Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices (LVADs) in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery not only of contractile function.We herein review the current knowledge on the effects of volume-unloading the left ventricle via different methods of heterotopic heart transplantation in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under reloaded conditions.While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced remodeling of the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients

Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling.

Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under "reloaded" conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients

Is surgery in acute aortic dissection type A still contraindicated in the presence of preoperative neurological symptoms?†

OBJECTIVES Severe neurological deficit (ND) due to acute aortic dissection type A (AADA) was considered a contraindication for surgery because of poor prognosis. Recently, more aggressive indication for surgery despite neurological symptoms has shown acceptable postoperative clinical results. The aim of this study was to evaluate early and mid-term outcomes of patients with AADA presenting with acute ND. METHODS Data from 53 patients with new-onset ND who received surgical repair for AADA between 2005 and 2012 at our institution were retrospectively reviewed. ND was defined as focal motor or sensory deficit, hemiplegia, paraplegia, convulsions or coma. Neurological symptoms were evaluated preoperatively using the Glasgow Coma Scale (GCS) and modified Rankin Scale (mRS), and at discharge as well as 3-6 months postoperatively using the mRS and National Institutes of Health Stroke Scale. Involvement of carotid arteries was assessed in the pre- and postoperative computed tomography. Logistic regression analysis was performed to detect predictive factors for recovery of ND. RESULTS Of the 53 patients, 29 (54.7%) showed complete recovery from focal ND at follow-up. Neurological symptoms persisted in 24 (45.3%) patients, of which 8 (33%) died without neurological assessment at follow-up. Between the two groups (patients with recovery and those with persisting ND), there was no significant difference regarding the duration of hypothermic circulatory arrest (28 ± 14 vs 36 ± 20 min) or severely reduced consciousness (GCS <8). Multivariate analysis showed significant differences for the preoperative mRS between the two groups (P < 0.007). A high preoperative mRS was associated with persistence of neurological symptoms (P < 0.02). Cardiovascular risk factors, age or involvement of supra-aortic branches were not predictive for persistence of ND. CONCLUSION More than half of our patients recovered completely from ND due to AADA after surgery. Severity of clinical symptoms had a predictive value. Patients suffering from AADA and presenting with ND before surgery should not be excluded from emergency surger

S100A1 gene therapy for heart failure: a novel strategy on the verge of clinical trials

Representing the common endpoint of various cardiovascular disorders, heart failure (HF) shows a dramatically growing prevalence. As currently available therapeutic strategies are not capable of terminating the progress of the disease, HF is still associated with a poor clinical prognosis. Among the underlying molecular mechanisms, the loss of cardiomyocyte Ca(2+) cycling integrity plays a key role in the pathophysiological development and progression of the disease. The cardiomyocyte EF-hand Ca(2+) sensor protein S100A1 emerged as a regulator both of sarcoplasmic reticulum (SR), sarcomere and mitochondrial function implicating a significant role in cardiac physiology and dysfunction. In this review, we aim to recapitulate the translation of S100A1-based investigation from first clinical observations over basic research experiments back to a near-clinical setting on the verge of clinical trials today. We also address needs for further developments towards "second-generation" gene therapy and discuss the therapeutic potential of S100A1 gene therapy for HF as a promising novel strategy for future cardiologists. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy"

Characterization of cytoskeleton features and maturation status of cultured human iPSC-derived cardiomyocytes.

Recent innovations in stem cell technologies and the availability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have opened new possibilities for studies and drug testing on human cardiomyocytes in vitro. Still, there are concerns about the precise nature of such 'reprogrammed' cells. We have performed an investigation using immunocytochemistry and confocal microscopy on several cellular features using commercially available hiPSC-CMs. For some selected developmentally regulated or cardiac chamber-specific proteins, we have compared the results from hiPSC-derived cardiomyocytes with freshly isolated, ventricular cardiomyocytes from adult rats. The results show that all typical cardiac proteins are expressed in these hiPSC-CMs. Furthermore, intercalated disc-like structures, calcium cycling proteins, and myofibrils are present. However, some of these proteins are only known from early developmental stages of the ventricular myocardium or the diseased adult heart. A heterogeneous expression pattern in the cell population was noted for some muscle proteins, such as for myosin light chains, or incomplete organization in sarcomeres, such as for telethonin. These observations indicate that hiPSC-CMs can be considered genuine human cardiomyocytes of an early developmental state. The here described marker proteins of maturation may become instrumental in future studies attempting the improvement of cardiomyocyte in vitro models

Enhanced Cardiac S100A1 Expression Improves Recovery from Global Ischemia-Reperfusion Injury.

Gene-targeted therapy with the inotropic Ca2 + -sensor protein S100A1 rescues contractile function in post-ischemic heart failure and is being developed towards clinical trials. Its proven beneficial effect on cardiac metabolism and mitochondrial function suggests a cardioprotective effect of S100A1 in myocardial ischemia-reperfusion injury (IRI). Fivefold cardiomyocyte-specific S100A1 overexpressing, isolated rat hearts perfused in working mode were subjected to 28 min ischemia (37 °C) followed by 60 min reperfusion. S100A1 overexpressing hearts showed superior hemodynamic recover: Left ventricular pressure recovered to 57 ± 7.3% of baseline compared to 51 ± 4.6% in control (p = 0.025), this effect mirrored in LV work and dP/dt(max). Troponin T and lactate dehydrogenase was decreased in the S100A1 group, as well as FoxO pro-apoptotic transcription factor, indicating less tissue necrosis, whereas phosphocreatine content was higher after reperfusion. This is the first report of a cardioprotective effect of S100A1 overexpression in a global IRI model

Validation of 3D-reconstructed computed tomography images using OsiriX® software for pre-transcatheter aortic valve implantation aortic annulus sizing

Abstract OBJECTIVES We report validation of OsiriX® —an image processing freeware—to measure multi-slice computed tomography-derived annulus diameters for preprocedural transcatheter aortic valve implantation planning. METHODS A total of 137 patients (82 ± 6.5 years, 42.3% male, logistic EuroSCORE 24.1 ± 14.2%) with severe aortic stenosis at high surgical risk underwent transcatheter aortic valve implantation assessment: transoesophageal echocardiography, angiography and multi-slice computed tomography. Retrospectively, 3D multi-slice computed tomography reconstructions were generated using OsiriX and the reliability evaluated regarding inter- and intraobserver variability, intermodality correlation and estimation of the clinical impact on transcatheter aortic valve implantation sizing. RESULTS Reliability of the novel OsiriX software was high with an interobserver mean difference of 0.6 ± 1.4 mm and intraclass correlation of absolute agreement of 0.84 (95% confidence interval 0.74-0.90). The intermodality accuracy between OsiriX measurements and conventional 2D computed tomography reconstructions, transoesophageal echocardiography and angiography revealed significantly larger sizing with OsiriX, with a mean difference to 2D computed tomography of 0.4 ± 2.2 mm, which would have changed valve sizing in 38% of patients. In 28%, a larger size would have been chosen, and this correlated highly with the occurrence of postoperative severe aortic regurgitation (P < 0.001). CONCLUSIONS While OsiriX measurements are an accurate and reproducible assessment of the aortic annulus, there are distinct and clinically relevant differences in aortic annulus dimensions between OsiriX measurements and previously standard imaging modalities. Sizing with OsiriX resulted in a larger perimeter compared with conventional 2D imaging. Careful assessment of valve size will take into account multiple imaging modalities

Validation of 3D-reconstructed computed tomography images using OsiriX® software for pre-transcatheter aortic valve implantation aortic annulus sizing

We report validation of OsiriX -an image processing freeware-to measure multi-slice computed tomography-derived annulus diameters for preprocedural transcatheter aortic valve implantation planning