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1. Exacerbated post‐infarct pathological myocardial remodelling in diabetes is associated with impaired autophagy and aggravated NLRP3 inflammasome activation

   https://doi.org/10.1002/ehf2.13754  

   Mao, Shuai ; Chen, Peipei ; Pan, Wenjun ; Gao, Lei ; Zhang, Minzhou ( December 2021 , ESC Heart Failure)

   Diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher mortality due to the more frequent development of subsequent pathological myocardial remodelling and concomitant functional deterioration. This study investigates the molecular pathways underlying accelerated cardiac remodelling in a well‐established mouse model of diabetes exposed to MI.

   Myocardial infarction in DM mice was established by ligating the left anterior descending coronary artery. Cardiac function was assessed by echocardiography. Myocardial hypertrophy and cardiac fibrosis were determined histologically 6 weeks post‐MI or sham operation. Autophagy, the NLRP3 inflammasome, and caspase‐1 were evaluated by western blotting or immunofluorescence. Echocardiographic imaging revealed significantly increased left ventricular dilation in parallel with increased mortality after MI in DM mice (53.33%) compared with control mice (26.67%,P < 0.05). Immunoblotting, electron microscopy, and immunofluorescence staining for LC3 and p62 indicated impaired autophagy in DM + MI mice compared with control mice (P < 0.05). Furthermore, defective autophagy was associated with increased NLRP3 inflammasome and caspase‐1 hyperactivation in DM + MI mouse cardiomyocytes (P < 0.05). Consistent with NLRP3 inflammasome and caspase‐I hyperactivation, cardiomyocyte death and IL‐1β and IL‐18 secretion were increased in DM + MI mice (P < 0.05). Importantly, the autophagy inducer and the NLRP3 inhibitor attenuated the cardiac remodelling of DM mice after MI.

   In summary, our results indicate that DM aggravates cardiac remodelling after MI through defective autophagy and associated exaggerated NLRP3 inflammasome activation, proinflammatory cytokine secretion, suggesting that restoring autophagy and inhibiting NLRP3 inflammasome activation may serve as novel targets for the prevention and treatment of post‐infarct remodelling in DM.

    

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2. Right Ventricular Function and T1 ‐Mapping in Boys With Duchenne Muscular Dystrophy

   https://doi.org/10.1002/jmri.27729  

   Dual, Seraina A. ; Maforo, Nyasha G. ; McElhinney, Doff B. ; Prosper, Ashley ; Wu, Holden H. ; Maskatia, Shiraz ; Renella, Pierangelo ; Halnon, Nancy ; Ennis, Daniel B. ( May 2021 , Journal of Magnetic Resonance Imaging)

   Clinical management of boys with Duchenne muscular dystrophy (DMD) relies on in‐depth understanding of cardiac involvement, but right ventricular (RV) structural and functional remodeling remains understudied.

   To evaluate several analysis methods and identify the most reliable one to measure RV pre‐ and postcontrast T1 (RV‐T1) and to characterize myocardial remodeling in the RV of boys with DMD.

   Prospective.

   Boys with DMD (N = 27) and age‐/sex‐matched healthy controls (N = 17) from two sites.

   3.0 T using balanced steady state free precession, motion‐corrected phase sensitive inversion recovery and modified Look‐Locker inversion recovery sequences.

   Biventricular mass (Mi), end‐diastolic volume (EDVi) and ejection fraction (EF) assessment, tricuspid annular excursion (TAE), late gadolinium enhancement (LGE), pre‐ and postcontrast myocardial T1 maps. The RV‐T1 reliability was assessed by three observers in four different RV regions of interest (ROI) using intraclass correlation (ICC).

   The Wilcoxon rank sum test was used to compare RV‐T1 differences between DMD boys with negative LGE(−) or positive LGE(+) and healthy controls. Additionally, correlation of precontrast RV‐T1 with functional measures was performed. AP‐value <0.05 was considered statistically significant.

   A 1‐pixel thick RV circumferential ROI proved most reliable (ICC > 0.91) for assessing RV‐T1. Precontrast RV‐T1 was significantly higher in boys with DMD compared to controls. Both LGE(−) and LGE(+) boys had significantly elevated precontrast RV‐T1 compared to controls (1543 [1489–1597] msec and 1550 [1402–1699] msec vs. 1436 [1399–1473] msec, respectively). Compared to healthy controls, boys with DMD had preserved RVEF (51.8 [9.9]% vs. 54.2 [7.2]%,P = 0.31) and significantly reduced RVMi (29.8 [9.7] g vs. 48.0 [15.7] g), RVEDVi (69.8 [29.7] mL/m²vs. 89.1 [21.9] mL/m²), and TAE (22.0 [3.2] cm vs. 26.0 [4.7] cm). Significant correlations were found between precontrast RV‐T1 and RVEF (β = −0.48%/msec) and between LV‐T1 and LVEF (β = −0.51%/msec).

   Precontrast RV‐T1 is elevated in boys with DMD compared to healthy controls and is negatively correlated with RVEF.

   1

   Stage 2

    

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3. In vivo assessment of mitral valve leaflet remodelling following myocardial infarction

   https://doi.org/10.1038/s41598-022-22790-0  

   Rego, Bruno V. ; Khalighi, Amir H. ; Lai, Eric K. ; Gorman, Robert C. ; Gorman, III, Joseph H. ; Sacks, Michael S. ( October 2022 , Scientific Reports)

   Each year, more than 40,000 people undergo mitral valve (MV) repair surgery domestically to treat regurgitation caused by myocardial infarction (MI). Although continual MV tissue remodelling following repair is believed to be a major contributor to regurgitation recurrence, the effects of the post-MI state on MV remodelling remain poorly understood. This lack of understanding limits our ability to predict the remodelling of the MV both post-MI and post-surgery to facilitate surgical planning. As a necessary first step, the present study was undertaken to noninvasively quantify the effects of MI on MV remodelling in terms of leaflet geometry and deformation. MI was induced in eight adult Dorset sheep, and real-time three-dimensional echocardiographic (rt-3DE) scans were collected pre-MI as well as at 0, 4, and 8 weeks post-MI. A previously validated image-based morphing pipeline was used to register corresponding open- and closed-state scans and extract local in-plane strains throughout the leaflet surface at systole. We determined that MI inducedpermanentchanges in leaflet dimensions in the diastolic configuration, which increased with time to 4 weeks, then stabilised. MI substantially affected the systolicshapeof the MV, and therange of stretchexperienced by the MV leaflet at peak systole was substantially reduced when referred to the current time-point. Interestingly, when we referred the leaflet strains to the pre-MI configuration, the systolic strains remained very similar throughout the post-MI period. Overall, we observed that post-MI ventricular remodeling induced permanent changes in the MV leaflet shape. This predominantly affected the MV’s diastolic configuration, leading in turn to a significant decrease in the range of stretch experienced by the leaflet when referenced to the current diastolic configuration. These findings are consistent with our previous work that demonstrated increased plastic (i.e. non-recoverable) leaflet deformations post-MI, that was completely accounted for by the associated changes in collagen fiber structure. Moreover, we demonstrated through noninvasive methods that the state of the MV leaflet can elucidate the progression and extent of MV adaptation following MI and is thus highly relevant to the design of current and novel patient specific minimally invasive surgical repair strategies.

    

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4. High frequency alternating current neurostimulation decreases nocifensive behavior in a disc herniation model of lumbar radiculopathy

   https://doi.org/10.1186/s42234-023-00119-0  

   Dewberry, Lauren Savannah ; Porche, Ken ; Koenig, Travis ; Allen, Kyle D. ; Otto, Kevin J. ( July 2023 , Bioelectronic Medicine)

   The purpose of this study was to evaluate if kilohertz frequency alternating current (KHFAC) stimulation of peripheral nerve could serve as a treatment for lumbar radiculopathy. Prior work shows that KHFAC stimulation can treat sciatica resulting from chronic sciatic nerve constriction. Here, we evaluate if KHFAC stimulation is also beneficial in a more physiologic model of low back pain which mimics nucleus pulposus (NP) impingement of a lumbar dorsal root ganglion (DRG).

   To mimic a lumbar radiculopathy, autologous tail NP was harvested and placed upon the right L5 nerve root and DRG. During the same surgery, a cuff electrode was implanted around the sciatic nerve with wires routed to a headcap for delivery of KHFAC stimulation. Male Lewis rats (3 mo.,n = 18) were separated into 3 groups: NP injury + KHFAC stimulation (n = 7), NP injury + sham cuff (n = 6), and sham injury + sham cuff (n = 5). Prior to surgery and for 2 weeks following surgery, animal tactile sensitivity, gait, and static weight bearing were evaluated.

   KHFAC stimulation of the sciatic nerve decreased behavioral evidence of pain and disability. Without KHFAC stimulation, injured animals had heightened tactile sensitivity compared to baseline (p < 0.05), with tactile allodynia reversed during KHFAC stimulation (p < 0.01). Midfoot flexion during locomotion was decreased after injury but improved with KHFAC stimulation (p < 0.05). Animals also placed more weight on their injured limb when KHFAC stimulation was applied (p < 0.05). Electrophysiology measurements at end point showed decreased, but not blocked, compound nerve action potentials with KHFAC stimulation (p < 0.05).

   KHFAC stimulation decreases hypersensitivity but does not cause additional gait compensations. This supports the idea that KHFAC stimulation applied to a peripheral nerve may be able to treat chronic pain resulting from sciatic nerve root inflammation.

    

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5. Effects of Chronic Nicotine Inhalation on Systemic and Pulmonary Blood Pressure and Right Ventricular Remodeling in Mice

   https://doi.org/10.1161/HYPERTENSIONAHA.119.14608  

   Oakes, Joshua M. ; Xu, Jiaxi ; Morris, Tamara M. ; Fried, Nicholas D. ; Pearson, Charlotte S. ; Lobell, Thomas D. ; Gilpin, Nicholas W. ; Lazartigues, Eric ; Gardner, Jason D. ; Yue, Xinping ( May 2020 , Hypertension)

   null (Ed.)

   Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases; however, the role of nicotine in the pathogenesis of these diseases is incompletely understood. The purpose of this study was to examine the effects of chronic nicotine inhalation on the development of cardiovascular and pulmonary disease with a focus on blood pressure and cardiac remodeling. Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hour on/12 hour off) for 8 weeks. Systemic blood pressure was recorded weekly by radio-telemetry, and cardiac remodeling was monitored by echocardiography. At the end of the 8 weeks, mice were subjected to right heart catheterization to measure right ventricular systolic pressure. Nicotine-exposed mice exhibited elevated systemic blood pressure from weeks 1 to 3, which then returned to baseline from weeks 4 to 8, indicating development of tolerance to nicotine. At 8 weeks, significantly increased right ventricular systolic pressure was detected in nicotine-exposed mice compared with the air controls. Echocardiography showed that 8-week nicotine inhalation resulted in right ventricular (RV) hypertrophy with increased RV free wall thickness and a trend of increase in RV internal diameter. In contrast, there were no significant structural or functional changes in the left ventricle following nicotine exposure. Mechanistically, we observed increased expression of angiotensin-converting enzyme and enhanced activation of mitogen-activated protein kinase pathways in the RV but not in the left ventricle. We conclude that chronic nicotine inhalation alters both systemic and pulmonary blood pressure with the latter accompanied by RV remodeling, possibly leading to progressive and persistent pulmonary hypertension. 

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