A Clinico-pathological "Bird's-Eye" View of Left Atrial Myocardial Fibrosis in 121 Patients with Persistent Atrial Fibrillation: Developing Architecture and Main Cellular Players

Background - Scientific research on atrial fibrosis in atrial fibrillation (AF) has mainly focused on quantitative and/or molecular features. The purpose of this study was to perform a clinico-architectural/structural investigation of fibrosis to provide one key to understanding the electrophysiological/clinical aspects of AF. Methods - We characterized the fibrosis (amount, architecture, cellular components, and ultrastructure) in left atrial biopsies from 121 patients with persistent/long-lasting persistent AF (Group 1) (59 males; 60±11 years; 91 mitral disease-related AF, 30 non-mitral disease-related AF) and from 39 patients in sinus rhythm with mitral-valve regurgitation (Group 2; 32 males; 59±12 years). Ten autopsy hearts served as controls. Results - Qualitatively, the fibrosis exhibited the same characteristics in all cases and displayed particular architectural scenarios (which we arbitrarily subdivided into four stages) ranging from isolated foci to confluent sclerotic areas. The percentage of fibrosis was larger and at a more advanced stage in Group 1 vs. Group 2 and, within Group 1, in patients with rheumatic disease vs. non-rheumatic cases. In AF patients with mitral disease and no rheumatic disease, the percentage of fibrosis and the fibrosis stages correlated with both left atrial volume index and AF duration. The fibrotic areas mainly consisted of type I collagen with only a minor cellular component (especially fibroblasts/myofibroblasts; average value range 69-150 cells/mm2, depending on the areas in AF biopsies). A few fibrocytes-circulating and bone marrow-derived mesenchymal cells-were also detectable. The fibrosis-entrapped cardiomyocytes showed sarcolemmal damage and connexin 43 redistribution/internalization. Conclusions - Atrial fibrosis is an evolving and inhomogeneous histological/architectural change which progresses through different stages ranging from isolated foci to confluent sclerotic zones which - seemingly - constrain impulse conduction across restricted regions of electrotonically-coupled cardiomyocytes. The fibrotic areas mainly consist of type I collagen extracellular matrix and, only to a lesser extent, mesenchymal cells

Long-term benefits of dapagliflozin on renal outcomes of type 2 diabetes under routine care: a comparative effectiveness study on propensity score matched cohorts at low renal risk

Background Despite the overall improvement in care, people with type 2 diabetes (T2D) experience an excess risk of end-stage kidney disease. We evaluated the long-term effectiveness of dapagliflozin on kidney function and albuminuria in patients with T2D. Methods We included patients with T2D who initiated dapagliflozin or comparators from 2015 to 2020. Propensity score matching (PSM) was performed to balance the two groups. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) from baseline to the end of observation. Secondary endpoints included changes in albuminuria and loss of kidney function. Findings We analysed two matched groups of 6197 patients each. The comparator group included DPP-4 inhibitors (40%), GLP-1RA (22.3%), sulphonylureas (16.1%), pioglitazone (8%), metformin (5.8%), or acarbose (4%). Only 6.4% had baseline eGFR <60 ml/min/1.73 m(2) and 15% had UACR >30 mg/g. During a mean follow-up of 2.5 year, eGFR declined significantly less in the dapagliflozin vs comparator group by 1.81 ml/min/1.73 m(2) (95% C.I. from 1.13 to 2.48; p < 0.0001). The mean eGFR slope was significantly less negative in the dapagliflozin group by 0.67 ml/min/1.73 m(2)/year (95% C.I. from 0.47 to 0.88; p < 0.0001). Albuminuria declined significantly in new-users of dapagliflozin within 6 months and remained on average 44.3 mg/g lower (95% C.I. from-66.9 to-21.7; p < 0.0001) than in new-users of comparators. New-users of dapagliflozin had significantly lower rates of new-onset CKD, loss of kidney function, and a composite renal outcome. Results were confirmed for all SGLT2 inhibitors, in patients without baseline CKD, and when GLP-1RA were excluded from comparators. Interpretation Initiating dapagliflozin improved kidney function outcomes and albuminuria in patients with T2D and a low renal risk. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)