Nima Hatam

Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig.

INTRODUCTION Anthracyclines are widely used in oncogenic therapy. Owing to their cardiotoxic side effects, their application is subdued to dose limitations. Many cardioprotective approaches have failed. This study examined the role of matrix metalloproteinases (MMP) in the remodeling process of extracellular matrix after treatment with doxorubicin (Adriamycin) as a toehold for a new therapeutic approach, for example, treatment with MMP inhibitors. METHODS Severe heart failure was induced in 6 pigs by the repetitive intracoronary application of Adriamycin. Degree of dilatation and insufficiency were measured by echocardiography and hemodynamics. Before and after treatment, MMP activity (fluorogenic assay: MMP-1, MMP-2) and gene expression (reverse transcription-polymerase chain reaction [RT-PCR]: MMP-1, -2, -9; membrane type-1 matrix metalloproteinase, [MT1MMP]; tissue inhibitor of metalloproteinase 1 [TIMP-1]) were measured. Spatial distribution of MMP-1, MMP-2, and collagen were visualized in antibody-stained frozen sections. One-way analysis of variance was used for data analysis. RESULTS Severe myocardial insufficiency (ejection fractions < 50% of baseline values) developed in all animals. No severe side effects were encountered. We found a strong activation of MMP-1 and MMP-2 in fluorogenic and PCR assays. RT-PCR revealed a significant activation of MMP-9 and MT1-MMP and a weaker induction of TIMP-1. Histology showed typical signs of myocardial fibrosis, with myocardial cell loss, collagen disorder, and vacuoles. CONCLUSION We showed a strong transcriptional activation for several specific MMPs in Adriamycin-induced cardiac remodeling. Contrary to published data on myocardial infarction, early inhibitory therapy before myocardial injury is possible in Adriamycin-treated patients. Local application by our catheter-based system would additionally help to avoid systemic side effects.

The role of hypoxia-inducible factor-1α and vascular endothelial growth factor in late-phase preconditioning with xenon, isoflurane and levosimendan in rat cardiomyocytes

OBJECTIVES The protective effects of late-phase preconditioning can be triggered by several stimuli. Unfortunately, the transfer from bench to bedside still represents a challenge, as concomitant medication or diseases influence the complex signalling pathways involved. In an established model of primary neonatal rat cardiomyocytes, we analysed the cardioprotective effects of three different stimulating pharmaceuticals of clinical relevance. The effect of additional β-blocker treatment was studied as these were previously shown to negatively influence preconditioning. METHODS Twenty-four hours prior to hypoxia, cells pre-treated with or without metoprolol (0.55 µg/ml) were preconditioned with isoflurane, levosimendan or xenon. The influences of these stimuli on hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) as well as inducible and endothelial nitric synthase (iNOS/eNOS) and cyclooxygenase-2 (COX-2) were analysed by polymerase chain reaction and western blotting. The preconditioning was proved by trypan blue cell counts following 5 h of hypoxia and confirmed by fluorescence staining. RESULTS Five hours of hypoxia reduced cell survival in unpreconditioned control cells to 44 ± 4%. Surviving cell count was significantly higher in cells preconditioned either by 2 × 15 min isoflurane (70 ± 16%; P = 0.005) or by xenon (59 ± 8%; P = 0.049). Xenon-preconditioned cells showed a significantly elevated content of VEGF (0.025 ± 0.010 IDV [integrated density values when compared with GAPDH] vs 0.003 ± 0.006 IDV in controls; P = 0.0003). The protein expression of HIF-1α was increased both by levosimendan (0.563 ± 0.175 IDV vs 0.142 ± 0.042 IDV in controls; P = 0.0289) and by xenon (0.868 ± 0.222 IDV; P < 0.0001) pretreatment. A significant elevation of mRNA expression of iNOS was measureable following preconditioning by xenon but not by the other chosen stimuli. eNOS mRNA expression was found to be suppressed by β-blocker treatment for all stimuli. In our model, independently of the chosen stimulus, β-blocker treatment had no significant effect on cell survival. CONCLUSIONS We found that the stimulation of late-phase preconditioning involves several distinct pathways that are variably addressed by the different stimuli. In contrast to isoflurane treatment, xenon-induced preconditioning does not lead to an increase in COX-2 gene transcription but to a significant increase in HIF-1α and subsequently VEGF.

PAS-Port® clampless proximal anastomotic device for coronary bypass surgery in porcelain aorta.

OBJECTIVES The severely calcified so-called porcelain aorta is one of the most dangerous and challenging findings in patients requiring coronary bypass surgery. Several techniques and technologies have been invented to handle this potentially lethal disease. We report on our initial experience with the PAS-Port® automated proximal clampless anastomotic device (Cardica, Inc., Redwood City, CA, USA), especially focussing on these patients. METHODS PAS-Port® anastomoses (for saphenous vein grafts) were performed in 17 patients undergoing coronary artery bypass graft (CABG) surgery. Of these, eight presented with the entity of porcelain aorta. In two patients, the diagnosis was previously known, in six cases heavily calcified aortas prohibiting any clamp manoeuvre were incidentally found intra-operatively. The site of anastomosis was determined by palpation and in individual cases with epi-aortic echocardiography. Other indications for PAS-Port® were localised dissection, acute myocardial infarction and partial sternotomy. Multislice computed tomography (CT) was performed in every patient to evaluate graft and anastomoses patency and appearance. RESULTS All 25 PAS-Port® anastomoses were triggered successfully. Two patients developed neurological deficits (prolonged reversible ischaemic neurological deficits, (PRIND)), with use of cardiopulmonary bypass (CPB) being the major predisposing factor (p=0.02). Graft patency could be affirmed in all grafts by multislice CT in all patients. CONCLUSIONS PAS-Port® anastomoses can be performed quickly, easily and, above all, safely in conditions prohibiting aortic clamping. Short-term results are excellent. Clear visualisation of anastomoses using multislice CT is an important advantage of the PAS-Port® device.

A new approach to interventional atrioventricular valve therapy

OBJECTIVE Transcatheter replacement or repair of mitral valve regurgitation has proved demanding. We aimed for a new approach to anchor a biologic heart valve in the mitral position by inserting a valve-carrying hollow body into the left atrium. This approach was investigated in both a simulation and an animal model. METHODS After creating a mold representing the porcine left atrium from the pulmonary veins as far as the mitral valve, a nitinol skeleton was sutured onto interlaced yarns of polyvinylidene fluoride fitting the mold. The resulting device was equipped with a commercially available stentless valve (25 mm) and investigated in a simulator regarding basic functionality. Furthermore, the device was implanted in 8 female pigs through incision of the left atrium during extracorporeal circulation. Before implantation, artificial regurgitation was created by means of excision from the posterior mitral leaflet. Hemodynamic, echocardiographic, and radiologic examinations followed. For a postmortem examination, the entire heart and the lungs were excised. RESULTS We could demonstrate the functionality of the heart valve in a complex, collapsible, and self-expanding hollow body. The device adapted to the surrounding structures, leading to an exclusion of the left atrium. Sufficient treatment of mitral regurgitation was monitored hemodynamically and by means of echocardiographic analysis, although overall visualization remained difficult. Therefore in 4 animals computed tomographic scans were performed. Autopsy revealed proper positioning without major trauma to the surrounding structures. CONCLUSION Anchoring an additional heart valve in the atrioventricular position does not necessarily need to be performed in the heart valve structure itself. Placement of an additional valve in the mitral position is feasible through this approach.

Targeting of cardiac autonomic plexus for modulation of intracardiac neural tone

AIMS Ventricular rate control is considered as an initial choice of therapy in many patients with atrial fibrillation (AF). We could previously show that electrostimulation of the right inferior ganglionated plexus (RIGP), which supplies the AV node, instantly decreases ventricular rate during AF. This study describes the development of a technique to reliably implant a chronic lead inside the RIGP. METHODS AND RESULTS In nine mongrel dogs with AF, the RIGP was identified by neuromapping with probatory high-frequency stimulation (20 Hz) over steerable electrode catheters until a significant ventricular rate slowing was achieved. Then an active fixation, permanent pacemaker lead was fixed closed to the mapping catheter left in place as anatomical marker. Initially (n = 4) available guiding catheters and steerable lead stylets were employed to navigate and anchor the lead, which resulted in repetitive screw-in attempts. Therefore, a guiding catheter was developed, which allowed angiography, lead advancement through its lumen, and probatory neurostimulation over its tip. This tool allowed lead delivery within 40 min (n = 5). Neurostimulation via the permanent lead elicited negative dromotropic effects with stimulation frequency, voltage, and impulse duration as determinants of stimulation efficacy. CONCLUSION Active fixation of a permanent pacing lead inside the RIGP is feasible without thoracotomy. Thereby, ventricular rate control during AF can be achieved with stimulus voltages applied for myocardial electrostimulation.

A novel approach to an anatomical adapted stent design for the percutaneous therapy of tricuspid valve diseases: preliminary experiences from an engineering point of view.

Tricuspid valve regurgitation mostly occurs as result of dilation of the right ventricle, secondary to left heart valve diseases. Until recently, little attention has been given to the development of percutaneous therapeutic tools exclusively designed for tricuspid valve disease. A new approach to the interventional therapy of tricuspid regurgitation, in particular, the design of a conceptual new valve-bearing, self-expansible stent, is presented here. A three-dimensional computer model of a right porcine heart was developed to gain a realistic anatomical geometry. The new design consists of two tubular stent elements, one inside the superior vena cava and the other inside the tricuspid valve annulus after being eventually equipped with a biological valve prosthesis, which are connected by struts. Anchoring to the heart structure is provided primarily by the vena cava stent, strengthened by the struts. The stents are designed to be cut from a 10 mm tube and later expanded to their designated diameter. Simulation software analyzing the expansion process with respect to the intended geometrical design is used in an iterative process. A validation of the anatomical geometry and function of the stent design inside a silicone model within in vitro tests and a random porcine heart shows an accurate anatomical fitting.

Influence of aortic dimensions on the hemodynamic performance of small aortic valve prostheses: impact on patient/prosthesis mismatch.

BACKGROUND Since Doppler echocardiography takes no account of pressure recovery, the true hemodynamic burden of aortic valve prostheses remains vague. The purpose of this study was to elucidate the methodological error of Doppler gradient estimation by means of a model demonstrating the different influence of aortic root diameters on net and Doppler gradients, respectively. This matters especially in small valves and the related patient/prosthesis mismatch calculation. METHODS Two bileaflet small aortic valve prostheses (19 mm SJM Regent® and On-X® valve) were tested using a pulsatile circulatory mock loop simulator with two different aortic models: one with statistically normal diameters according to annular size, another one simulating an aortic aneurysm of 50 mm. Doppler and simultaneously recorded net gradients as well as systolic energy losses were obtained for different hemodynamic conditions. RESULTS In all measurements a significant amount of pressure recovery was observed. In cases of aortic aneurysm systolic energy loss increased significantly for each cardiac output at each heart rate ( P < 0.0028), reflected by a significant ( P < 0.0001) increase in net gradients. The corresponding Doppler gradients were unchanged. This indicates significantly less pressure recovery ( P < 0.0001) in the aneurysmatic aorta. CONCLUSIONS Geometry of the ascending aorta considerably alters aortic valve hemodynamic parameters. The hemodynamic function of small aortic valve prostheses, especially with corresponding normal outflow dimensions, is much better than expected from Doppler gradients. Thus, calculation of a patient/prosthesis mismatch can be misleading.

Video-assisted pericardioscopic surgery: refinement of a new technique for implanting epimyocardial pacemaker leads

OBJECTIVE Current alternative approaches for pacemaker lead implantation imply the breach of the pleural space. Recently, the feasibility of experimental lead implantation by rigid endoscopy has been described. The use of flexible endoscopes and a standardised application has not been realised yet. Our main goal was to compare rigid and flexible endoscopy and to establish a standardised protocol for the implementation of a closed-chest subxiphoid approach for epimyocardial lead implantation. METHODS Rigid and flexible endoscopes were used for placement of screw-in pacing leads (4-F). A total of 17 adult pigs (80 kg) were anaesthetised and a 10-mm subxiphoid axial incision performed. The pericardium was opened and entered under endoscopic vision. Epimyocardial electrodes were implanted through the endoscope onto all four chambers. Standard haemodynamic measurements and pacing measurements were carried out. RESULTS Both methods were deployed in the first three individuals. Superior endorsement of rigid endoscopy, due to better orientation and stability, led to its exclusive deployment in the remaining 14 individuals. Access to the implantation sites was quick (<10 min). A plastic cover had to be applied to reduce arrhythmia (VentricularExtraSystoles(bare): 17 ± 2.2 min(-1) vs VentricularExtraSystoles(cover): 5 ± 1.9 min(-1); n = 4). Measured pacing parameters were comparable with classic endocardial-derived thresholds. Post-mortem examination revealed no relevant damage/injury and/or bleeding in the heart and circumjacent tissue. There was no evidence of injury at the implantation sites and the corresponding pericardium. The electrodes showed excellent anchorage inside the myocardial tissue (penetration depths: 3 ± 0.2mm) and resisted high tractive forces. CONCLUSION Flexible endoscopy is not suitable for exclusive deployment inside the pericardial space, whereas rigid endoscopy presented itself as a safe, fast and simple approach for epimyocardial lead implantation using an insulating trocar. Without cover, malignant arrhythmia constrains the implementation of video-assisted pericardioscopic surgery (VAPS). Subxiphoid VAPS permits optimal lead positioning under direct vision without fluoroscopy, without the breach of the pleural space and with a short procedural duration (<60 min). Our standardised minimal-invasive approach allows visualisation and intervention, potentially of all intrapericardial structures.

A personalized approach to interventional treatment of tricuspid regurgitation: experiences from an acute animal study

OBJECTIVES Interventional treatment of tricuspid valve disease has so far received little attention due to the anatomical challenges in a thrombogenic surrounding. In the present study, we present an imaging-based, personalized interventional approach to the therapy of tricuspid regurgitation. METHODS In our porcine model, we used rapid prototyping to build a matrix reproducing the geometry of the right atrium that was previously derived from computer tomography (CT) scans. Over this matrix, a braided nitinol device fitting almost completely the right atrium was crafted. An additional tubular stent component was developed to carry a tissue valve prosthesis. This part was designed to be connectable to the annular portion of the main device. In our feasibility study, the crimped device was implanted via jugular access into the right atrium of 12 pigs and expanded subsequently. Following isolated implantation of the device without the valve-carrying component, further procedures included implantation of the whole composite device, including the mentioned tissue valve. Representing a only feasibility study, all implantations were performed under full bypass and direct sight. On-site visualization was performed by both echocardiography and fluoroscopy. Additional imaging was realized by postoperative CT scans. RESULTS Following implantation, 9 of 12 animals were weaned from cardiopulmonary bypass. Correct positioning of the device and orthodromic blood flow as maintained by the valve prosthesis were demonstrated by echocardiography and fluoroscopy. Postoperative contrast CT evaluation demonstrated proper fitting of the device into the right-sided heart cavities without obstruction of the outflow tract. Autopsy additionally confirmed its correct positioning without major trauma to surrounding structures. CONCLUSIONS We demonstrated the feasibility in principle of a personalized interventional treatment for tricuspid regurgitation using a braided stent, based on individual cardiac imaging, with anchoring forces mainly exerted on the venae cavae and on the inner surface of the right atrium. The design process of this device is a good indicator of the growing potential of an imaging-based personalized simulation and production approach for the treatment of tricuspid valve disease.

Feasibility and efficacy of bypassing the right ventricle and pulmonary circulation to treat right ventricular failure: an experimental study

BackgroundRight ventricular failure (RVF) and -support is associated with poor results. We aimed for a new approach of right - sided assistance bypassing the right ventricle and pulmonary circulation in order to better decompress the right ventricle and optimize left ventricular filling.MethodsFrom a microaxial pump (Abiomed), a low resistance oxygenator (Maquet and Novalung) and two cannulas (28 and 27 Fr) a system was set up and evaluated in an ovine model (n = 7). Connection with the heart was the right and left atrium. One hour the system was operated without RVF and turned of again. Then a RVF was induced and the course with the system running was evaluated. Complete hemodynamic monitoring was performed as well as echocardiography, flow measurement and blood gas analysis.ResultsThe overall performance of the system was reliable. Without RVF no relevant changes of hemodynamics occurred; blood gases were supra normal. In RVF a cardiogenic shock developed (MAP 35 ± 13 mmHg, CO 1,1 ± 0,7 l/min). Immediately after starting the system the circulation normalized (significant increase of MAP to 85 ± 13 mmHg, of CO to 4,5 ± 1,9). Echocardiography also revealed right ventricular recovery. After stopping the system, RVF returned.ConclusionsBypassing the right ventricle and pulmonary circulation with an oxygenating assist device, which may offer the advantages of enhanced right ventricular decompression and augmented left atrial filling, is feasible and effective in the treatment of acute RVF. Long time experiments are needed.