Effects of pirfenidone on scar size and ventricular remodeling after myocardial infarction: a preclinical study

Background: An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling. We investigated the effects of the antifibrotic drug pirfenidone in this setting. Methods: Male Wistar rats were randomized to: sham procedure (n = 13), reperfused MI-induced by ligating the left anterior descending artery (LAD) for 45 min (n = 17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta blocker, and mineralocorticoid receptor antagonist) (n = 17), reperfused MI plus pirfenidone alone (n = 17), or reperfused MI plus standard therapy and pirfenidone (n = 17). Rats surviving MI induction underwent cardiac magnetic resonance scans after 72 h and 30 days from MI, and were sacrificed on day 31. Results: Rats completing the whole protocol numbered 11 in the sham group, 9 in the untreated MI group, 8 in the standard treatment group, 9 in the pirfenidone alone group, and 9 in the standard treatment plus pirfenidone group. No significant differences emerged between LV volumes, ejection fraction or mass at 30 days or the differences from 72 h to 30 days. Small, nonsignificant differences between rats on pirfenidone alone vs. those on standard therapy emerged. The total extent of LV fibrosis, quantified as area and percentage of the tissue sample, did not differ significantly between rats on pirfenidone alone vs. those on standard therapy alone. Conclusion: Pirfenidone does not have additional effects on LV remodeling or fibrosis compared with standard therapy, but its effects are similar to standard therapy alone

Left cardiac vagotomy rapidly reduces contralateral cardiac vagal electrical activity in anesthetized Göttingen minipigs

Background: The impact of acute unilateral injury on spontaneous electrical activity in both vagus nerves at the heart level is poorly understood. We investigated the immediate neuroelectrical response after right or left cardiac vagal nerve transection (VNTx) by recording spiking activity of each heart vagus nerve (VN). Methods: Fourteen male Göttingen minipigs underwent sternotomy. Multi-electrode cuffs were implanted below the cut level to record vagal electroneurographic signals during electrocardiographic and hemodynamic monitoring, before and immediately after cardiac VNTx (left: L-cut, n = 6; right: R-cut, n = 8). Results: Left cardiac VNTx significantly reduced multi-unit electrical activity (MUA) firing rate in the vagal stump (-30.7% vs pre-cut) and intact right VN (-21.8% vs pre-cut) at the heart level, without affecting heart rate, heart rate variability, or hemodynamics. In contrast, right cardiac VNTx did not acutely alter MUA in either VN but slightly increased (p < 0.022) the root mean square of successive RR interval differences (rMSSD), an index of parasympathetic outflow, without affecting hemodynamics. Conclusions: Our study reveals an early left-lateralized pattern in vagal spiking activity following unilateral cardiac vagotomy. These findings enhance understanding of the neuroelectrical response to vagal injury and provide insights into preserving vagal outflow after unilateral cardiac vagotomy. Importantly, monitoring spiking activity of the cardiac right VN may predict onset of left vagal pathway injury, which is detrimental to cardiac patients and can occur as a complication of catheter ablation for atrial fibrillation

Local modulation of thyroid hormone signaling in the retina affects the development of diabetic retinopathy

Thyroid hormone (TH) dyshomeostasis is associated with poor prognosis in acute and prolonged illness, but its role in diabetic retinopathy (DR) has never been investigated. Here, we characterized the TH system in the retinas of db/db mice and highlighted regulatory processes in MIO-M1 cells. In the db/db retinas, typical functional traits and molecular signatures of DR were paralleled by a tissue-restricted reduction of TH levels. A local condition of low T3 (LT3S) was also demonstrated, which was likely to be induced by deiodinase 3 (DIO3) upregulation, and by decreased expression of DIO2 and of TH receptors. Concurrently, T3-responsive genes, including mitochondrial markers and microRNAs (miR-133-3p, 338-3p and 29c-3p), were downregulated. In MIO-M1 cells, a feedback regulatory circuit was evidenced whereby miR-133-3p triggered the post-transcriptional repression of DIO3 in a T3-dependent manner, while high glucose (HG) led to DIO3 upregulation through a nuclear factor erythroid 2-related factor 2-hypoxia-inducible factor-1 pathway. Finally, an in vitro simulated condition of early LT3S and hyperglycemia correlated with reduced markers of both mitochondrial function and stress response, which was reverted by T3 replacement. Together, the data suggest that, in the early phases of DR, a DIO3-driven LT3S may be protective against retinal stress, while, in the chronic phase, it not only fails to limit HG-induced damage, but also increases cell vulnerability likely due to persistent mitochondrial dysfunction

Regional Characterization of the Gottingen Minipig Brain by [18 F]FDG Dynamic Pet Modeling.

Purpose: To determine the best kinetic model to be applied on dynamic brain [18 F]FDG PET images by characterizing the regional brain glucose metabolism of normal Göttingen minipigs. Methods: Nine Göttingen minipigs were scanned with a clinical PET/CT tomograph, starting from the injection of an intravenous bolus of [18 F]FDG, for about 25 min. Dynamic images were reconstructed and nine brain regions of interest (ROI), plus a vascular region, were defined and time-activity curves (TAC) were determined. Three kinetic models were considered for fitting with experimental TACs: one-tissue compartment model 1TC, two-tissue irreversible compartment model 2TCi and two-tissue reversible model 2TC. Akaike Information Criterion was considered to evaluate the goodness of each model fitting. Regional and global kinetic parameter values were evaluated, in addition to the partition coefficient, net influx rate and retention index (RI). Results: Both 2TCi and 2TC models turned out to be good choices for the next analysis. Parameter values were very similar between the different brain regions, with similar values to when the brain as a whole is considered (kinetic parameters mean values, from 2TCi model: K1 = 1.0 ml/g/min, k2 = 0.49 min− 1, k3 = 0.034 min− 1, K1/k2 = 2.14ml/g, Ki =0.069 ml/g/min; from 2TC model: K1 = 1.10 ml/g/min, k2 = 0.54 min− 1, k3 = 0.058 min− 1, k4 = 0.039 min− 1, K1/k2 = 2.18 ml/g, Ki = 0.10 ml/g/min; RI mean ± sd: 0.147 ± 0.037 min− 1), with the exception of the cerebellum (mean values from the 2TCi model: K1 = 0.52 ml/g/min, k2 = 0.56 min− 1, k3 = 0.025 min− 1, K1/k2 = 0.98ml/g, Ki=0.022 ml/g/min; from 2TC model: K1 = 0.54 ml/g/min, k2 = 0.61 min− 1, k3 = 0.044 min− 1, k4 = 0.038 min− 1, K1/k2 = 0.95ml/g, Ki=0.032 ml/g/min; RI mean ± sd: 0.071 ± 0.018 min− 1). Conclusion: The two-tissue model is able to describe the regional brain metabolism in Göttingen minipigs. Compared to the 2TCi model, in the 2TC model the k4 micro-parameter was also evaluated. This led to adjustments of the other microparameters, especially k3 and consequently the net influx rate Ki. For healthy minipigs, the glucose metabolism was similar in all of the brain regions analyzed, with the exception of the cerebellum, where the FDG uptake was lower

Implantable Fiber Bragg Grating sensor for continuous heart activity monitoring: ex-vivo and in-vivo validation

Continuous and reliable cardiac function monitoring could improve medication adherence in patients at risk of heart failure. This work presents an innovative implantable Fiber Bragg Grating-based soft sensor designed to sense mechanical cardiac activity. The sensor was tested in an isolated beating ovine heart platform, with 3 different hearts operated in wide-ranging conditions. In order to investigate the sensor capability to track the ventricular beats in real-time, two causal algorithms were proposed for detecting the beats from sensor data and to discriminate artifacts. The first based on dynamic thresholds while the second is a hybrid convolutional and recurrent Neural Network. An error of 2.7 ± 0.7 beats per minute was achieved in tracking the heart rate. Finally, we have confirmed the sensor reliability in monitoring the heart activity of healthy adult minipig with an error systematically lower than 1 Bpm