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1.  Comparison of Transcatheter and Surgical Aortic Valve Replacement in Severe Aortic Stenosis: A Longitudinal Study of Echo Parameters in Cohort A of the PARTNER Trial 
To compare echocardiographic findings in patients with critical aortic stenosis following surgical (SAVR) or transcatheter aortic valve replacement (TAVR
The Placement of Aortic Transcatheter Valves trial randomized patients 1:1 to SAVR or TAVR
Echocardiograms were obtained at baseline, discharge, 30 days, 6 months, 1 year, and 2 years post procedure and analyzed in a core laboratory. For the analysis of post-implant variables, the first interpretable study (≤ 6 mos) was used.
Both groups showed a decrease in aortic valve gradients and increase in effective orifice area (EOA) (p < 0.0001) which remained stable over 2 years. Compared to SAVR, TAVR resulted in: larger indexed EOA (p = 0.038), less prosthesis-patient mismatch (p = 0.019), and more total and paravalvular aortic regurgitation (AR) (p < 0.0001). Baseline echocardiographic univariate predictors of death were: lower peak transaortic gradient in TAVR patients; low left ventricular diastolic volume (LVDV), low stroke volume, and greater severity of mitral regurgitation in SAVR patients. Post-implantation echocardiographic univariate predictors of death were: larger LVDV, systolic volume (LVSV) and EOA, decreased ejection fraction, and greater AR in TAVR patients; smaller LVSV and LVDV, low stroke volume, smaller EOA and prosthesis-patient mismatch in SAVR patients.
Patients randomized to either SAVR or TAVR experience enduring, significant reductions in transaortic gradients and increase in EOA. Compared to SAVR, TAVR patients had higher indexed EOA, lower prosthesis-patient mismatch and more AR. Univariate predictors of death for the TAVR group and SAVR groups differed and may allow future refinement in patient selection.
PMCID: PMC3931006  PMID: 23623915
transcatheter aortic valve replacement; aortic stenosis; echocardiography
2.  Endoscopic radial artery harvesting procedure for coronary artery bypass grafting 
Annals of Cardiothoracic Surgery  2013;2(4):557-564.
Development and adoption of endoscopic minimally invasive saphenous vein harvesting prompted its application to the radial artery in an effort to minimize surgical trauma. Recently, we reported that endoscopic radial artery harvesting was associated with better wound appearance and it proved to be safe and effective, with less pain and fewer wound complications than the open surgical technique. Based on this positive experience, our institution adopted endoscopic radial artery harvesting, hence the aim of this manuscript is to describe the minimally invasive endoscopic radial artery harvesting for coronary artery bypass grafting.
PMCID: PMC3741886  PMID: 23977636
Radial artery; minimally invasive endoscopic harvesting; radial artery endoscopic dissection
3.  Comparison of multicenter registries and randomized control trials for transcatheter aortic valve replacement (TAVR) 
Indian Heart Journal  2013;65(4):400-411.
TAVR has emerged as an attractive alternative for treatment of severe aortic stenosis in high risk surgical patients. Despite several large multicenter registries, only one randomized trial (PARTNER) has been published.
We aimed to compare the outcomes obtained using multicenter registries and the PARTNER trial.
Standard MEDLINE search strategy was used to find multicenter registries, reporting clinical outcomes following TAVR. Meta-analytic techniques were utilized to calculate pooled outcomes across multicenter registries and compare them to outcomes in PARTNER trial.
Pooled 30-day mortality rate from the registries was 9.2%, which was significantly higher than that in the PARTNER trial (3.8%). Medium-term mortality rates were similar between the PARTNER trial and the multicenter registries. Pooled 30-day and 1-year stroke rates in multicenter registries were 2.6% and 3.8%, respectively. On the other hand, the corresponding rates in PARTNER trial were 5.2% and 7.6%, respectively. In the registry-related cohorts, pooled 30-day and 1-year mortality rates were 6.8% and 20.8% in the transfemoral group and 12.2% and 32.2% in the transapical group. In the PARTNER trial, the pooled incidence of 30-day and 1-year mortality rates were 3.9% and 26.2% in the transfemoral group and 3.8% and 29.0% in the transapical group.
Short-term results in PARTNER were better than those reported in the registries, which may be due to better patient selection and aggressive bailout techniques. Similarity of medium-term outcomes between registries and PARTNER highlights that patient selection for TAVR is critical due to considerable risk of mortality in the first year even after the successful procedure.
PMCID: PMC3860977  PMID: 23993001
Transcatheter aortic valve replacement; Randomized control trials; Multicenter registries; Meta-analysis
4.  A meta-analysis of deep hypothermic circulatory arrest alone versus with adjunctive selective antegrade cerebral perfusion 
Annals of Cardiothoracic Surgery  2013;2(3):261-270.
Recognizing the importance of neuroprotection in aortic arch surgery, deep hypothermic circulatory arrest (DHCA) now underpins operative practice as it minimizes cerebral metabolic activity. When prolonged periods of circulatory arrest are required, selective antegrade cerebral perfusion (SACP) is supplemented as an adjunct. However, concerns exist over the risks of SACP in introducing embolism and hypo- and hyper-perfusing the brain. The present meta-analysis aims to compare postoperative outcomes in arch surgery using DHCA alone or DHCA + SACP as neuroprotection strategies.
Electronic searches were performed using six databases from their inception to January 2013. Two reviewers independently identified all relevant studies comparing DHCA alone with DHCA + SACP. Data were extracted and meta-analyzed according to pre-defined clinical endpoints.
Nine comparative studies were identified in the present meta-analysis, with 648 patients employing DHCA alone and 370 utilizing DHCA + SACP. No significant differences in temporary or permanent neurological outcomes were identified. DHCA + SACP was associated with significantly better survival outcomes (P=0.008, I2=0%), despite longer cardiopulmonary bypass time. Infrequent and inconsistent reporting of other clinical results precluded analysis of systemic outcomes.
The present meta-analysis indicate the superiority of DHCA + SACP in terms of mortality outcomes.
PMCID: PMC3741855  PMID: 23977593
Deep hypothermic circulatory arrest; antegrade cerebral perfusion; aortic arch surgery; meta-analysis
5.  Consensus on hypothermia in aortic arch surgery 
Annals of Cardiothoracic Surgery  2013;2(2):163-168.
Considered a standard part of aortic arch surgery, hypothermia can sufficiently reduce cerebral metabolic demand to permit reasonable periods of circulatory arrest. Yet despite its ubiquitous application and critical importance, temperature classification in hypothermic circulatory arrest is still without clear definition. The following Consensus from experts in high-volume aortic institutions defines ‘profound’, ‘deep’, ‘moderate’, and ‘mild’ hypothermia and recommends standardized monitoring sites, so as to facilitate more consistent reporting and robust analysis.
PMCID: PMC3741830  PMID: 23977577
Aortic arch surgery; consensus statement; hypothermic circulatory arrest; cerebral protection
6.  A meta-analysis of deep hypothermic circulatory arrest versus moderate hypothermic circulatory arrest with selective antegrade cerebral perfusion 
Annals of Cardiothoracic Surgery  2013;2(2):148-158.
A recent concern of deep hypothermic circulatory arrest (DHCA) in aortic arch surgery has been its potential association with increased risk of coagulopathy, elevated inflammatory response and end-organ dysfunction. Recently, moderate hypothermic circulatory arrest (MHCA) with selective antegrade circulatory arrest (SACP) seeks to negate potential hypothermia-related morbidities, while maintaining adequate neuroprotection. The present meta-analysis aims to compare postoperative outcomes in arch surgery using DHCA or MHCA+SACP as neuroprotective strategies.
Electronic searches were performed using six databases from their inception to January 2013. Two reviewers independently identified all relevant studies comparing DHCA with MHCA+SACP, as defined by a recent hypothermia temperature consensus. Data were extracted and meta-analyzed according to pre-defined clinical endpoints.
Nine comparative studies were identified for inclusion in the present meta-analysis. Stroke rates were significantly lower in patients undergoing MHCA+SACP (P=0.0007, I2=0%), while comparable results were observed with temporary neurological deficit, mortality, renal failure or bleeding. Infrequent and inconsistent reporting of systemic outcomes precluded analysis of other systemic outcomes.
The present meta-analysis indicated the superiority of MHCA+SACP in terms of stroke risk.
PMCID: PMC3741839  PMID: 23977575
Deep hypothermic circulatory arrest; moderate hypothermic circulatory arrest; antegrade cerebral perfusion; meta-analysis
7.  Clinical and economic outcomes after surgical aortic valve replacement in Medicare patients 
Aortic valve replacement (AVR) is the standard of care for patients with severe, symptomatic aortic stenosis who are suitable surgical candidates, benefiting both non-high-risk and high-risk patients. The purpose of this study was to report long-term medical resource use and costs for patients following AVR and validate our assumption that high-risk patients have worse outcomes and are more costly than non-high-risk patients in this population.
Patients with aortic stenosis who underwent AVR were identified in the 2003 Medicare 5% Standard Analytic Files and tracked over 5 years to measure clinical outcomes, medical resource use, and costs. An approximation to the logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) based on administrative data was used to assess surgical risk, with a computed logistic EuroSCORE > 20% considered high-risk.
We identified 1474 patients with aortic stenosis who underwent AVR, of whom 1222 (82.9%) were non-high-risk and 252 (17.1%) were high-risk. Among those who were non-high-risk, the mean age was 73.3 years, 464 (38.2%) were women, and the mean logistic EuroSCORE was 7%, whereas in those who were high-risk, the mean age was 77.6 years, 134 (52.8%) were women, and the mean logistic EuroSCORE was 37%. All-cause mortality was 33.2% for non-high-risk and 66.7% for high-risk patients at 5 years. Over this time period, non-high-risk patients experienced an average of 3.9 inpatient hospitalizations and total costs of $106,277 per patient versus 4.7 hospitalizations and total costs of $144,183 for high-risk patients.
Among elderly patients undergoing AVR, long-term mortality and costs are substantially greater for high-risk than for non-high-risk individuals. These findings indicate that further research is needed to understand whether newer approaches to aortic valve replacement such as transcatheter AVR may be a lower cost, clinically valuable alternative.
PMCID: PMC3496980  PMID: 23152716
aortic valve; replacement; health economics
8.  Humanized Mouse Model of Skin Inflammation Is Characterized by Disturbed Keratinocyte Differentiation and Influx of IL-17A Producing T Cells 
PLoS ONE  2012;7(10):e45509.
Humanized mouse models offer a challenging possibility to study human cell function in vivo. In the huPBL-SCID-huSkin allograft model human skin is transplanted onto immunodeficient mice and allowed to heal. Thereafter allogeneic human peripheral blood mononuclear cells are infused intra peritoneally to induce T cell mediated inflammation and microvessel destruction of the human skin. This model has great potential for in vivo study of human immune cells in (skin) inflammatory processes and for preclinical screening of systemically administered immunomodulating agents. Here we studied the inflammatory skin response of human keratinocytes and human T cells and the concomitant systemic human T cell response.
As new findings in the inflamed human skin of the huPBL-SCID-huSkin model we here identified: 1. Parameters of dermal pathology that enable precise quantification of the local skin inflammatory response exemplified by acanthosis, increased expression of human β-defensin-2, Elafin, K16, Ki67 and reduced expression of K10 by microscopy and immunohistochemistry. 2. Induction of human cytokines and chemokines using quantitative real-time PCR. 3. Influx of inflammation associated IL-17A-producing human CD4+ and CD8+ T cells as well as immunoregulatory CD4+Foxp3+ cells using immunohistochemistry and -fluorescence, suggesting that active immune regulation is taking place locally in the inflamed skin. 4. Systemic responses that revealed activated and proliferating human CD4+ and CD8+ T cells that acquired homing marker expression of CD62L and CLA. Finally, we demonstrated the value of the newly identified parameters by showing significant changes upon systemic treatment with the T cell inhibitory agents cyclosporine-A and rapamycin.
In summary, here we equipped the huPBL-SCID-huSkin humanized mouse model with relevant tools not only to quantify the inflammatory dermal response, but also to monitor the peripheral immune status. This combined approach will gain our understanding of the dermal immunopathology in humans and benefit the development of novel therapeutics for controlling inflammatory skin diseases.
PMCID: PMC3477148  PMID: 23094018
9.  Development of Transgenic Cloned Pig Models of Skin Inflammation by DNA Transposon-Directed Ectopic Expression of Human β1 and α2 Integrin 
PLoS ONE  2012;7(5):e36658.
Integrins constitute a superfamily of transmembrane signaling receptors that play pivotal roles in cutaneous homeostasis by modulating cell growth and differentiation as well as inflammatory responses in the skin. Subrabasal expression of integrins α2 and/or β1 entails hyperproliferation and aberrant differentiation of keratinocytes and leads to dermal and epidermal influx of activated T-cells. The anatomical and physiological similarities between porcine and human skin make the pig a suitable model for human skin diseases. In efforts to generate a porcine model of cutaneous inflammation, we employed the Sleeping Beauty DNA transposon system for production of transgenic cloned Göttingen minipigs expressing human β1 or α2 integrin under the control of a promoter specific for subrabasal keratinocytes. Using pools of transgenic donor fibroblasts, cloning by somatic cell nuclear transfer was utilized to produce reconstructed embryos that were subsequently transferred to surrogate sows. The resulting pigs were all transgenic and harbored from one to six transgene integrants. Molecular analyses on skin biopsies and cultured keratinocytes showed ectopic expression of the human integrins and localization within the keratinocyte plasma membrane. Markers of perturbed skin homeostasis, including activation of the MAPK pathway, increased expression of the pro-inflammatory cytokine IL-1α, and enhanced expression of the transcription factor c-Fos, were identified in keratinocytes from β1 and α2 integrin-transgenic minipigs, suggesting the induction of a chronic inflammatory phenotype in the skin. Notably, cellular dysregulation obtained by overexpression of either β1 or α2 integrin occurred through different cellular signaling pathways. Our findings mark the creation of the first cloned pig models with molecular markers of skin inflammation. Despite the absence of an overt psoriatic phenotype, these animals may possess increased susceptibility to severe skin damage-induced inflammation and should be of great potential in studies aiming at the development and refinement of topical therapies for cutaneous inflammation including psoriasis.
PMCID: PMC3349713  PMID: 22590584
10.  A Sleeping Beauty DNA transposon-based genetic sensor for functional screening of vitamin D3 analogues 
BMC Biotechnology  2011;11:33.
Analogues of vitamin D3 are extensively used in the treatment of various illnesses, such as osteoporosis, inflammatory skin diseases, and cancer. Functional testing of new vitamin D3 analogues and formulations for improved systemic and topical administration is supported by sensitive screening methods that allow a comparative evaluation of drug properties. As a new tool in functional screening of vitamin D3 analogues, we describe a genomically integratable sensor for sensitive drug detection. This system facilitates assessment of the pharmacokinetic and pharmadynamic properties of vitamin D3 analogues. The tri-cistronic genetic sensor encodes a drug-sensoring protein, a reporter protein expressed from an activated sensor-responsive promoter, and a resistance marker.
The three expression cassettes, inserted in a head-to-tail orientation in a Sleeping Beauty DNA transposon vector, are efficiently inserted as a single genetic entity into the genome of cells of interest in a reaction catalyzed by the hyperactive SB100X transposase. The applicability of the sensor for screening purposes is demonstrated by the functional comparison of potent synthetic analogues of vitamin D3 designed for the treatment of psoriasis and cancer. In clones of human keratinocytes carrying from a single to numerous insertions of the vitamin D3 sensor, a sensitive sensor read-out is detected upon exposure to even low concentrations of vitamin D3 analogues. In comparative studies, the sensor unveils superior potency of new candidate drugs in comparison with analogues that are currently in clinical use.
Our findings demonstrate the use of the genetic sensor as a tool in first-line evaluation of new vitamin D3 analogues and pave the way for new types of drug delivery studies in sensor-transgenic animals.
PMCID: PMC3083354  PMID: 21473770
12.  Comparison of the effects of vitamin D products in a psoriasis plaque test and a murine psoriasis xenograft model 
The aim of the present study was to compare the effects of Daivobet® and calcipotriol on clinical score and biomarker responses in a modified version of the Scholtz-Dumas psoriasis plaque assay. Furthermore, it was the aim to compare the effects of calcipotriol and betamethasone in the murine psoriasis xenograft model. Twenty four patients with psoriasis were treated topically once daily for three weeks, whereas the grafted mice were treated for four weeks. Clinical responses were scored twice weekly and biopsies were taken at the end of each study to analyse for skin biomarkers by histology and immunohistochemistry. The results clearly demonstrate effects on both clinical signs and biomarkers. In the patient study the total clinical score was reduced significantly with both Daivobet® and calcipotriol. Both treatments reduced epidermal thickness, Ki-67 and cytokeratin 16 expression. T cell infiltration was significantly reduced by Daivobet® but only marginally by calcipotriol. Both treatments showed strong effects on the epidermal psoriatic phenotype.
Results from the xenograft model essentially showed the same results. However differences were observed when investigating subtypes of T cells.
The study demonstrates the feasibility of obtaining robust biomarker data in the psoriasis plaque test that correlate well with those obtained in other clinical studies. Furthermore, the biomarker data from the plaque test correlate with biopsy data from the grafted mice.
PMCID: PMC2804591  PMID: 20017943

Results 1-12 (12)