Myocardial tissue remodeling after orthotopic heart transplantation: a pilot cardiac magnetic resonance study.

After orthotopic heart transplantation (OHT), the allograft undergoes characteristic alterations in myocardial structure, including hypertrophy, increased ventricular stiffness, ischemia, and inflammation, all of which may decrease overall graft survival. Methods to quantify these phenotypes may clarify the pathophysiology of progressive graft dysfunction post-OHT. We performed cardiac magnetic resonance (CMR) with T1 mapping in 26 OHT recipients (mean age 47 ± 7 years, 30 % female, median follow-up post-OHT 6 months) and 30 age-matched healthy volunteers (mean age 50.5 ± 15 years; LVEF 63.5 ± 7 %). OHT recipients had a normal left ventricular ejection fraction (LVEF 65.3 ± 11 %) with higher LV mass relative to age-matched healthy volunteers (114 ± 27 vs. 85.8 ± 18 g; p < 0.001). There was no late gadolinium enhancement in either group. Both myocardial extracellular volume fraction (ECV) and intracellular lifetime of water (τic), a measure of cardiomyocyte hypertrophy, were higher in patients post-OHT (ECV: 0.39 ± 0.06 vs. 0.28 ± 0.03, p < 0.0001; τic: 0.12 ± 0.08 vs. 0.08 ± 0.03, p < 0.001). ECV was associated with LV mass (r = 0.74, p < 0.001). In follow-up, OHT recipients with normal biopsies by pathology (ISHLT grade 0R) in the first year post-OHT exhibited a lower ECV relative to patients with any rejection ≥2R (0.35 ± 0.02 for 0R vs. 0.45 ± 0, p < 0.001). Higher ECV but not LVEF was significantly associated with a reduced rejection-free survival. After OHT, markers of tissue remodeling by CMR (ECV and τic) are elevated and associated with myocardial hypertrophy. Interstitial myocardial remodeling (by ECV) is associated with cellular rejection. Further research on the impact of graft preservation and early immunosuppression on tissue-level remodeling of the allograft is necessary to delineate the clinical implications of these findings.

Correction: Atorvastatin Improves Ventricular Remodeling after Myocardial Infarction by Interfering with Collagen Metabolism.

[This corrects the article DOI: 10.1371/journal.pone.0166845.].

Atorvastatin Improves Ventricular Remodeling after Myocardial Infarction by Interfering with Collagen Metabolism.

PURPOSE: Therapeutic strategies that modulate ventricular remodeling can be useful after acute myocardial infarction (MI). In particular, statins may exert effects on molecular pathways involved in collagen metabolism. The aim of this study was to determine whether treatment with atorvastatin for 4 weeks would lead to changes in collagen metabolism and ventricular remodeling in a rat model of MI. METHODS: Male Wistar rats were used in this study. MI was induced in rats by ligation of the left anterior descending coronary artery (LAD). Animals were randomized into three groups, according to treatment: sham surgery without LAD ligation (sham group, n = 14), LAD ligation followed by 10mg atorvastatin/kg/day for 4 weeks (atorvastatin group, n = 24), or LAD ligation followed by saline solution for 4 weeks (control group, n = 27). After 4 weeks, hemodynamic characteristics were obtained by a pressure-volume catheter. Hearts were removed, and the left ventricles were subjected to histologic analysis of the extents of fibrosis and collagen deposition, as well as the myocyte cross-sectional area. Expression levels of mediators involved in collagen metabolism and inflammation were also assessed. RESULTS: End-diastolic volume, fibrotic content, and myocyte cross-sectional area were significantly reduced in the atorvastatin compared to the control group. Atorvastatin modulated expression levels of proteins related to collagen metabolism, including MMP1, TIMP1, COL I, PCPE, and SPARC, in remote infarct regions. Atorvastatin had anti-inflammatory effects, as indicated by lower expression levels of TLR4, IL-1, and NF-kB p50. CONCLUSION: Treatment with atorvastatin for 4 weeks was able to attenuate ventricular dysfunction, fibrosis, and left ventricular hypertrophy after MI in rats, perhaps in part through effects on collagen metabolism and inflammation. Atorvastatin may be useful for limiting ventricular remodeling after myocardial ischemic events.

Diacerein improves left ventricular remodeling and cardiac function by reducing the inflammatory response after myocardial infarction.

BACKGROUND: The inflammatory response has been implicated in the pathogenesis of left ventricular (LV) remodeling after myocardial infarction (MI). An anthraquinone compound with anti-inflammatory properties, diacerein inhibits the synthesis and activity of pro-inflammatory cytokines, such as tumor necrosis factor and interleukins 1 and 6. The purpose of this study was to investigate the effects of diacerein on ventricular remodeling in vivo. METHODS AND RESULTS: Ligation of the left anterior descending artery was used to induce MI in an experimental rat model. Rats were divided into two groups: a control group that received saline solution (n = 16) and a group that received diacerein (80 mg/kg) daily (n = 10). After 4 weeks, the LV volume, cellular signaling, caspase 3 activity, and nuclear factor kappa B (NF-κB) transcription were compared between the two groups. After 4 weeks, end-diastolic and end-systolic LV volumes were reduced in the treatment group compared to the control group (p < .01 and p < .01, respectively). Compared to control rats, diacerein-treated rats exhibited less fibrosis in the LV (14.65%± 7.27% vs. 22.57%± 8.94%; p < .01), lower levels of caspase-3 activity, and lower levels of NF-κB p65 transcription. CONCLUSIONS: Treatment with diacerein once a day for 4 weeks after MI improved ventricular remodeling by promoting lower end-systolic and end-diastolic LV volumes. Diacerein also reduced fibrosis in the LV. These effects might be associated with partial blockage of the NF-κB pathway.

Early changes in contractility indices and fibrosis in two minimally invasive congestive heart failure models.

BACKGROUND: Heart failure is a common and often fatal disease. Numerous animal models are used to study its aetiology, progression and treatment. This article aims to demonstrate two minimally invasive models of congestive heart failure in a rabbit model and a precise method to assess cardiac performance. METHODS: Fifty New Zealand White rabbits underwent cervicotomy incision and were then divided into three groups. Aortic regurgitation (AR group) was induced in 17 animals by catheter lesion through the right carotid artery, proximal aortic constriction (AC group) was created in 17 animals by metallic clip placement in the ascending aorta through a neck incision, while 16 animals served as controls (CO group). Eight weeks later, myocardial function and contractility indices were assessed by sonomicrometry crystals. Hearts were then collected for morphometric measurements and left ventricular tissues were subjected to immunohistochemical analysis of fibrosis, necrosis and apoptosis. Statistical analysis was by analysis of variance (ANOVA) with a Dunnett's post hoc test or by Kruskal-Wallis test with Dunn's post hoc test as appropriate, with significance at p< or =0.05. RESULTS: The model of aortic regurgitation indicated early stages of heart failure by volume overload with increased end-diastolic and end-systolic volumes, stroke volume, cardiac output and pressure-volume loop areas. The elastance was higher in the control group compared with that in the AC and AR groups (131.00+/-51.27 vs 88.77+/-40.11 vs 75.29+/-50.70; p=0.01). The preload recruitable stroke work was higher in the control group compared with that in the AC and AR groups (47.70+/-14.19 vs 33.87+/-7.46 vs 38.58+/-9.45; p=0.01). Aortic constriction produced left ventricular concentric hypertrophy. Fibrosis appeared in both heart failure models and was elevated by aortic constriction when compared with that in controls. Necrosis and apoptosis indices were very low in all the groups. Clinical signs of congestive heart failure were not present. CONCLUSIONS: The two heart failure models we describe were relatively simple to create and maintain, minimally invasive, accurate, inexpensive and, importantly, had a low mortality rate. These models rapidly induced deterioration of contractility indices and onset of fibrosis, the hallmarks of early myocardial dysfunction associated with heart failure. Sonomicrometry assessments were able to detect early contractility changes prior to clinical signs.