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

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

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

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

High prevalence of unsuspected abdominal aortic aneurysms in patients hospitalised for surgical coronary revascularisation

Objectives: Prevalence of abdominal aortic aneurysms (AAA) is not exactly known among patients with coronary artery disease (CAD) who are considered for surgical revascularisation. We evaluated the value of screening AAA among coronary patients admitted in our cardiovascular surgery unit. Methods: Over a 24-month period, an abdominal echography was proposed to male patients aged 60 or more while hospitalised for surgical coronary revascularisation. Patients with previous investigation of the aorta were excluded. The aorta was considered aneurysmal when the anterior-posterior diameter was of 30 mm or more. Results: Three hundred and ninety-five consecutive patients all accepted a proposed abdominal echographic screening for AAA. Forty unsuspected AAA were detected (10.1%). The mean diameter was 38.9±1.3 mm. Four AAA were larger than 50 mm and considered for surgery after the CABG procedure. Surveillance was proposed to the other 36, especially the 10 patients with an AAA larger than 40 mm. Patients with AAA were significantly older than those without AAA (71.3±0.8 vs. 69.4±0.3 years, P<0.05). Smoking history (P<0.05) and hypertension (P<0.05) were also associated more frequently with AAA. More than 16% of the patients being smokers and suffering hypertension presented with unsuspected AAA. Conclusions: In-hospital screening of AAA is very efficient among patients with coronary artery disease. Therefore, patients with CAD may be considered for routine AAA screenin

Augmented venous return for minimally invasive open heart surgery with selective caval cannulation

Objective: Minimally invasive open heart surgery involves limited intrathoracic cannulation sites necessitating cardiopulmonary bypass to be initiated via peripheral access using percutaneous cannulae with the tip placed into the right atrial cavity. However, surgery involving the opening of the right heart obliges the surgeon to maintain the end of the cannulae into the vena cavae. The impeded venous return due to the smaller diameter may be alleviated by inserting a centrifugal pump in the venous line. Methods: Right anterior mini-thoracotomy and exposure of the femoral site were performed before the patient was heparinized. Cannulation of the femoral artery, the inferior vena cava via the femoral vein and the superior vena cava through the mini-thoracotomy was performed and cardiopulmonary bypass was initiated. Venous drainage was augmented with the centrifugal pump. Cardiac arrest was provoked and both vena cavae were snared before performing the intracardiac procedure. Results: Twenty consecutive patients were operated on using this technique (15 males/five females; age: 44.8±14.3 years; bodyweight: 73.5±15.1 kg; body surface area: 1.8±0.2 m2; theoretical blood flow rate: 4.4±0.5 l/min). The cannula sizes were 21.9±2.2 Fr for the femoral artery, 26.5±1.7 Fr for the inferior vena cava and 23.8±2.5 Fr for the superior vena cava. Venous drainage through the single inferior vena cava cannula was 2.1±0.6 l/min (48.8±13.3% of the theoretical flow). Adding the superior vena cava cannula increased the venous flow to 3.1±0.4 l/min (70.7±9.6% of the theoretical value, P<0.005). The use of the centrifugal pump increased the flow to 4.1±0.6 l/min (93.4±8.9% of the theoretical flow, P<0.001) with a mean inlet negative pressure of −69.1±10.2 mmHg. The mean bypass time was 64.0±24.6 min for a mean operative time of 226.3±61.0 min. Minimum venous saturation was 69.4±8.5%. Conclusions: Despite the smaller diameter of the vena cavae compared to the right atrium, and a smaller internal diameter of percutaneous cardiopulmonary bypass cannulae compared to classic ones; the centrifugal pump improves the venous drainage significantly so that minimally invasive open heart procedures can be performed under optimal and safe perfusion condition

Hemodynamics optimization during off-pump coronary artery bypass: the ‘no compression' technique

Objective: Heart manipulation during OPCAB may cause hemodynamical instability in particular for access to the posterior and lateral walls. The ‘no compression' technique involves enucleation of the heart without any compression on the cavities, and stabilization of the target area with a suction device. The impact of this technique on hemodynamics is assessed. Methods: In order to analyze a homogeneous group, 26 consecutive patients with triple grafts, one to each side of the heart in the same sequential order (posterior, lateral and anterior wall successively) were selected. Heart rate (HR), mean pulmonary arterial pressure (PAP, mmHg), pulmonary capillary wedge pressure (PCWP, mmHg), mean arterial pressure (MAP, mmHg), cardiac output index (COI, l/min per m2), and central venous saturation (SvO2,%) were monitored. A coronary shunt was used for all the anastomoses. Results: HR was stable with baseline value of 60±10 and the highest value for the anterior wall, 63.6±8 (P=0.23). PAP and PCWP exhibited their highest increase, when compared with baseline, for the lateral wall, 23.9±4.7 vs. 20.7±6.2 (P=0.06), and 17.2±4.7 vs. 14.9±5.6 (P=0.16), respectively. MAP, COI and SvO2, exhibited their largest drop, when compared with baseline, for the lateral wall too, 73.1±9.1 vs. 77.1±7.5 (P=0.12), 1.99±0.47 vs. 2.26±0.55 (P=0.09), and 70.5±8.4 vs. 74.8±9.3 (P=0.12), respectively. Conclusions: None of the hemodynamical parameter differed significantly from baseline value for all three territories. While hemodynamics was perfectly maintained during the posterior and anterior walls revascularization, exposure of the lateral wall led to marginal changes onl

Clinical Relevance of Troponin T Profile Following Cardiac Surgery

Background: Peak post-operative cardiac troponin T (cTnT) independently predicts mid- and long-term outcome of cardiac surgery patients. A few studies however have reported two peaks of cTnT over the first 48–72 h following myocardial reperfusion. The aim of the current study was to better understand underlying reasons of these different cTnT profiles and their possible relevance in terms of clinical outcome.Methods: All consecutive adult cardiac surgical procedures performed with an extra-corporeal circulation during a &gt;6 years period were retrospectively evaluated. Patients with a myocardial infarction (MI) &lt; 8 days were excluded. cTnT profile of patients with at least one value ≥1 ng/mL value were categorized according to the time occurrence of the peak value. Univariable and multivariable analysis were performed to identify factors influencing early vs. late increase of cTnT values, and to verify the correlation of early vs. late increase with clinical outcome.Results: Data of 5,146 patients were retrieved from our prospectively managed registry. From 953 with at least one cTnT value ≥1 ng/mL, peak occurred ≤ 6 h (n = 22), &gt;6 to ≤ 12 h (n = 366), &gt;12 to ≤ 18 h (n = 176), &gt;18 to ≤ 24 h (171), &gt;24 h (218). Age (OR: 1.023; CI: 1.016–1.030) and isolated CABG (OR: 1.779; CI: 1.114–2.839) were independent predictors of a late increase of cTnT over a limit of 1 ng/ml (p &lt; 0.05), whereas isolated valve procedures (OR: 0.685; CI: 0.471–0.998) and cross-clamp duration (OR: 0.993; CI: 0.990–0.997) independently predicted an early elevation (p &lt; 0.05). Delayed elevation as opposed to early elevation correlated with a higher rate of post-operative complications including MI (19.8 vs. 7.2%), new renal insufficiency (16.3 vs. 6.7%), MACCE (32.0 vs. 15.5%), or death (7.4 vs. 4.4%).Conclusion: Profile of cTnT elevation following cardiac surgery depends on patients' intrinsic factors, type of surgery and duration of cross-clamp time. Delayed increase is of higher clinically relevance than prompt post-operative elevation

Myocardial infarction stabilization by cell-based expression of controlled Vascular Endothelial Growth Factor levels

Vascular Endothelial Growth Factor (VEGF) can induce normal or aberrant angiogenesis depending on the amount secreted in the microenvironment around each cell. Towards a possible clinical translation, we developed a Fluorescence Activated Cell Sorting (FACS)‐based technique to rapidly purify transduced progenitors that homogeneously express a desired specific VEGF level from heterogeneous primary populations. Here, we sought to induce safe and functional angiogenesis in ischaemic myocardium by cell‐based expression of controlled VEGF levels. Human adipose stromal cells (ASC) were transduced with retroviral vectors and FACS purified to generate two populations producing similar total VEGF doses, but with different distributions: one with cells homogeneously producing a specific VEGF level (SPEC), and one with cells heterogeneously producing widespread VEGF levels (ALL), but with an average similar to that of the SPEC population. A total of 70 nude rats underwent myocardial infarction by coronary artery ligation and 2 weeks later VEGF‐expressing or control cells, or saline were injected at the infarction border. Four weeks later, ventricular ejection fraction was significantly worsened with all treatments except for SPEC cells. Further, only SPEC cells significantly increased the density of homogeneously normal and mature microvascular networks. This was accompanied by a positive remodelling effect, with significantly reduced fibrosis in the infarcted area. We conclude that controlled homogeneous VEGF delivery by FACS‐ purified transduced ASC is a promising strategy to achieve safe and functional angiogenesis in myocardial ischaemia