Profibrotic Remodeling Research Articles

24 Month Event-Recorder Based Follow-up of Post-MAZE-Patients. Freedom From Atrial Fibrillation and Atrial Re-Remodeling Correlates with BMI Control and Afib Entity

Background: Paroxysmal and persistent atrial fibrillations (Afib) are the most common cardiac arrhythmias. MAZE procedures reach freedom form atrial fibrillation (FFA) depending on the arrhythmogenic entity. Obesity associated atrial profibrotic remodeling contributes to Afib sustainability. Predictors for postoperative MAZE-success are vacant. Methods: In a prospective all comers study 109 patients with paroxysmal (n = 38) or persistent (n = 71) Afib underwent standardized MAZE (bipolar radiofrequency, eventrecorder(ER)) additive to baseline procedure. Patients underwent follow-up at our department each 6 month (2 years; electrocardiogram, ER-readout, echocardiography, blood-sample, physical examination). FFA was defined as single episode-duration less than 5 minutes and total amount of Afib lower 10% / 6 month. We offered electrophysiological heart-team-control in case of Afib-maintenance after 12 month. Results: We reached FFA in 97,2% of paroxysmal Afib (24 month). Persistent Afib endured stronger but reached FFA in 58,9% after 24 month. EuroScore II was 6,1 ± 0,7% (paroxysmal) and 6,4 ± 0,4% (persistent). 30-day mortality remained lower overall (5,3 ± 0,2%,paroxysmal; 4,1 ± 0,3%, persistent; p < 0,05 versus EuroScore). Neither Euro-, nor CHADS-score nor patient´s sex correlated with FFA significantly. In paroxysmal Afib FFA after 24 month reduced left atrial diameter (−6,7 ± 2,2 mm) and improved LVEF (+ 7,3 ± 2,8%) while patients remaining in fibrillation showed further atrial dilation (+ 8,0 ± 1,0 mm) and reduction of LVEF (−7,0 ± 1,3%) (p < 0,05), long-term changes were less distinct in persistent atrial fibrillation. Increased preoperative left atrial diameter reduced FFA in permanent Afib but had nearly no effect in paroxysmal Afib. In persistent, but not in paroxysmal Afib, FFA correlated negatively with patient age. All electrophysiological re-examined patients reached FFA. More interesting, FFA and duration of episodes after 6 to 24 month correlated negatively with BMI in all patients. Weight control and moderate weight reduction in obese patients consolidated FFA. Conclusion: Paroxysmal and persistent Afib exhibit structural and therapeutically characteristics. MAZE shows high therapeutically benefit even in high-risk-patients. Atrial re-remodeling can be achieved in paroxysmal Afib. Increased BMI reduces FFA consistently. Preoperative left atrial diameter, patient´s age and BMI may be used as predictors of therapeutically success in persistent Afib.

Blood Sampled Directly from Varicose Veins Reveals Activation of Inflammatory Processes.

insult using the EIM model left an anatomic channel that allowed room for the second insult as confirmed by duplex imaging. Compared with sham control, recurrent groups produce a clot that integrates itself into the vein wall, producing heavier IVC walls. Recurrent groups also have higher levels of fibrin, transforming growth factor-b, elastin, MMP-9, and MMP-2 gene expression in the IVC wall (Table). Conclusions: We successfully produced recurrent thrombi in all primarily thrombosed IVC. Experimental recurrent thrombi are structurally and compositionally different from the primary DVT, with a greater profibrotic remodeling vein wall profile. This work provides a novel DVT recurrence model in the IVC that will help improve the current understanding of the biologic mechanisms and directed treatment of recurrent DVT.

The mineralocorticoid receptor promotes pro-fibrotic remodeling in atrial fibrillation

Purpose: We studied the role of the mineralocorticoid receptor (MR) for the signalling that promotes atrial fibrosis. Methods and results: Left atrial myocardium (LA) of patients with atrial fibrillation (AF) had increased hydroxyproline content (425±103%) compared to patients matched for atrial size in sinus rhythm (SR). AF patients showed similar expression of MR but had increased expression of 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2; 376±115%), a glucocorticoid inactivating enzyme providing minderalocorticoid access to MR. Hydroxyproline in LA correlated with upregulated 11β-HSD2, connective tissue growth factor (CTGF) and secreted protein acidic and rich in cysteine (SPARC). In cultured cardiac fibroblasts, aldosterone increased hydroxyproline expression (244±46%), which was completely prevented by BR-4628, a dihydropyridine-derived non-steroidal and selective MR antagonist, and by spironolactone. Aldosterone and TGF-β enhanced the expression of CTGF (207±34% and 176±22%, respectively), and BR-4628 as well as spironolactone prevented these effects. Compared to control, CTGF expression was diminished with either BR-4628 or spironolactone treatment (59±17% and 51±155%, respectively). The Rho kinase inhibitor Y-27632 decreased both aldosterone and TGF-β induced CTGF upregulation (52±15% and 95±8%, respectively), whereas the RhoA activator CN03 increased CTGF expression (206±28%). This effect persisted after BR-4628 or spironolactone pre-treatment. CTGF and aldosterone increased lysyl oxidase (LOX) expression (194±19% and 272±37%, respectively). The aldosterone but not the CTGF effect was reduced by MR antagonists indicating that CTGF induces LOX expression downstream of the MR. Aldosterone elevated miR-21 expression (415±120%) and suppressed the miR-21 target Sprouty-1 (43±8%), both effects were prevented by BR-4628 and spironolactone. All reported effects are significant with p<0.05. Conclusions: Mineralocorticoid receptor signalling through hydroxyproline, CTGF, LOX and miR-21 contributes to pro-fibrotic remodeling. Inhibition of the MR pathways may therefore represent a target for the prevention of fibrosis which is a substrate for atrial fibrillation.

Transcriptional changes in right ventricular tissues are enriched in the outflow tract compared with the apex during chronic pulmonary embolism in rats

Moderate to severe pulmonary embolism (PE) can cause pulmonary arterial hypertension and right ventricular (RV) heart damage. Previous studies from our laboratory indicate that the basal outflow tract of the RV is injured and has acute inflammation followed by tissue remodeling while the apex appears normal. The present studies examine transcription responses to chronic PE in RV apex and outflow tracts using DNA microarrays to identify transcription responses by region. Changes predominated in the RV outflow tract (8,575 genes showed >/=1.5-fold expression change). Gene ontology and KEGG analyses indicated a significant decrease in genes involved in cellular respiration and energy metabolism and increases in inflammatory cell adhesion molecules and extracellular matrix proteins. Signal pathways for wound healing such as fibroblast growth factor, collagen synthesis, and CCN proteins (named for the first three members of the family: cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene) were strongly upregulated. In comparison, few genes (422) showed significant change in the RV apex tissue. Apex-selective genes included two genes affecting metabolism and a stretch-sensitive transcription factor (ankyrin repeat domain 1). We conclude that the RV outflow tract is subject to strong proinflammatory and profibrotic remodeling transcriptional responses in chronic PE. Severe loss of genes involved in cellular respiration is consistent with previous histology indicating a shift in cell types present within the outflow tract tissue away from highly energy-dependant cardiomyocytes to less metabolically active cells during remodeling. The apex region of the RV had few compensating adaptations.