Results of the Diaphragmatic Plication Database: 10 Years' Experience.

BACKGROUND: Unilateral diaphragmatic paralysis or paresis (UDP) in adults is an often overlooked disease which relevantly impairs the patient's lung function and quality of life. Particularly in idiopathic UDP, there is no evidence for conservative therapy and only little evidence for surgical therapy. METHODS: The method involves retrospective single-center analysis of patients with UDP persistent for at least 1 year who were operated by diaphragmatic resection, plication, and augmentation with a polypropylene mesh. The patients were tested for lung and diaphragmatic function, six-minute walk test (6MWT), and blood gas analysis before, 3 and 12 months after surgery. RESULTS: In total, 85 patients received surgery for UDP. The most frequent reasons for UDP were idiopathic (67%), iatrogenic (mainly cardiac and cervical spine surgery; 24%), and trauma (9%). The mean operation time was 84 ± 24 minutes, the length of hospital stay 8.4 ± 3.9 days, chest tubes were removed after 11.7 ± 4.1 days. Overall morbidity was 42%, mortality 0%. Forced expiratory volume in one second (FEV1) in supine position improved by 12.4% absolute, vital capacity by 11.8% absolute, and sniff nasal inspiratory pressure by 1.4 kPa 12 months after surgery (p <0.001 each). Total lung capacity increased by 6.8% absolute at 12 months (p = 0.001) The 6MWT distance improved by 45.9 m at 3 months and 50.9 m at 12 months (p = 0.001, each). CONCLUSION: Surgical therapy for UDP is highly effective in the long term. The superiority over conservative treatments needs to be evaluated prospectively with standardized physiotherapeutic protocols. FEV1 in supine position and 6MWT are easy to perform tests and represent statistically and patient-relevant outcomes.

Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy.

INTRODUCTION: Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp). METHODS: A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS). RESULTS: METamp tumors (n = 278) had a high frequency of co-occurring mutations (>80% for all amplification levels), whereas 57.6% of the 59 patients with MET gene and exon 14 (METex14) tumors had no additional mutations. In the METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN < 4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN < 4: 43.2%; GCN ≥ 10: 11.8%). A total of 10.1% of all the METamp tumors with a GCN ≥ 10 had a significant worse OS (4.0 mo; 95% CI: 1.9-6.0) compared with the tumors with GCN < 10 (12.0 mo; 95% confidence interval [CI]: 9.4-14.6). In the METamp NSCLC, OS with immune checkpoint inhibitor (ICI) therapy was significantly better compared with chemotherapy with 19.0 months (95% CI: 15.8-22.2) versus 8.0 months (95% CI: 5.8-10.2, p < 0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147). CONCLUSIONS: METex14, METamp GCN ≥ 10, and METamp GCN < 10 represent the subgroups of MET-dysregulated NSCLC with distinct molecular and clinical features. The patients with METex14 do not seem to benefit from immunotherapy in contrast to the patients with METamp, which is of particular relevance for the prognostically poor METamp GCN ≥ 10 subgroup.

The impact of preoperative elevated serum C-reactive protein on postoperative morbidity and mortality after anatomic resection for lung cancer.

INTRODUCTION: The aim of this study was to determine whether preoperative elevated serum C-reactive protein (CRP) is an independent risk factor of postoperative morbidity and mortality after pulmonary resection for lung cancer. MATERIAL AND METHODS: A retrospective analysis of prospectively collected data on 1414 consecutive patients that underwent an anatomic resection for lung cancer was performed. Patients' characteristics, operative procedures and the postoperative outcome were assessed with a standardised data entry form. Univariate and multivariate analyses were conducted to identify factors that affect morbidity and mortality. RESULTS: Postoperative complications occurred in 35.5% of the patients. The mortality rate was 3.2%. Patients with preoperative C-reactive protein above 40mg/l showed more overall complications and a higher mortality than patients below this limit. Patients with a CRP level between 3mg/l and 40mg/l had no significant increase in morbidity and mortality compared to patients with values ​​below the detection limit (< 3mg/l). CONCLUSIONS: Preoperative serum C-reactive protein level is an independent and significant indicator for elevated morbidity and mortality after pulmonary resection. We propose the evaluation of CRP levels as a preoperative diagnostic modality of risk assessment in addition to standardised functional testing.

Unilateral Lobe Resection by Video-Assisted Thoracoscopy Leads to the Most Optimal Functional Improvement in Severe Emphysema.

Background Lung volume reduction surgery (LVRS) is a well-established treatment option for pulmonary emphysema, but the most advantageous technical approach remains debatable. Methods Short- and long-term outcomes were comparably assessed in pulmonary emphysema patients who underwent unilateral LVRS with either lobe or sublobe (segment or wedge) resection. Patients were consecutively enrolled in the study after careful conventional and computer-based definition of the target region. Results A total of 36 patients with a mean age of 62.1 ± 8.9 years (range, 41-79 years) were recruited. Video-assisted thoracoscopy (VATS) was performed in 33 patients, while 3 patients with additional early-stage lung cancer received anterolateral thoracotomy. Surgery duration was longer for lobectomy (median 93 minutes, range 44-168 minutes) as compared with sublobe resection (median 52 minutes, range 25-131 minutes; p = 0.0007), but complication rates were similar. After 90 days postsurgery, mortality was zero and lung function improved to a similar degree in both the groups. After 1 year, total lung capacity (TLC) was still reduced by 17.2 ± 20.6% predicted as compared with the baseline values for lobe resection, while TLC was increased by 12.1 ± 14.5% predicted for sublobe resection. In addition, the 6-minute walking distance improved following LVRS, with slightly better results in lobe resection patients. Conclusions By careful definition of the target region, unilateral VATS-LVRS with lobe resection in severely affected pulmonary emphysema patients is a safe procedure that is superior to unilateral sublobe VATS resection in terms of improving long-term 1-year lung hyperinflation. Therefore, unilateral VATS lobe resection is a promising treatment approach that should be further evaluated by randomized controlled trials.

Spontaneous regression of non-small cell lung cancer after biopsy of a mediastinal lymph node metastasis: a case report.

INTRODUCTION: Spontaneous regression of cancer is defined as a complete or partial, temporary or permanent disappearance of tumor in the absence of specific therapy. With only a few cases reported, spontaneous regression is extremely rare in primary lung cancer. Regarding spontaneous regression in lung cancer, recent investigations revealed the role of immunological mechanisms, thus indicating potential treatment options by specific immunotherapy in the future. CASE PRESENTATION: A 76-year-old Caucasian man with progressive dyspnea presented to our hospital. A computed tomography scan revealed a tumor mass in the upper lobe of his right lung and enlarged mediastinal lymph nodes. A biopsy of a paratracheal lymph node by mediastinoscopy disclosed metastatic lung cancer. By immunohistochemical findings the tumor was classified as large cell carcinoma. Diagnosed with clinical stage IIIA non-small cell lung cancer, a neoadjuvant therapy concept was indicated. However, before starting chemoradiation, a computed tomography scan showed a regression of both the tumor mass in the upper lobe of his right lung and the mediastinal lymphadenopathy. As a repeated computed tomography scan showed further regression, we agreed with our patient to perform routine follow-up instead of starting therapy. To date, no relapse has been reported. CONCLUSIONS: Given the circumstances that regression started after the biopsy and involved both the tumor in the upper lobe of his right lung and the mediastinal lymph node metastases, an immune response is a reasonable explanation for the observed spontaneous regression in this case.

A Comparison of Atrial Fibrillation Monitoring Strategies After Cryptogenic Stroke (from the Cryptogenic Stroke and Underlying AF Trial).

Ischemic stroke cause remains undetermined in 30% of cases, leading to a diagnosis of cryptogenic stroke. Paroxysmal atrial fibrillation (AF) is a major cause of ischemic stroke but may go undetected with short periods of ECG monitoring. The Cryptogenic Stroke and Underlying Atrial Fibrillation trial (CRYSTAL AF) demonstrated that long-term electrocardiographic monitoring with insertable cardiac monitors (ICM) is superior to conventional follow-up in detecting AF in the population with cryptogenic stroke. We evaluated the sensitivity and negative predictive value (NPV) of various external monitoring techniques within a cryptogenic stroke cohort. Simulated intermittent monitoring strategies were compared to continuous rhythm monitoring in 168 ICM patients of the CRYSTAL AF trial. Short-term monitoring included a single 24-hour, 48-hour, and 7-day Holter and 21-day and 30-day event recorders. Periodic monitoring consisted of quarterly monitoring through 24-hour, 48-hour, and 7-day Holters and monthly 24-hour Holters. For a single monitoring period, the sensitivity for AF diagnosis was lowest with a 24-hour Holter (1.3%) and highest with a 30-day event recorder (22.8%). The NPV ranged from 82.3% to 85.6% for all single external monitoring strategies. Quarterly monitoring with 24-hour Holters had a sensitivity of 3.1%, whereas quarterly 7-day monitors increased the sensitivity to 20.8%. The NPVs for repetitive periodic monitoring strategies were similar at 82.6% to 85.3%. Long-term continuous monitoring was superior in detecting AF compared to all intermittent monitoring strategies evaluated (p <0.001). Long-term continuous electrocardiographic monitoring with ICMs is significantly more effective than any of the simulated intermittent monitoring strategies for identifying AF in patients with previous cryptogenic stroke.

Absence of amplification of the FGFR1-gene in human malignant mesothelioma of the pleura: a pilot study.

BACKGROUND: Mesothelioma (MPM) is a rare malignant disease with a worse outcome. Fibroblast growth factor 1 (FGFR1) may be an interesting target for selective tyrosine kinases inhibitors (TKI) in MPM. The aim of this study was to evaluate the amplification of the FGFR1 gene in patients suffering from MPM. FINDINGS: We identified nineteen male patients treated in our department between August 2008 and July 2010 matching the inclusion criteria. Mean age was 68 years. Histopathological examination confirmed thirteen patients with epitheloid subtype, five with biphasic and one patient with sarcomatoid. Fluorescence in situ hybridization analysis revealed no polysomy nor an amplification of the FGFR gene copy number in any case. CONCLUSION: Regarding that also EGFR amplifications in MPM are absolute rarities, our findings may be a hint that TKI's will not satisfy the hope for a new era in the treatment of MPM.

Cryptogenic stroke and underlying atrial fibrillation.

BACKGROUND: Current guidelines recommend at least 24 hours of electrocardiographic (ECG) monitoring after an ischemic stroke to rule out atrial fibrillation. However, the most effective duration and type of monitoring have not been established, and the cause of ischemic stroke remains uncertain despite a complete diagnostic evaluation in 20 to 40% of cases (cryptogenic stroke). Detection of atrial fibrillation after cryptogenic stroke has therapeutic implications. METHODS: We conducted a randomized, controlled study of 441 patients to assess whether long-term monitoring with an insertable cardiac monitor (ICM) is more effective than conventional follow-up (control) for detecting atrial fibrillation in patients with cryptogenic stroke. Patients 40 years of age or older with no evidence of atrial fibrillation during at least 24 hours of ECG monitoring underwent randomization within 90 days after the index event. The primary end point was the time to first detection of atrial fibrillation (lasting >30 seconds) within 6 months. Among the secondary end points was the time to first detection of atrial fibrillation within 12 months. Data were analyzed according to the intention-to-treat principle. RESULTS: By 6 months, atrial fibrillation had been detected in 8.9% of patients in the ICM group (19 patients) versus 1.4% of patients in the control group (3 patients) (hazard ratio, 6.4; 95% confidence interval [CI], 1.9 to 21.7; P<0.001). By 12 months, atrial fibrillation had been detected in 12.4% of patients in the ICM group (29 patients) versus 2.0% of patients in the control group (4 patients) (hazard ratio, 7.3; 95% CI, 2.6 to 20.8; P<0.001). CONCLUSIONS: ECG monitoring with an ICM was superior to conventional follow-up for detecting atrial fibrillation after cryptogenic stroke. (Funded by Medtronic; CRYSTAL AF ClinicalTrials.gov number, NCT00924638.).

Benign stenosis of the trachea.

Benign stenosis of trachea results mainly from tracheotomy, ventilation, or trauma. The combination of a defect of the mucosa or the tracheal wall and infection produce secondary scar tissue healing with shrinkage of the tracheal lumen or instability of the tracheal wall. Standard of treatment consists of resection of the pathologic segment of the trachea with end-to-end anastomosis. In case of involvement of the larynx, partial resections of the anterior cricoid cartilage or division of the larynx with tracheolaryngeal silicone stents are used. Short-term and long-term results are satisfying considering some technical recommendations.

Species-specificity of the BamA component of the bacterial outer membrane protein-assembly machinery.

The BamA protein is the key component of the Bam complex, the assembly machinery for outer membrane proteins (OMP) in gram-negative bacteria. We previously demonstrated that BamA recognizes its OMP substrates in a species-specific manner in vitro. In this work, we further studied species specificity in vivo by testing the functioning of BamA homologs of the proteobacteria Neisseria meningitidis, Neisseria gonorrhoeae, Bordetella pertussis, Burkholderia mallei, and Escherichia coli in E. coli and in N. meningitidis. We found that no BamA functioned in another species than the authentic one, except for N. gonorrhoeae BamA, which fully complemented a N. meningitidis bamA mutant. E. coli BamA was not assembled into the N. meningitidis outer membrane. In contrast, the N. meningitidis BamA protein was assembled into the outer membrane of E. coli to a significant extent and also associated with BamD, an essential accessory lipoprotein of the Bam complex.Various chimeras comprising swapped N-terminal periplasmic and C-terminal membrane-embedded domains of N. meningitidis and E. coli BamA proteins were also not functional in either host, although some of them were inserted in the OM suggesting that the two domains of BamA need to be compatible in order to function. Furthermore, conformational analysis of chimeric proteins provided evidence for a 16-stranded ß-barrel conformation of the membrane-embedded domain of BamA.

Haemodynamic adaptation during sudden gravity transitions.

Haemodynamic responses during parabolic flight were studied. The hypothesis that haemodynamic changes may be counteracted by a transient vagal reflex during acute gravity transitions was tested. ECG, arterial pressure and respiration were recorded continuously in seven male subjects during parabolic flight. Beat-to-beat haemodynamic parameters were estimated. In the supine position no significant differences were shown among the different gravity phases. In the upright position, significant within-group differences were observed across gravity phases for all parameters. Postural differences in haemodynamic data disappeared during the microgravity phase and were enlarged during hypergravity phases. Detailed temporal analysis of cardiac time series in standing subjects confirmed the hypothesized biphasic response of initial parasympathetic modulation: a sharp increase of RRI within 3-5 s followed by a 10% decrease in the remaining period of microgravity (p < 0.001); a sharp increase in SAP within 2-4 s followed by a slow decrease of 25%. Significant within-group differences were observed in the standing position for mean RRI (836 ± 170 ms, p = 0.003), DAP (66 ± 8 mmHg, p < 0.001), MAP (139 ± 12 mmHg, p = 0.001), RRI HF amplitude (17.6 ± 7.5 ms, p < 0.001), SV (146 ± 5%, p < 0.001) and SVR (73 ± 10%, p = 0.020). In standing subjects, the initial baroreflex-mediated vagal heart rate response is limited to a transition period at early microgravity lasting about 3-5 s, followed by a gradual heart rate recovery during the remaining 15-17 s due to a parasympathetic withdrawal. The resultant increase in cardiac output induces a baroreflex-mediated systemic vasodilatation, which may be the driving force for a decreased arterial pressure in weightlessness.

Cryptogenic Stroke and underlying Atrial Fibrillation (CRYSTAL AF): design and rationale.

BACKGROUND: Patients with atrial fibrillation (AF) are at increased risk for ischemic stroke. In patients who have suffered a stroke, screening for AF is routinely performed only for a short period after the stroke as part of the evaluation for possible causes. If AF is detected after an ischemic stroke, oral anticoagulation therapy is recommended for secondary stroke prevention. In 25% to 30% of stroke patients, the stroke mechanism cannot be determined (cryptogenic stroke). The incidence of paroxysmal AF undetected by short-term monitoring in patients with cryptogenic stroke is unknown, but has important therapeutic implications on patient care. The optimum monitoring duration and method of AF detection after stroke are unknown. The purpose of this study is to evaluate the incidence of AF and time to AF detection in patients with cryptogenic stroke using an insertable cardiac monitor. STUDY DESIGN: The CRYSTAL AF trial is a randomized prospective study to evaluate a novel approach to long-term monitoring for AF detection in patients with cryptogenic stroke. Four hundred fifty cryptogenic stroke patients (by definition, without a history of AF) will be enrolled at approximately 50 sites in Europe, Canada, and the United States. Patients will be randomized in a 1:1 fashion to standard arrhythmia monitoring (control arm) or implantation of the subcutaneous cardiac monitor (Reveal XT; Medtronic, Inc, Minneapolis, MN) (continuous monitoring arm). OUTCOMES: The primary end point is time to detection of AF within 6 months after stroke. The clinical follow-up period will be at least 12 months. Study completion is expected at the end of 2012.

Effects of mental stress on autonomic cardiac modulation during weightlessness.

Sustained weightlessness affects all body functions, among these also cardiac autonomic control mechanisms. How this may influence neural response to central stimulation by a mental arithmetic task remains an open question. The hypothesis was tested that microgravity alters cardiovascular neural response to standardized cognitive load stimuli. Beat-to-beat heart rate, brachial blood pressure, and respiratory frequency were collected in five astronauts, taking part in three different short-duration (10 to 11 days) space missions to the International Space Station. Data recording was performed in supine position 1 mo before launch; at days 5 or 8 in space; and on days 1, 4, and 25 after landing. Heart rate variability (HRV) parameters were obtained in the frequency domain. Measurements were performed in the control condition for 10 min and during a 5-min mental arithmetic stress task, consisting of deducting 17 from a four-digit number, read by a colleague, and orally announcing the result. Our results show that over all sessions (pre-, in-, and postflight), mental stress induced an average increase in mean heart rate (Delta7 +/- 1 beats/min; P = 0.03) and mean arterial pressure (Delta7 +/- 1 mmHg; P = 0.006). A sympathetic excitation during mental stress was shown from HRV parameters: increase of low frequency expressed in normalized units (Delta8.3 +/- 1.4; P = 0.004) and low frequency/high frequency (Delta1.6 +/- 0.3; P = 0.001) and decrease of high frequency expressed in normalized units (Delta8.9 +/- 1.4; P = 0.004). The total power was not influenced by mental stress. No effect of spaceflight was found on baseline heart rate, mean arterial pressure, and HRV parameters. No differences in response to mental stress were found between pre-, in-, and postflight. Our findings confirm that a mental arithmetic task in astronauts elicits sympathovagal shifts toward enhanced sympathetic modulation and reduced vagal modulation. However, these responses are not changed in space during microgravity or after spaceflight.

Adaptation of heart rate and blood pressure to short and long duration space missions.

To what extent does going to space affect cardiovascular function? Although many studies have addressed this question, the answer remains controversial. Even for such primary parameters as heart rate (HR) and blood pressure (BP) contradictory results have been presented. The purpose of this investigation was to evaluate HR and arterial BP in 11 male astronauts who each took part in nine different space missions aboard the International Space Station (ISS), for up to 6 months. Pre-flight HR and BP readings were obtained in both the standing and supine positions on Earth and were taken as reference values. Our results show that HR and arterial BP in space equal pre-flight supine values. In all subjects, HR and mean arterial BP (MAP) were lower in space compared with pre-flight standing (both p<0.05). HR in space was well maintained at pre-flight supine level for up to 6 months in all astronauts while MAP tended to adapt to a level in between the ground-based standing and supine positions. Also pulse pressure (PP) decreased over the course of long duration spaceflight. In conclusion, our data indicate that weightlessness relaxes the circulation in humans for an extended duration of up to 6 months in space.

Cardiac autonomic regulation under hypnosis assessed by heart rate variability: spectral analysis and fractal complexity.

OBJECTIVE: This study examined the effects of hypnosis on autonomic cardiac control. We hypothesized a modification of autonomic modulation of the heart rate with an enhanced vagal tone during hypnosis compared to baseline. METHODS: In 12 healthy subjects (6 men and 6 women, 22.2 +/- 1.0 years of age) ECG was recorded at baseline and during hypnosis. Heart rate variability parameters were obtained in the frequency domain (LFnu: low frequency normalized units, and HFnu: high frequency normalized units) and from nonlinear analysis methods (detrended fluctuation analysis, DFA). RESULTS: Compared to the control condition, hypnosis showed a significantly decreased LFnu, a significantly increased HFnu, and a significantly decreased LF/HF. DFA showed a significantly decreased short-range similarity. Heart rate remained unchanged. CONCLUSION: Autonomic cardiac tone is significantly modified during hypnosis by shifting the balance of the sympathovagal interaction toward an enhanced parasympathetic modulation, accompanied by a reduction of the sympathetic tone and a decreased short-range similarity but without a concomitant change in heart rate. Central and secondary autonomous nervous system changes induced by hypnosis are a possible explanation for our results. Another highly probable explanation is given by a variation in the depth of respiration. Hypnosis appears to prevent the autonomic responses expected during neutral stimulation.

The beta-barrel outer membrane protein assembly complex of Neisseria meningitidis.

The evolutionarily conserved protein Omp85 is required for outer membrane protein (OMP) assembly in gram-negative bacteria and in mitochondria. Its Escherichia coli homolog, designated BamA, functions with four accessory lipoproteins, BamB, BamC, BamD, and BamE, together forming the beta-barrel assembly machinery (Bam). Here, we addressed the composition of this machinery and the function of its components in Neisseria meningitidis, a model organism for outer membrane biogenesis studies. Analysis of genome sequences revealed homologs of BamC, BamD (previously described as ComL), and BamE and a second BamE homolog, Mlp. No homolog of BamB was found. As in E. coli, ComL/BamD appeared essential for viability and for OMP assembly, and it could not be replaced by its E. coli homolog. BamE was not essential but was found to contribute to the efficiency of OMP assembly and to the maintenance of OM integrity. A bamC mutant showed only marginal OMP assembly defects, but the impossibility of creating a bamC bamE double mutant further indicated the function of BamC in OMP assembly. An mlp mutant was unaffected in OMP assembly. The results of copurification assays demonstrated the association of BamC, ComL, and BamE with Omp85. Semi-native gel electrophoresis identified the RmpM protein as an additional component of the Omp85 complex, which was confirmed in copurification assays. RmpM was not required for OMP folding but stabilized OMP complexes. Thus, the Bam complex in N. meningitidis consists of Omp85/BamA plus RmpM, BamC, ComL/BamD, and BamE, of which ComL/BamD and BamE appear to be the most important accessory components for OMP assembly.

Complexity of cardiovascular regulation in small animals.

Oscillations of heart rate and blood pressure are related to the activity of the underlying control mechanism. They have been investigated mostly with linear methods in the time and frequency domains. Also, in recent years, many different nonlinear analysis methods have been applied for the evaluation of cardiovascular variability. This review presents the most commonly used nonlinear methods. Physiological understanding is obtained from various results from small animals.

Cardiovascular function and gravity transitions during parabolic flight.

Cardiovascular function and gravity transitions during parabolic flight.

Self-terminating AF depends on electrical remodeling while persistent AF depends on additional structural changes in a rapid atrially paced sheep model.

The development of atrial fibrillation (AF) is associated with electrical and structural remodeling. The aim of this study was to assess the contribution of electrical and structural remodeling to the development of AF in a rapid atrially paced ovine model with and without His bundle ablation and to determine the role of the angiotensin pathway and matrix metalloproteinases in this process. Thirty-five sheep were rapidly paced in the atrium and were randomized to undergo His bundle ablation (HBA) (21 sheep; HBA sheep) or not (14 sheep; non-HBA sheep). After HBA the ventricles were paced at 80 bpm. Both groups were subdivided to receive active treatment (quinapril+losartan) or placebo. Sheep were followed for 15 weeks. Inducible AF was defined as a rapid irregular atrial rhythm lasting >1 min. Inducible AF was considered to be persistent if during further follow-up no sinus rhythm (SR) was documented anymore. The inducibility of AF with atrial tachypacing was not different between the 4 groups. On the other hand, non-HBA sheep developed persistent AF significantly earlier than HBA sheep (p=0.028). They had elevated ventricular rates, diminished atrial MMP-2, increased TIMP-2 expression, and more extensive atrial fibrosis. Active treatment in these sheep significantly lowered AT-II (p=0.018), prevented atrial fibrogenesis (p<0.001) and slowed the development of persistent AF (p=0.049). Electrical remodeling is sufficient to induce AF, while structural changes are needed for persistent AF. Fibrosis development in our model is the result of an increased expression of AT-II in combination with changes in MMP expression. Inhibition of the angiotensin pathway suppresses atrial fibrosis and the development of persistent AF.