Understanding the use of observational and randomized data in cardiovascular medicine.

The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called 'real-world', and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular disease.

CNB-001 reduces paraplegia in rabbits following spinal cord ischemia.

Spinal cord ischemia associated with trauma and surgical procedures including thoraco-abdominal aortic aneurysm repair and thoracic endovascular aortic repair results in devastating clinical deficits in patients. Because spinal cord ischemia is inadequately treated, we studied the effects of [4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl) vinyl)-2-methoxy-phenol)] (CNB-001), a novel curcumin-based compound, in a rabbit SCI model. CNB-001 is known to inhibit human 5-lipoxygenase and 15-lipoxygenase and reduce the ischemia-induced inflammatory response. Moreover, CNB-001 can reduce the level of oxidative stress markers and potentiate brain-derived neurotrophic factor and brain-derived neurotrophic factor receptor signaling. The Tarlov scale and quantal analysis technique results revealed that CNB-001 administered as an intravenous dose (bolus) 30 minutes prior to spinal cord ischemia improved the behaviors of female New Zealand White rabbits. The improvements were similar to those produced by the uncompetitive N-methyl-D-aspartate receptor antagonist memantine. At 48 hours after aortic occlusion, there was a 42.7% increase (P < 0.05) in tolerated ischemia duration (n = 14) for rabbits treated with CNB-001 (n = 16), and a 72.3% increase for rabbits treated with the positive control memantine (P < 0.05) (n = 23) compared to vehicle-treated ischemic rabbits (n = 22). CNB-001 is a potential important novel treatment for spinal cord ischemia induced by aortic occlusion. All experiments were approved by the CSMC Institutional Animal Care and Use Committee (IACUC #4311) on November 1, 2012.

Evaluation of Hybrid Surgical Access Approaches for Pulmonary Valve Implantation in an Acute Swine Model.

Percutaneous implantation of the pulmonary valve through peripheral vascular access can be limited due to poor venous access, low patient weight, hemodynamic or rhythmic instability, and size constraints related to the valve. In such cases, hybrid procedures may provide alternatives. Because the most commonly used median sternotomy is unsuitable for chronic trials in large animals, we evaluated several hybrid approaches for pulmonary valve replacement in a swine model. We tested the feasibility of hybrid pulmonary valve implantation in pigs by using inhouse-generated valves containing bare-metal or nitinol stents. Valves consisted of bovine jugular veins, bovine pericardial valves, or sprayed polyurethane valves. Access was achieved through median sternotomy, lower partial sternotomy, transverse sternotomy, or right lateral thoracotomy. The delivery device was introduced in a transventricular manner. Implantation took place under fluoroscopic and epicardial echocardiographic guidance. We achieved implantation of the stented valve in 12 (92.3%) pigs, of which 5 (41.7%) of the implanted valves were in an optimal position. Paravalvular leakage occurred in 2 trials (16.7%). Lower partial sternotomy provided the best trade-off between feasibility and minimized trauma for long-term animal trials. Here we describe our experience with hybrid pulmonary valve implantation in an acute large-animal (swine) model. We demonstrate the feasibility of the procedure in terms of surgical technique and the perioperative management and preparation of the field for a chronic trial.

CNB-001, a pleiotropic drug is efficacious in embolized agyrencephalic New Zealand white rabbits and ischemic gyrencephalic cynomolgus monkeys.

Ischemic stroke is an acute neurodegenerative disease that is extremely devastating to patients, their families and society. Stroke is inadequately treated even with endovascular procedures and reperfusion therapy. Using an extensive translational screening process, we have developed a pleiotropic cytoprotective agent with the potential to positively impact a large population of brain ischemia patients and revolutionize the process used for the development of new drugs to treat complex brain disorders. In this unique translational study article, we document that the novel curcumin-based compound, CNB-001, when administered as a single intravenous dose, has significant efficacy to attenuate clinically relevant behavioral deficits following ischemic events in agyrencephalic rabbits when administered 1 h post-embolization and reduces infarct growth in gyrencephalic non-human primates, when administered 5 min after initiation of middle cerebral artery occlusion. CNB-001 is safe and does not increase morbidity or mortality in either research species. Mechanistically, CNB-001 inhibits human 5- and 15-lipoxygenase in vitro, and can attenuate ischemia-induced inflammatory markers, and oxidative stress markers, while potentially promoting synaptic plasticity mediated by enhanced brain-derived neurotrophic factor (BDNF).

Type A aortic dissection model to improve endovascular research and technologies.

OBJECTIVE: Type A aortic dissection is a life-threatening disease requiring immediate surgical treatment. With emerging catheter-based technologies, endovascular stent-graft implantation to treat aneurysms and dissections has become a standardized procedure. However, endovascular treatment of the ascending aorta remains challenging. Thus we designed an ascending aortic dissection model to allow simulation of endovascular treatment. METHODS: Five formalin-fixed human aortas were prepared. The ascending aorta was opened semicircularly in the middle portion and the medial layer was separated from the intima. The intimal tube was readapted using running monofilament sutures. The preparations were assessed by 128-slice computed tomography. A bare-metal stent was implanted for thoracic endovascular aortic repair in 4 of the aortic dissection models. RESULTS: Separation of the intimal and medial layer of the aorta was considered to be sufficient because computed tomography showed a clear image of the dissection membrane in each aorta. The dissection was located 3.9 ± 1.4 cm proximally from the aortic annulus, with a length of 4.6 ± 0.9 cm. Before stent implantation, the mean distance from the intimal flap to the aortic wall was measured as 0.63 ± 0.163 cm in the ascending aorta. After stent implantation, this distance decreased to 0.26 ± 0.12 cm. CONCLUSION: This model of aortic dissection of the ascending human aorta was reproducible with a comparable pathological and morphological appearance. The technique and model can be used to evaluate new stent-graft technologies to treat type A dissection and facilitate training for surgeons.

Left Subclavian Arterial Coverage and Stroke During Thoracic Aortic Endografting: A Systematic Review.

Stroke is a devastating complication of thoracic endovascular aortic repair (TEVAR). Whether left subclavian artery (LSA) coverage and LSA revascularization affect stroke rate is debated. Whether patients with aneurysms or dissections undergoing TEVAR have higher stroke rates is also debated. We report a systematic review of 63 studies comprising more than 3,000 patients. We conclude that stroke risk after TEVAR is increased by LSA coverage, and that LSA revascularization reduces stroke risk. LSA revascularization may lower the rate of posterior stroke. TEVAR for aneurysm is associated with increased stroke risk compared to TEVAR for dissection.

Methodology of motor evoked potentials in a rabbit model.

Spinal cord ischemia (SCI) is a devastating complication of aortic operations. Neuromonitoring using motor evoked potentials (MEPs) is a sensitive modality to detect SCI in humans. We describe a leporine SCI model using MEPs to test pharmaceutical therapeutics and other neuroprotective adjuncts. In 80 rabbits, methods to obtain MEPs in normotensive and ischemic rabbits were developed. The effects of isoflurane, propofol, apnea, and hypotension on lower extremity MEPs were studied. Lower extremity MEPs disappear upon SCI induction in 78 of 78 (100 %) rabbits. Prior to SCI induction and during apneic episodes, lower extremity MEPs were lost in all (100 %) and upper extremity MEPs in one (25 %). Isoflurane was used in four experiments, with loss of lower extremity MEPs in all four (100 %) and loss of upper extremity MEPs in zero. With propofol upper extremity, MEPs were obtainable in 80 of 80 rabbits (100 %) and lower extremity MEPs in 78 of 80 rabbits (97.5 %) prior to SCI induction. The presence of these lower extremity MEPs prior to SCI induction was not correlated with systolic or diastolic blood pressure. Disappearance of MEPs occurred in all 45 rabbits with postoperative lower extremity impairment. MEPs in the leporine model correlate closely with paraplegia. MEPs are influenced by inhaled anesthetics and apnea but not by hypotension alone. Propofol anesthesia provides reliable MEPs. This study provides the basis for a reproducible model of SCI to be used for novel therapeutic drug development.

Thoracic endovascular aortic repair: are we approaching total endovascular solutions for thoracic aortic disease?

Thoracic endovascular aortic repair (TEVAR) has become an attractive alternative treatment option for thoracic aortic disease. New devices and advanced image-guided procedures are continuously expanding the indications. This article focuses on currently available endovascular solutions for thoracic aortic disease and future 'all endovascular' directions of TEVAR. Currently available endovascular solutions, such as hybrid operations, chimney stent grafting and transapical stent graft deployment, for ascending aortic pathologies are presented. Additionally, the impact of upcoming new technologies, such as endovascular treatment of Stanford Type A dissections of the ascending aorta, is elaborated. With improving device technology, diverse available stent grafts and imaging modalities, TEVAR has become safer and holds promising potential to expand treatment options, especially for the ascending aorta and the aortic arch.

In vitro comparison of novel polyurethane aortic valves and homografts after seeding and conditioning.

The aim of the study was to compare the behavior of seeded cells on synthetic and natural aortic valve scaffolds during a low-flow conditioning period. Polyurethane (group A) and aortic homograft valves (group B) were consecutively seeded with human fibroblasts (FB), and endothelial cells (EC) using a rotating seeding device. Each seeding procedure was followed by an exposure to low pulsatile flow in a dynamic bioreactor for 5 days. For further analysis, samples were taken before and after conditioning. Scanning electron microscopy showed confluent cell layers in both groups. Immunohistochemical analysis showed the presence of EC and FB before and after conditioning as well as the establishment of an extracellular matrix (ECM) during conditioning. A higher expression of ECM was observed on the scaffolds' inner surface. Real-time polymerase chain reaction showed higher inflammatory response during the conditioning of homografts. Endothelialization caused a decrease in inflammatory gene expression. The efficient colonization, the establishment of an ECM, and the comparable inflammatory cell reaction to the scaffolds in both groups proved the biocompatibility of the synthetic scaffold. The newly developed bioreactor permits conditioning and cell adaption to shear stress. Therefore, polyurethane valve scaffolds may offer a new option for aortic valve replacement.

Transcatheter valve replacement: new concepts for microsurgery inside the heart.

OBJECTIVE: Transcatheter aortic valve implantation gained clinical relevance with an impressive and peerless power; however, the procedure induces unsolved complications such as paravalvular leakage, occlusion of coronary ostia, and vascular complications. The safe removal of bulky calcified valves will improve the outcome, well known through the open surgical procedure. In this article, a new stapler-based resection and implantation device as well as a new approach for valve isolation during normal heart cycle without extracorporeal circulation will be analyzed. METHODS: First, a novel stapler-based instrument for transapical aortic valve replacement [removal and implantation; stapler-based aortic valve replacement (StapAVR)] was constructed and analyzed in an aortic debris model. Artificial aortic valves (N = 20), containing fluorescent granules to simulate the calcification, were placed into an aortic model in anatomical supine position (DP) and right-sided lateral position (RP). With the StapAVR, resection before implantation was performed in a water-filled basin. Black light was used for debris visualization. The procedures have been digitally recorded and analyzed due to procedural times, and the debris amount in thoracic side branches. Second, an enhanced prototype of the pulmonary valve isolation chamber (PVIC) was analyzed in porcine in vitro (n = 10) and in vivo models (n = 1). This PVIC contains a microaxial pump (Impella; Abiomed, Aachen, Germany) in the central bypass channel. It was deployed through the right ventricular wall. Once the PVIC was in place, the pump was started before isolating the valve. The complete hemodynamic monitoring was digitally recorded. RESULTS: The deployment of the StapAVR in the correct position and the valve resection time took a mean (SD) of 95.8 (19) seconds in DP and 90.1 (18) seconds in RP. Fluorescent debris was found: in the left coronary artery, 22% in DP and 7% in RP; in the ascending aorta, 0% in DP and 11% in RP; in the aortic bulbous, 5% in DP and 10% in RP; in the left ventricle, 8% in DP and 14% in RP; in the brachiocephalic trunk, 4% in DP and 9% in RP; and in the descending aorta, 46% in DP and 1% in RP. Consecutive valved stent implantation was performed without complications. The PVIC deployment time in vivo was 5 minutes, replacements included. The total valve isolation time was 21 minutes, with a mean (SD) bypass flow of 2.1 (0.4) L/min. The oxygen saturation showed a median of 91% (range, 83%-97%), and the median arterial blood pressure was 69 mm Hg (systolic; range, 47-120 mm Hg) and 40mm Hg (diastolic; range, 32-56 mm Hg) without the use of inotropes or vasopressors. Electrocardiogram confirmed sinus rhythm during isolation. CONCLUSIONS: The resection of the artificial valves followed by valved stent implantation was possible with the StapAVR. In vivo, the procedure will be carried out under rapid pacing and sudden vacuum; however, the results of this in vitro debris model underline the need for isolation or filter devices during transcatheter aortic valve implantation to avoid embolization. Secondly, the use of the pump-advanced PVIC showed stable heart function for 21 minutes under isolated pulmonary valve conditions. This time will be adequate to remove bulky calcifications and to implant a valved stent. Improvements of both prototypes are ongoing. Nevertheless, the presented concepts showed promising application possibilities in the future.

Partial inferior sternotomy and deep hypothermic circulatory arrest for rescue of a failed TAVI case: what does constitute 'inoperable'?

A 65-year-old male patient was considered inoperable by conventional means for a previous triple coronary artery bypass grafting with a patent in situ right internal mammary artery graft to the left anterior descending artery crossing the thorax at midline directly behind the sternum. Transcatheter aortic valve implantation failed due to loss of the prosthetic device in the left ventricular outflow tract. Mandatory conversion was accomplished by an inferior partial T-shape sternotomy and extracorporeal circulation draining from the right atrium and feeding into the right femoral artery. A conventional 27-mm aortic valve bioprosthesis was successfully implanted during deep hypothermic circulatory arrest. The patient recovered normally exhibiting no neurological or cardiocirculatory complications.

Transcatheter aortic valve implantation in aortic coarctation.

A 77-year-old male patient was scheduled for transcatheter aortic valve implantation for symptomatic and severe aortic valve stenosis. Severe multidirectional kinking of the aorta based on aortic coarctation did not allow for the transfemoral, but only for the transapical approach. The procedure was complicated because of the technically challenging retrograde passage of the transfemorally inserted pig-tail catheter required for intraoperative angiography of the aortic root. Correct positioning of the pig-tail catheter into the ascending aorta was accomplished by use of a loop snare, which was advanced into the descending aorta via the antegrade route, passing the cardiac apex, the stenotic aortic valve, and the coarctation-associated kinking. The pig-tail catheter tip was manipulated into the loop snare, pulled traverse the coarctation, and released within the proximal ascending aorta. Subsequent procedures were uneventful and followed the standardized protocol. A 29 mm Edwards Lifescience transcatheter Sapien bioprosthesis was successfully implanted.

An update on endovascular management of acute thoracic aortic disease and future directions.

Thoracic endovascular aortic repair (TEVAR) has become an alternative treatment option for acute thoracic aortic disease. This review focuses on current endovascular treatment of acute thoracic aortic disease and future directions of TEVAR. TEVAR is a promising alternative approach to open surgery, with lower early mortality and morbidity rates, especially in high-risk cohorts. Furthermore, with accumulating experience and improving device technology and imaging modalities, TEVAR has become safer and has potential to expand treatment options to include ascending and arch pathologies.

J-147 a Novel Hydrazide Lead Compound to Treat Neurodegeneration: CeeTox™ Safety and Genotoxicity Analysis.

J-147 is a broad spectrum neuroprotective phenyl hydrazide compound with significant neurotrophic properties related to the induction of brain-derived neurotrophic factor (BDNF). Because this molecule is pleiotropic, it may have substantial utility in the treatment of a wide range of neurodegenerative diseases including acute ischemic stroke (AIS), traumatic brain injury(TBI), and Alzheimer's disease(AD) where both neuroprotection and neurotrophism would be beneficial. Because of the pleiotropic actions of J-147, we sought to determine the safety profile of the drug using multiple assay analysis. For CeeTox analyses, we used a rat hepatoma cell line (H4IIE) resulted in estimated CTox value (i.e.: sustained concentration expected to produce toxicity in a 14 day repeat dosing study) of 90 µM for J-147. The CeeTox panel shows that J-147 produced some adverse effects on cellular activities, in particular mitochondrial function, but only with high concentrations of the drug. J-147 was also not genetoxic with or without Aroclor-1254 treatment. For J-147, based upon extensive neuroprotection assay data previously published, and the CeeTox assay (CTox value of 90 µM) in this study, we estimated in vitro neuroprotection efficacy (EC50 range 0.06-0.115 µM)/toxicity ratio is 782.6-1500 fold and the neurotrophism (EC50 range 0.025 µM)/toxicity ratio is 3600, suggesting that there is a significant therapeutic safety window for J-147 and that it should be further developed as a novel neuroprotective-neurotrophic agent to treat neurodegenerative disease taking into account current National Institute of Neurological Disorders and Stroke (NINDS) RIGOR guidelines.

Management of thoracic aortic lesions--the future is endovascular.

Open surgical repair of lesions of the descending thoracic aorta, such as aneurysm, dissection and traumatic rupture, has been the "state-of-the-art" treatment for many decades. However, in specialized cardiovascular centers, thoracic endovascular aortic repair and hybrid aortic procedures have been implemented as novel treatment options. The current clinical results show that these procedures can be performed with low morbidity and mortality rates. However, due to a lack of randomized trials, the level of reliability of these new treatment modalities remains a matter of discussion. Clinical decision-making is generally based on the experience of the vascular center as well as on individual factors, such as life expectancy, comorbidity, aneurysm aetiology, aortic diameter and morphology. This article will review and discuss recent publications of open surgical, hybrid thoracic aortic (in case of aortic arch involvement) and endovascular repair in complex pathologies of the descending thoracic aorta.

Transapical mitral valved stent implantation: a survival series in swine.

OBJECTIVE: To assess short-term survival after transcatheter mitral valve replacement using a unique mitral valved stent design and anchoring system. METHODS: The new nitinol self-expandable valved stent houses a trileaflet glutaraldehyde-preserved bioprosthesis and contains atrial and ventricular fixation systems. Eight pigs underwent transesophageal echocardiogram-guided transapical mitral valved stent implantation through a lower mini-sternotomy. Intracardiac pressure gradients were estimated by transesophageal echocardiogram. RESULTS: The mean mitral annulus size was 24.6 +/- 1.4 mm, and the valved stent size was 26.0 +/- 2.6 mm. The average mean transvalvular gradient across the valved stent immediately after deployment, at 6 hours, and after 1 week remained low. The gradient across the neighboring left ventricular outflow tract was not affected. Average animal survival was 7.3 days (8 hours to 29 days). Animals that died before 1 week (n = 4) were found at necropsy to have valved stent malpositioning. Animals that survived 1 week or more had accurate deployment and only trace post-deployment paravalvular leak. The causes of death in this latter group were endocarditis (n = 1), failure of atrial fixation (n = 2), and failure of ventricular fixation (n = 1). There was no valved stent embolization in any of the animals. CONCLUSION: Adequate function and effective anchoring of the new mitral valved stent allowed for short-term animal survival after transapical mitral valved stent implantation.

Percutaneous tissue-engineered pulmonary valved stent implantation.

PURPOSE: The purpose of this study was to evaluate the feasibility of percutaneously implanted tissue-engineered valved stents in the ovine pulmonary valve position. DESCRIPTION: Porcine pulmonary heart valves and small intestinal submucosa were obtained from a slaughterhouse, and the intestinal submucosa used to cover the inside of the porcine pulmonary valved stents. Endothelial cells and autologous myofibroblasts were obtained from carotid artery segments of juvenile sheep. After myofibroblast seeding, constructs were placed in a dynamic bioreactor system and were cultured for 16 days. After Endothelial cell seeding, the tissue-engineered valved stents were deployed into the pulmonary valve annular site. Angiography was performed at implantation and explantation (4 weeks). Constructs were analyzed macroscopically and microscopically. EVALUATION: Orthotopic positioning of the stents (n = 3) at the time of implantation and explantation, as well as normal valve function, was observed through angiography. Gross morphology confirmed excellent opening and closing of all leaflets. Strong expression of alpha-smooth muscle actin in neointerstitial cells and of von-Willebrand-Factor in endothelial cells was revealed by immunocytochemistry. CONCLUSIONS: This study demonstrates successful merging of two novel technologies: (1) percutaneous valved stent implantation and (2) tissue engineering of autologous heart valves.

Percutaneous aortic valve replacement: emerging tractability for sufficient intracardiac resection of the aortic valve.

OBJECTIVE: : The feasibility of endovascular resection of highly calcified aortic valves has already been demonstrated by our group. Different endovascular and intracardiac tractability methods were applied. In this study, these technologies were analyzed comparing the tractability, the resection time, and the lesions in the surrounding tissue. METHODS: : All aortic valve resections (seven human hearts and 21 porcine hearts) were performed using a Thulium:YAG laser (continuous wave, wavelength of 2.01 µm, 20 watts power rating). In the first resection system, the laser fiber was controlled by a free in-lying flexible endoscope (Ø 2.5 mm, length of 600 mm). The distal part of the endoscope (40 mm) was moved in one plane by proximal manual control (three degrees of freedom). The resection system was separated into defined rooms assigning one room for one tool. The fiber was controlled by the above-mentioned endoscope (*) (three degrees of freedom). The third resection system was a mechanical microactuator carrying the laser fiber (three degrees of freedom). The fourth resection system contains a rotatable inlay with defined rooms and a newly designed nitinol (NiTi) microactuator that controlled the laser fiber (four degrees of freedom). The resection time per leaflet was measured in minutes. Gross anatomy and histology in the surrounding tissue were evaluated. RESULTS: : The resection time in approaches 1, 2, 3, and 4 was 5.5 ± 2.3 minutes, 7.4 ± 2.7 minutes, ± 6.6 minutes, and2.3 ± 1.2 minutes, respectively. The gross anatomy and histology of collateral damages revealed only superficial lesions of the surrounding tissue. The amount of lesions and the resection time were lower in the fourth approach with four degrees of freedom. CONCLUSIONS: : This analysis demonstrated that a precise tractability with four degrees of freedom is necessary for a faster and safer endovascular resection of the aortic valve. The analysis will help to optimize the ongoing development of the endovascular and intracardiac resection technology.