULTS: After 45 days, transesophageal echocardiography revealed no abnormal thrombus apposition. During a follow-up of 417 ± 323 days, 7 patients died. No stroke or transient ischemic attack occurred. Nonfatal myocardial infarction occurred in 1 patient. There was a nonsignificant trend for lower all-cause mortality (P = 0.159) and occurrence of MACCE (P = 0.096) in the NOAC group compared with the DAPT group. Overall, 6 patients suffered from a major bleeding (NOAC, n = 3; DAPT, n = 3). In NOAC group, major bleedings (at day 205, 688, and 736) occurred long after termination of NOAC therapy. There was no significant difference in the frequency of major bleedings in different groups. CONCLUSIONS: Our pilot study suggests that NOAC therapy within the first 45 days after interventional LAA closure is safe and effective.

Impact of lung diseases on morbidity and mortality after transcatheter aortic valve implantation: insights from spirometry and body plethysmography.

BACKGROUND: The study aims to determine the impact of different lung diseases on morbidity and mortality after transcatheter aortic valve implantation (TAVI). METHODS: Transcatheter aortic valve implantation was performed transfemoral or transaxillary with CoreValve prosthesis or Edwards SAPIEN prosthesis in patients with symptomatic severe aortic valve stenosis and high surgical risk. Examinations comprised spirometry, body plethysmography echocardiography, and x-ray before TAVI. The primary study end point was death from any cause after TAVI. RESULTS: During follow-up of 750 ± 538 days, 63 of 212 patients died. Logistic European System for Cardiac Operative Risk Evaluation (hazard risk [HR] 1.032, P < .001), aortic mean gradient (HR 0.96, P < .001), chronic obstructive pulmonary disease (COPD; each degree of COPD: HR 1.436, P = .001), restrictive ventilatory disease (HR 2.252, P = .002), oxygen dependency (HR 3.291, P = .004), and noninvasive ventilation (HR 3.799, P = .005) were independent predictors of long-term mortality. Restrictive ventilatory disease was associated with lower left ventricular ejection fraction, higher B-type natriuretic peptide levels, and pulmonary edema. CONCLUSION: In patients undergoing TAVI, lung diseases are an independent predictor of all-cause mortality. In particular, oxygen dependency patients and patients with severe COPD and noninvasive ventilation indicate a dismal prognosis. Transcatheter aortic valve implantation seems to have a dubious prognostic benefit in these patients.

Three-year outcomes after transcatheter aortic valve implantation with the CoreValve prosthesis.

There is little known about the long-term results of the CoreValve prosthesis. The aim of this study was to assess the 3-year clinical and hemodynamic outcomes of the CoreValve prosthesis. One hundred fifty consecutive patients with severe aortic stenosis successfully underwent transcatheter aortic valve implantation (TAVI) with the CoreValve prosthesis. The primary study end point was death from any cause after TAVI. The secondary end points were defined as (1) cardiovascular death and (2) prosthesis-related mortality and morbidity. At 1 to 3 years, all-cause mortality rates were 25%, 32%, and 41%, respectively, and cardiovascular mortality rates were 14%, 21%, and 27%, respectively. Before TAVI, 95% of patients were in New York Heart Association class III or IV. Of the surviving patients, rates of New York Heart Association class III or IV at 1 to 3 years were 33%, 39%, and 38%, respectively. There was an annual decrease of the valve area of approximately 0.1 cm². Aortic restenosis occurred in 2 patients. Moderate or severe aortic regurgitation (AR) occurred in 15% of patients immediately after TAVI. Twenty patients (13%) had a slight worsening of AR within 3 years. New severe AR did not occur. The incidence of prosthesis-related endocarditis was 0.66% per year. Overall, 7 patients (incidence of 1.5% per year) had a clinically relevant problem of the prosthesis. In conclusion, TAVI with the CoreValve prosthesis had favorable effects on symptoms and outcomes even after 3 years. These results are clouded by side effects, such as AR and prosthesis-related mortality and morbidity.

Total atrial conduction time assessed by tissue doppler imaging (PA-TDI Interval) to predict early recurrence of persistent atrial fibrillation after successful electrical cardioversion.

BACKGROUND: The aim of this study was to investigate whether total atrial conduction time (TACT) assessed via tissue Doppler imaging (PA-TDI interval) can identify patients with early recurrent atrial fibrillation (ERAF) after successful direct-current electrical cardioversion (CV) of persistent atrial fibrillation (persPAF). METHODS AND RESULTS: A total of 54 patients without antiarrhythmic drug medication (mean ± SD: 66 ± 10.4 years; 33% women) with persPAF and successful CV were enrolled between May 2012 and May 2013. TACT was measured 6 hours after successful CV in the left atrium by tissue Doppler imaging (PA-TDI interval). ERAF was determined via Holter-electrocardiogram over a period of 7 days after CV. Receiver opearting characteristic analysis was used to determine an optimal cutoff value of PA-TDI interval for prognosis of ERAF. Based on this result, recurrence-free survival was assessed with Mantel-Haenszel's log-rank test. ERAF occurred in 23 patients (43%). PA-TDI interval was longer in patients with ERAF compared to those who maintained sinus rhythm (mean ± SD: 163.5 ± 11.1 vs 132.3 ± 11.2 milliseconds; P < 0.00001). At the cutoff value of 152 milliseconds, PA-TDI interval sensitivity and specificity related to ERAF were 87% and 100%, respectively. CONCLUSION: Measuring PA-TDI interval may help to predict ERAF after successful CV in patients with persAF.

B-type natriuretic peptide is a strong independent predictor of long-term outcome after transcatheter aortic valve implantation.

BACKGROUND AND AIM OF THE STUDY: The aim of this prospective study was to determine the impact of plasma B-type natriuretic peptide (BNP) on long-term outcome in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: TAVI was performed either transfemorally or transaxillary using either the CoreValve prosthesis or Edwards SAPIEN prosthesis in 226 patients with symptomatic severe aortic valve stenosis and at high surgical risk. The examinations included measurements of plasma BNP and echocardiography before and at 30 days after TAVI. The primary study end-point was death from any cause after TAVI; the secondary end-point was defined as cardiovascular death. RESULTS: During a mean follow up of 728 ± 549 days, 72 patients died; 52 deaths were cardiovascular-related. Those patients who died had higher preprocedural plasma BNP levels compared to those who survived (1,305 ± 1,238 pg/ml versus 716 ± 954 pg/ml; p < 0.001). Plasma BNP was the strongest independent predictor of all-cause mortality (BNP > 475 pg/ml, hazard risk [HR] 3.049; 95% confidence interval [CI] 1.804-5.151; p < 0.001) and cardiovascular mortality (BNP > 475 pg/ml, HR 3.479; 95% CI 1.817-6.662; p < 0.001). In surviving patients, plasma BNP levels were decreased by 30 days after TAVI (pre-TAVI 874 ± 1,122 pg/ml; post TAVI 471 ± 569 pg/ml; p < 0.001). A plasma BNP level > 328 pg/ml at 30 days postoperatively was also associated with all-cause mortality (HR 8.125; 95% CI 3.097-21.318; p < 0.001). CONCLUSION: In patients undergoing TAVI, plasma BNP is the strongest independent predictor of all-cause mortality and cardiovascular mortality. Plasma BNP levels at 30 days after TAVI may provide prognostic information that should, potentially, lead to a more intensive therapy of these patients.

Increased preoperative serum apoptosis marker fas ligand correlates with histopathology and new-onset of atrial fibrillation in patients after cardiac surgery.

BACKGROUND: We evaluated if preoperative serum apoptosis markers correlate with atrial histological remodeling and postoperative atrial fibrillation (POAF) after cardiac surgery. METHODS AND RESULTS: A total of 33 patients with sinus rhythm (SR) and without history of atrial fibrillation (AF) undergoing cardiac surgery were prospectively enrolled. Serum concentrations of Fas (apoptosis-stimulating fragment ligand) and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) were measured preoperatively. Right atrial appendage (RAA) tissue was obtained during surgery. Atrial apoptosis was assessed via TUNEL assay and degree of atrial fibrosis was categorized histologically by visual quantification. Continuous ECG-Monitoring was used to screen for POAF throughout 10 days after cardiac surgery. POAF occurred in 15 patients (45%). Atrial apoptosis was higher in patients with POAF as compared to those without (35.9 ± 9.8% vs 14.5 ± 7.5%; P < 0.0001) and correlated with the degree of atrial fibrosis (r = 0.69; P < 0.0001). In contrast to TRAIL (87.0 ± 8.2 pg/mL vs 83.3 ± 9.4 pg/mL; P = 0.77), preoperative Fas serum concentration was significantly higher in patients with POAF compared to patients in stable SR (91.3 ± 7.2 pg/mL vs 66.7 ± 3.0 pg/mL; P < 0.01). Serum Fas concentration correlated with the degree of atrial apoptosis (r = 0.63; P < 0.001) and the degree of atrial fibrosis (r = 0.39; P < 0.05). CONCLUSION: Preoperative evaluation of serum apoptosis marker Fas is useful to identify patients at risk for POAF undergoing cardiac surgery. Fas but not TRAIL correlates with the documented degree of atrial apoptosis and atrial fibrosis in RAA tissue. Further studies need to identify the prospective role of Fas in predicting POAF events.

Left atrial diameter, aortic mean gradient, and hemoglobin for risk stratification in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an alternative treatment of severe symptomatic aortic stenosis (AS) in patients with high operative risk. In spite of favorable entire results, long-term mortality of patients is high. HYPOTHESIS: The present study aims to identify independent preprocedural risk factors to improve risk stratification in these highly selected patients. METHODS: This prospective study included 202 consecutive patients with severe symptomatic AS and high operative risk (mean logistic European System for Cardiac Operative Risk Evaluation, 22±17%; mean age, 79±6 years; 107 female). Preprocedural comprehensive examinations were performed (laboratory, electrocardiography, echocardiography, cardiac catheterization). All patients received transfemoral or transaxillary TAVI with a CoreValve prosthesis (Medtronic, Minneapolis, MN). RESULTS: During a follow-up of 535±333 days, 56 patients (28%) reached the primary study end point (all-cause mortality). Independent predictors of long-term mortality were as follows: hemoglobin<12.5 g/dL (hazard risk [HR], 3.62; 95% confidence interval [CI], 2.025-6.468; P<0.001), aortic mean gradient≤41 mm Hg (HR, 2.16; 95% CI, 1.272-3.655; P=0.004), and left atrial diameter>42 mm (HR, 3.09; 95% CI, 1.588-6.019; P=0.001). Our risk-stratification model based on these independent predictors separated patients into 4 groups with high (74%), intermediate (37%), low (18%), and very low (3%) all-cause mortality. CONCLUSIONS: In patients undergoing TAVI, preprocedural assessment of hemoglobin, aortic mean gradient, and left atrial diameter provides independent prognostic information and therefore contributes to improved risk stratification in TAVI.

Correlation between total atrial conduction time estimated via tissue Doppler imaging (PA-TDI Interval), structural atrial remodeling and new-onset of atrial fibrillation after cardiac surgery.

BACKGROUND: Recent studies identified total atrial conduction time (TACT) as an independent and powerful predictor of new-onset atrial fibrillation (AF). The purpose of this study was to assess the association between the degree of atrial fibrosis, TACT, and frequency of postoperative atrial fibrillation (POAF) among patients undergoing cardiac surgery. METHODS AND RESULTS: Sixty patients in sinus rhythm (mean ± SD age 66 ± 10 years; 22% women) and without a history of AF undergoing cardiac surgery were prospectively enrolled. TACT was measured preoperatively in the left atrium by tissue-Doppler Imaging (PA-TDI interval). Holter-ECG/telemetry was used to screen for POAF throughout 10 days after cardiac surgery. Right atrial appendages (RAA) were obtained in 33 patients during surgery; atrial fibrosis was assessed by visual quantification (% area of positive van Gieson elastic staining). POAF occurred in 23 patients (38%). Fibrosis extent of RAA was higher in patients with POAF as compared to those without (27.5 ± 1.93 vs 15.8 ± 0.81% area; mean ± SEM; P < 0.001). PA-TDI interval was longer in patients with POAF versus patients who maintained in sinus rhythm (152.1 ± 3.0 vs 120.8 ± 1.8 milliseconds; P < 0.001) and correlated with the degree of atrial fibrosis (r = 0.73; P < 0.01). At the cut-off value of 133 milliseconds, TACT sensitivity and specificity related to POAF were 100% and 86%, respectively. CONCLUSION: PA-TDI interval is useful to identify patients at risk for POAF undergoing cardiac surgery and correlates with the degree of atrial fibrosis.