Cell therapies for heart function recovery: focus on myocardial tissue engineering and nanotechnologies

Cell therapies have gained increasing interest and developed in several approaches related to the treatment of damaged myocardium. The results of multiple clinical trials have already been reported, almost exclusively involving the direct injection of stem cells. It has, however, been postulated that the efficiency of injected cells could possibly be hindered by the mechanical trauma due to the injection and their low survival in the hostile environment. It has indeed been demonstrated that cell mortality due to the injection approaches 90%. Major issues still need to be resolved and bed-to-bench followup is paramount to foster clinical implementations. The tissue engineering approach thus constitutes an attractive alternative since it provides the opportunity to deliver a large number of cells that are already organized in an extracellular matrix. Recent laboratory reports confirmed the interest of this approach and already encouraged a few groups to investigate it in clinical studies. We discuss current knowledge regarding engineered tissue for myocardial repair or replacement and in particular the recent implementation of nanotechnological approaches

Atrial fibrillation and minimally invasive coronary artery bypass grafting: Risk factor analysis

Atrial fibrillation (AF) is a frequent arrhythmia after conventional coronary artery bypass grafting. With the advent of minimally invasive technique for left internal mammary artery-left anterior descending coronary artery (LIMA-LAD) grafting, we analyzed the incidence and the risk factors of postoperative AF in this patient population. This prospective study involves all patients undergoing isolated LIMA-LAD grafting with minimally invasive technique between January 1994 and June 2000. Twenty-four possible risk factors for postoperative AF were entered into univariate and multivariate logistic regression analyses. Postoperative AF occurred in 21 of the 90 patients (23.3%) analyzed. Double- or triple-vessel disease was present in 12/90 patients (13.3%). On univariate analysis, right coronary artery disease (p<0.01), age (p=0.01), and diabetes (p=0.04) were found to be risk factors for AF. On multivariate analysis, right coronary artery disease was identified as the sole significant risk factor (p=0.02). In this patient population, the incidence of AF after minimally invasive coronary artery bypass is in the range of that reported for conventional coronary artery bypass grafting. Right coronary artery disease was found to be an independent predictor, and this may be related to the fact that in this patient population the diseased right coronary artery was not revascularized at the time of the surgical procedure. For the same reason, this risk factor may find a broader application to noncardiac thoracic surger

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

Transmyocardial laser revascularisation in acutely ischaemic myocardium

Objective: Although recent experience suggests that transmyocardial laser revascularisation (TMLR) relieves angina, its mechanism of action remains undefined. We examined its functional effects and analysed its morphological features in an animal model of acute ischaemia. Methods: A total of 15 pigs were randomised to ligation of left marginal arteries (infarction group, n=5), to TMLR of the left lateral wall using a holmium:yttrium-aluminium garnet (Ho:YAG) laser (laser group, n=5), and to both (laser-infarction group, n=5). All the animals were sacrificed 1 month after the procedure. Haemodynamics and echocardiography with segmental wall motion score were carried out at both time intervals (scale 0-3: 0, normal; 1, hypokinesia; 2, akinesia; 3, dyskinesia). Histology of the involved area was analysed. Results: Laser group showed no change of the segmental wall motion score of the involved area 30 min after the laser channels were made (score: 0±0). Infarction and laser-infarction groups both showed a persistent and definitive increase of the segmental wall motion score (at 30 min: 1.6±0.3 and 2±0, respectively; at 1 month: 1.8±0.2 and 1.8±0.4, respectively). These increases were all statistically significant in comparison with baseline values (P<0.5), however comparison between infarction and laser-infarction groups showed no significant difference. On macroscopic examination of the endocardial surface, no channel was opened. On histology, there were signs of neovascularisation around the channels in the laser group, whereas in the laser-infarction group the channels were embedded in the infarction scar. Conclusions: In this acute pig model, TMLR did not provide improvement of contractility of the ischaemic myocardium. To the degree that the present study pertains to the clinical setting, the results suggest that mechanisms other than blood flow through the channels should be considered, such as a laser-induced triggering of neovascularisation or neural destructio

Angiotensinergic innervation of the human right atrium: implications for cardiac reflexes

Background: The right atrium is densely innervated and provides sensory input to important cardio-circulatory reflexes controlling cardiac output and blood pressure. Its angiotensin (Ang) II-expressing innervation may release Ang II as a neuropeptide co-transmitter to modulate reflexes but has not yet been characterized. Methods: Intraoperative surgical biopsies from human right atria (n=7) were immunocytologically stained for Ang II, tyrosine hydroxylase (TH) and synaptophysin (SYN). Tissue angiotensins were extracted and quantified by radioimmunoassay. Results: Angiotensinergic fibers were frequent in epicardial nerves and around vessels with variable TH co-localization (none to >50%/bundle). Fibers were also widely distributed between cardiomyocytes and in the endocardium where they were typically non-varicose, TH/SYN-negative and usually accompanied by varicose catecholaminergic fibers. In the endocardium, some showed large varicosities and were partially TH or SYN-positive. A few endocardial regions showed scattered non-varicose Ang fibers ending directly between endothelial cells. Occasional clusters of thin varicose terminals co-localizing SYN or TH were located underneath, or protruded into, the endothelium. Endocardial density of Ang and TH-positive fibers was 30–300 vs. 200–450/mm 2. Atrial Ang II, III and I concentrations were 67, 16 and 5 fmol/g (median) while Ang IV and V were mostly undetectable. Conclusions: The human right atrium harbours an abundant angiotensinergic innervation and a novel potential source of atrial Ang II. Most peripheral fibers were non-catecholaminergic afferents or preterminal vagal efferents and a minority was presumably sympathetic. Neuronal Ang II release from these fibers may modulate cardiac and circulatory reflexes independently from plasma and tissue Ang II sources

Impact of duration of chest tube drainage on pain after cardiac surgery

Objective: This study was designed to analyze the duration of chest tube drainage on pain intensity and distribution after cardiac surgery. Methods: Two groups of 80 cardiac surgery adult patients, operated on in two different hospitals, by the same group of cardiac surgeons, and with similar postoperative strategies, were compared. However, in one hospital (long drainage group), a conservative policy was adopted with the removal the chest tubes by postoperative day (POD) 2 or 3, while in the second hospital (short drainage group), all the drains were usually removed on POD 1. Results: There was a trend toward less pain in the short drainage group, with a statistically significant difference on POD 2 (P=0.047). There were less patients without pain on POD 3 in the long drainage group (P=0.01). The areas corresponding to the tract of the pleural tube, namely the epigastric area, the left basis of the thorax, and the left shoulder were more often involved in the long drainage group. There were three pneumonias in each group and no patient required repeated drainage. Conclusions: A policy of early chest drain ablation limits pain sensation and simplifies nursing care, without increasing the need for repeated pleural puncture. Therefore, a policy of short drainage after cardiac surgery should be recommende

Massive pulmonary embolism: surgical embolectomy versus thrombolytic therapy—should surgical indications be revisited?†

OBJECTIVES The treatment of massive pulmonary embolism (PE) is a matter of debate. We present our institutional experience of patients suffering from massive PE with the aim of comparing the early results, the outcome and quality of life (QoL) between patients primarily assigned to either pulmonary surgical embolectomy (SE) or thrombolytic therapy (TL). A subgroup of patients (TS) with failed responses to TL requiring SE was separately analysed. METHODS All consecutive patients (January 2001-December 2007) with computed tomography (CT)-scan-confirmed massive bilateral central or paracentral PE were reviewed. All clinical data were retrieved from our patients' registry and completed by the evaluation of the CT-scan-derived right ventricle/left ventricle ratio (RV/LV ratio). Follow-up focused on clinical outcome and QoL was obtained. RESULTS Eighty patients were analysed including 28 SE (35%) and 52 TL (65%), of whom 11 (21%) required TS. Demographics and preoperative characteristics were similar between SE and TL. Analysis of the RV/LV ratio revealed a ratio of 1.66 for SEand 1.44 for TL. The early mortality rate was not significantly different between the two groups (SE: 3.6% versus TL: 13.5%), whereas early mortality was 27% in those patients treated initially with thrombolysis and subsequently requiring SE (TS-group). Severe bleeding complications were lower in the SE-group (3.6% versus 26.5% P=0.013). Intracerebral bleeding rates and neurological events were not statistically different. After a mean follow-up of 63±21 months, the mortality rate was 17.9% in the SE-group and 23.1% in the TL-group. CONCLUSIONS SE is an excellent treatment option in massive PE with comparable early mortality rates and significantly less bleeding complications than TL. Patients having surgery after inefficient thrombolysis have the worst early outcome. The RV/LV CT-scan ratio might serve as a predictor to differentiate patients, who could profit from direct surgical intervention than thrombolytic treatment attempts. Further studies are required to confirm these result

Cardiac transplantation with hearts from donors after circulatory declaration of death: haemodynamic and biochemical parameters at procurement predict recovery following cardioplegic storage in a rat model†

OBJECTIVES Donation after circulatory declaration of death (DCDD) could significantly improve the number of cardiac grafts for transplantation. Graft evaluation is particularly important in the setting of DCDD given that conditions of cardio-circulatory arrest and warm ischaemia differ, leading to variable tissue injury. The aim of this study was to identify, at the time of heart procurement, means to predict contractile recovery following cardioplegic storage and reperfusion using an isolated rat heart model. Identification of reliable approaches to evaluate cardiac grafts is key in the development of protocols for heart transplantation with DCDD. METHODS Hearts isolated from anaesthetized male Wistar rats (n = 34) were exposed to various perfusion protocols. To simulate DCDD conditions, rats were exsanguinated and maintained at 37°C for 15-25 min (warm ischaemia). Isolated hearts were perfused with modified Krebs-Henseleit buffer for 10 min (unloaded), arrested with cardioplegia, stored for 3 h at 4°C and then reperfused for 120 min (unloaded for 60 min, then loaded for 60 min). Left ventricular (LV) function was assessed using an intraventricular micro-tip pressure catheter. Statistical significance was determined using the non-parametric Spearman rho correlation analysis. RESULTS After 120 min of reperfusion, recovery of LV work measured as developed pressure (DP)-heart rate (HR) product ranged from 0 to 15 ± 6.1 mmHg beats min−1 10−3 following warm ischaemia of 15-25 min. Several haemodynamic parameters measured during early, unloaded perfusion at the time of heart procurement, including HR and the peak systolic pressure-HR product, correlated significantly with contractile recovery after cardioplegic storage and 120 min of reperfusion (P < 0.001). Coronary flow, oxygen consumption and lactate dehydrogenase release also correlated significantly with contractile recovery following cardioplegic storage and 120 min of reperfusion (P < 0.05). CONCLUSIONS Haemodynamic and biochemical parameters measured at the time of organ procurement could serve as predictive indicators of contractile recovery. We believe that evaluation of graft suitability is feasible prior to transplantation with DCDD, and may, consequently, increase donor heart availabilit

Persistent sensitivity disorders at the radial artery and saphenous vein graft harvest sites: a neglected side effect of coronary artery bypass grafting procedures

Objective: The use of radial artery conduits in coronary artery bypass grafting (CABG) surgery is associated with improved long-term patency and patient survival rates as compared with saphenous vein conduits. Despite increasing popularity, relative incidence of local harvest-site complications and subjective perception of adverse long-term sequelae remain poorly described. Methods: To allow for direct comparison, we investigated a consecutive series of patients in whom both the radial artery and the saphenous vein had been harvested for isolated CABG during a 36-month period. Patients were identified from a prospective database that collects baseline clinical information. The patients' own perceptions were assessed by a standardized direct telephone survey regarding any persistent functional impairment from their arm and leg operation sites. Results: Out of 1756 CABG patients during the study period, 168 (10%) were eligible (78% men, median age: 60.1 ± 9.6 years, range: 29.6-82.4 years). Of these, 123 (73%) could be contacted and interviewed at a median follow-up time of 2.5 ± 0.9 years. Surgical wound complications at harvest sites (arms and legs) had occurred in 3% and 12%, respectively, and persistent symptoms (arms and legs) were self-reported as follows: chronic pain (5% and 8%), numbness (32% and 34%) and paresthesia/dysesthesia (14% and 7%). Overall, 39% of the patients reported persistent discomfort at the arm and 39% at the leg. Both sites were simultaneously affected in 21% (P = n.s., paired testing). Logistic regression modeling showed that patients with adverse long-term sequelae were younger (P < 0.005), had a higher body mass index (P < 0.05) and a lower EuroSCORE (P < 0.001) at the time of operation (EuroSCORE, European System for Cardiac Operative Risk Evaluation). Perioperative wound complications, however, did not predict persistence of symptoms. Conclusions: Persistent harvest-site discomfort occurs with astonishing frequency after CABG surgery and affects arms and legs equally. Although usually considered a minor complication, long-term limitation to quality of life may be substantial, particularly in younger and relatively healthy patients. Thus, harvest-site discomfort clearly belongs to the list of possible post-CABG complications of which patients need to be awar