Anthracycline-induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed.
The purpose of this study was to identify early doxorubicin-induced cardiotoxicity by ...serial multiparametric cardiac magnetic resonance (CMR) and its pathological correlates in a large animal model.
Twenty pigs were included. Of these, 5 received 5 biweekly intracoronary doxorubicin doses (0.45 mg/kg/injection) and were followed until sacrifice at 16 weeks. Another 5 pigs received 3 biweekly doxorubicin doses and were followed to 16 weeks. A third group was sacrificed after the third dose. All groups underwent weekly CMR examinations including anatomical and T2 and T1 mapping (including extracellular volume ECV quantification). A control group was sacrificed after the initial CMR.
The earliest doxorubicin-cardiotoxicity CMR parameter was T2 relaxation-time prolongation at week 6 (2 weeks after the third dose). T1 mapping, ECV, and left ventricular (LV) motion were unaffected. At this early time point, isolated T2 prolongation correlated with intracardiomyocyte edema secondary to vacuolization without extracellular space expansion. Subsequent development of T1 mapping and ECV abnormalities coincided with LV motion defects: LV ejection fraction declined from week 10 (2 weeks after the fifth and final doxorubicin dose). Stopping doxorubicin therapy upon detection of T2 prolongation halted progression to LV motion deterioration and resolved intracardiomyocyte vacuolization, demonstrating that early T2 prolongation occurs at a reversible disease stage.
T2 mapping during treatment identifies intracardiomyocyte edema generation as the earliest marker of anthracycline-induced cardiotoxicity, in the absence of T1 mapping, ECV, or LV motion defects. The occurrence of these changes at a reversible disease stage shows the clinical potential of this CMR marker for tailored anthracycline therapy.
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Although potentiodynamic polarization is a common technique for determining corrosion current, there is no consensus on the choice of scanning parameters. This study explores a 1D mathematical model ...of copper under oxygen reduction in a chloride containing medium to quantify the effects of scan rate, starting overpotential, and scan direction on the features of polarization curve. All the relevant tendencies of the cathodic branch are reproduced experimentally and explained by local oxygen consumption and coverage by CuCl. The corresponding effects on the precision of determining corrosion current are discussed, revealing that the largest deviation of up to 50% is obtained for the slowest scan rate and largest starting overpotential.
The impact of cardioprotective strategies and ischemia duration on postischemia/reperfusion (I/R) myocardial tissue composition (edema, myocardium at risk, infarct size, salvage, intramyocardial ...hemorrhage, and microvascular obstruction) is not well understood.
To study the effect of ischemia duration and protective interventions on the temporal dynamics of myocardial tissue composition in a translational animal model of I/R by the use of state-of-the-art imaging technology.
Four 5-pig groups underwent different I/R protocols: 40-minute I/R (prolonged ischemia, controls), 20-minute I/R (short-duration ischemia), prolonged ischemia preceded by preconditioning, or prolonged ischemia followed by postconditioning. Serial cardiac magnetic resonance (CMR)-based tissue characterization was done in all pigs at baseline and at 120 minutes, day 1, day 4, and day 7 after I/R. Reference myocardium at risk was assessed by multidetector computed tomography during the index coronary occlusion. After the final CMR, hearts were excised and processed for water content quantification and histology. Five additional healthy pigs were euthanized after baseline CMR as reference. Edema formation followed a bimodal pattern in all 40-minute I/R pigs, regardless of cardioprotective strategy and the degree of intramyocardial hemorrhage or microvascular obstruction. The hyperacute edematous wave was ameliorated only in pigs showing cardioprotection (ie, those undergoing short-duration ischemia or preconditioning). In all groups, CMR-measured edema was barely detectable at 24 hours postreperfusion. The deferred healing-related edematous wave was blunted or absent in pigs undergoing preconditioning or short-duration ischemia, respectively. CMR-measured infarct size declined progressively after reperfusion in all groups. CMR-measured myocardial salvage, and the extent of intramyocardial hemorrhage and microvascular obstruction varied dramatically according to CMR timing, ischemia duration, and cardioprotective strategy.
Cardioprotective therapies, duration of index ischemia, and the interplay between these greatly influence temporal dynamics and extent of tissue composition changes after I/R. Consequently, imaging techniques and protocols for assessing edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction should be standardized accordingly.
Corrosion of copper pipes may release high amounts of copper into the water, exceeding the maximum concentration of copper for drinking water standards. Typically, the events with the highest release ...of copper into drinking water are related to the presence of biofilms. This article reviews this phenomenon, focusing on copper ingestion and its health impacts, the physicochemical mechanisms and the microbial involvement on copper release, the techniques used to describe and understand this phenomenon, and the hydrodynamic effects. A conceptual model is proposed and the mathematical models are reviewed.
Abstract Background Pre-reperfusion administration of intravenous (IV) metoprolol reduces infarct size in ST-segment elevation myocardial infarction (STEMI). Objectives This study sought to determine ...how this cardioprotective effect is influenced by the timing of metoprolol therapy having either a long or short metoprolol bolus-to-reperfusion interval. Methods We performed a post hoc analysis of the METOCARD-CNIC (effect of METOprolol of CARDioproteCtioN during an acute myocardial InfarCtion) trial, which randomized anterior STEMI patients to IV metoprolol or control before mechanical reperfusion. Treated patients were divided into short- and long-interval groups, split by the median time from 15 mg metoprolol bolus to reperfusion. We also performed a controlled validation study in 51 pigs subjected to 45 min ischemia/reperfusion. Pigs were allocated to IV metoprolol with a long (−25 min) or short (−5 min) pre-perfusion interval, IV metoprolol post-reperfusion (+60 min), or IV vehicle. Cardiac magnetic resonance (CMR) was performed in the acute and chronic phases in both clinical and experimental settings. Results For 218 patients (105 receiving IV metoprolol), the median time from 15 mg metoprolol bolus to reperfusion was 53 min. Compared with patients in the short-interval group, those with longer metoprolol exposure had smaller infarcts (22.9 g vs. 28.1 g; p = 0.06) and higher left ventricular ejection fraction (LVEF) (48.3% vs. 43.9%; p = 0.019) on day 5 CMR. These differences occurred despite total ischemic time being significantly longer in the long-interval group (214 min vs. 160 min; p < 0.001). There was no between-group difference in the time from symptom onset to metoprolol bolus. In the animal study, the long-interval group (IV metoprolol 25 min before reperfusion) had the smallest infarcts (day 7 CMR) and highest long-term LVEF (day 45 CMR). Conclusions In anterior STEMI patients undergoing primary angioplasty, the sooner IV metoprolol is administered in the course of infarction, the smaller the infarct and the higher the LVEF. These hypothesis-generating clinical data are supported by a dedicated experimental large animal study.
Abstract Background Exercise has been proposed as a trigger for arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype manifestation; however, research is hampered by the limited ...availability of animal models in which disease-associated mutations can be tested. Objectives This study evaluated the impact of exercise on ARVC cardiac manifestations in mice after adeno-associated virus (AAV)–mediated gene delivery of mutant human PKP2 , which encodes the desmosomal protein plakophilin-2. Methods We developed a new model of cardiac tissue–specific transgenic-like mice on the basis of AAV gene transfer to test the potential of a combination of a human PKP2 mutation and endurance training to trigger an ARVC-like phenotype. Results Stable cardiac expression of mutant PKP2 (c.2203C>T), encoding the R735X mutant protein, was achieved 4 weeks after a single AAV9-R735X intravenous injection. High-field cardiac magnetic resonance over a 10-month postinfection follow-up did not detect an overt right ventricular (RV) phenotype in nonexercised (sedentary) mice. In contrast, endurance exercise training (initiated 2 weeks after AAV9-R735X injection) resulted in clear RV dysfunction that resembled the ARVC phenotype (impaired global RV systolic function and RV regional wall motion abnormalities on cardiac magnetic resonance). At the histological level, RV samples from endurance-trained R735X-infected mice displayed connexin 43 delocalization at intercardiomyocyte gap junctions, a change not observed in sedentary mice. Conclusions The introduction of the PKP2 R735X mutation into mice resulted in an exercise-dependent ARVC phenotype. The R735X mutation appears to function as a dominant-negative variant. This novel system for AAV-mediated introduction of a mutation into wild-type mice has broad potential for study of the implication of diverse mutations in complex cardiomyopathies.
The β1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on ...cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil-platelet interactions, fully abrogated metoprolol's infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil-platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.
We used bench-scale tests and mathematical modeling to explore chemical oxygen demand (COD) removal rates in a moving-bed biofilm reactor (MBBR) for winery wastewater treatment, using either urea or ...nitrate as a nitrogen source. With urea addition, the COD removal fluxes ranged from 34 to 45 gCOD/m
-d. However, when nitrate was added, fluxes increased up to 65 gCOD/m
-d, twice the amount reported for aerobic biofilms for winery wastewater treatment. A one-dimensional biofilm model, calibrated with data from respirometric tests, accurately captured the experimental results. Both experimental and modelling results suggest that nitrate significantly increased MBBR capacity by stimulating COD oxidation in the deeper, oxygen-limited regions of the biofilm. Our research suggests that the addition of nitrate, or other energetic and broadly used electron acceptors, may provide a cost-effective means of covering peak COD loads in biofilm processes for winery or another industrial wastewater treatment.
Early metoprolol administration protects against myocardial ischemia–reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total
n
= 122) ...underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography CT during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%,
p
= 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (
p
= 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%,
p
= 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.
Left ventricular noncompaction (LVNC) causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. ...We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction.
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