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In JoVE (1)
Other Publications (10)
- Respiratory Research
- BMC Pulmonary Medicine
- MMW Fortschritte Der Medizin
- American Journal of Physiology. Heart and Circulatory Physiology
- Primary Care Respiratory Journal : Journal of the General Practice Airways Group
- The Journal of Gene Medicine
- Circulation Research
- Molecular Therapy : the Journal of the American Society of Gene Therapy
- The International Journal of Cardiovascular Imaging
- American Journal of Physiology. Heart and Circulatory Physiology
Articles by Lisa Tilemann in JoVE
Gene Transfer for Ischemic Heart Failure in a Preclinical Model
Kiyotake Ishikawa, Dennis Ladage, Lisa Tilemann, Kenneth Fish, Yoshiaki Kawase, Roger J. Hajjar
Cardiovascular Research Center, Mount Sinai School of Medicine
A method of gene transfer for the treatment of ischemic heart failure is described using a swine model of myocardial infarction. Our simple and reproducible method enables us to readily evaluate the efficacy of various gene transfers with a very simple and reproducible way.
Other articles by Lisa Tilemann on PubMed
Diagnosing Asthma in General Practice with Portable Exhaled Nitric Oxide Measurement--results of a Prospective Diagnostic Study: FENO < or = 16 Ppb Better Than FENO < or =12 Ppb to Rule out Mild and Moderate to Severe Asthma [added]
Respiratory Research. 2009 | Pubmed ID: 19254389
To evaluate the sensitivity, specificity and predictive values of fractional exhaled nitric oxide (FENO) for the diagnosis of asthma in general practice.
BMC Pulmonary Medicine. 2009 | Pubmed ID: 19591673
To evaluate the sensitivity, specificity and predictive values of spirometry for the diagnosis of chronic obstructive pulmonary disease (COPD) and asthma in patients suspected of suffering from an obstructive airway disease (OAD) in primary care.
American Journal of Physiology. Heart and Circulatory Physiology. Aug, 2011 | Pubmed ID: 21551276
A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled. To induce progressive stenosis, a plastic occluder with a fixed diameter of 1.0 mm fitted with an 18-gauge copper wire was placed around the proximal left anterior descending (LAD) coronary artery. Coronary angiography, hemodynamic measurements, and echocardiography were performed at 2 wk and 1, 2, and 3 mo. Overall mortality was 26% at 3 mo, and up to 80% of the pigs showed total occlusion of LAD at 1 mo. A significant depression of peak LV pressure rate of rise (+dP/dt(max)) was observed in the animals showing total artery occlusion throughout the study. Left ventricular ejection fraction was also impaired, and the left ventricular volumes tended to be larger in the pigs with occlusion. Approximately 10% of scar tissue was found in the LAD occluded pigs, whereas the coronary flow pattern in the rest of the area took the pattern of hibernating myocardium. At the same time, histological and protein analysis established the presence of fibrosis and ongoing apoptosis in the ischemic area. In this model, the timing and incidence of total occlusion and low mortality offer significant advantages over other ischemic cardiomyopathy models in conducting preclinical studies.
Primary Care Respiratory Journal : Journal of the General Practice Airways Group. Dec, 2011 | Pubmed ID: 21808940
Asthma and chronic obstructive pulmonary disease (COPD) are characterised by airway and systemic inflammation, but little is known about differences and similarities in inflammatory markers in patients with obstructive airways disease.
The Journal of Gene Medicine. Oct, 2011 | Pubmed ID: 21954037
Gene therapy for the treatment of heart failure is emerging as a multidisciplinary field demonstrating advances with respect to identifying key signaling pathways, modernized vector creation and delivery technologies. Although these discoveries offer significant progress, selecting optimal methods for the vector delivery remains a key component for efficient cardiac gene therapy to validate the targets in rodent models and to test clinically relevant ones in pre-clinical models. Although the goals of higher transduction efficiency and cardiac specificity can be achieved with several delivery methods, the invasiveness and patient safety remain unclear for clinical application. In this review, we discuss various features of the currently available vector delivery methods for cardiac gene therapy.
Inhibition of PKCα/β with Ruboxistaurin Antagonizes Heart Failure in Pigs After Myocardial Infarction Injury
Circulation Research. Dec, 2011 | Pubmed ID: 21998327
Protein kinase Cα (PKCα) activity and protein level are induced during cardiac disease where it controls myocardial contractility and propensity to heart failure in mice and rats. For example, mice lacking the gene for PKCα have enhanced cardiac contractility and reduced susceptibility to heart failure after long-term pressure overload or after myocardial infarction injury. Pharmacological inhibition of PKCα/β with Ro-32-0432, Ro-31-8220 or ruboxistaurin (LY333531) similarly enhances cardiac function and antagonizes heart failure in multiple models of disease in both mice and rats.
Concomitant Intravenous Nitroglycerin With Intracoronary Delivery of AAV1.SERCA2a Enhances Gene Transfer in Porcine Hearts
Molecular Therapy : the Journal of the American Society of Gene Therapy. Jan, 2012 | Pubmed ID: 22215018
SERCA2a gene therapy improves contractile and energetic function of failing hearts and has been shown to be associated with benefits in clinical outcomes, symptoms, functional status, biomarkers, and cardiac structure in a phase 2 clinical trial. In an effort to enhance the efficiency and homogeneity of gene uptake in cardiac tissue, we examined the effects of nitroglycerin (NTG) in a porcine model following AAV1.SERCA2a gene delivery. Three groups of Göttingen minipigs were assessed: (i) group A: control intracoronary (IC) AAV1.SERCA2a (n = 6); (ii) group B: a single bolus IC injection of NTG (50 µg) immediately before administration of intravenous (IV) AAV1.SERCA2a (n = 6); and (iii) group C: continuous IV NTG (1 µg/kg/minute) during the 10 minutes of AAV1.SERCA2a infusion (n = 6). We found that simultaneous IV infusion of NTG and AAV1.SERCA2a resulted in increased viral transduction efficiency, both in terms of messenger RNA (mRNA) as well as SERCA2a protein levels in the whole left ventricle (LV) compared to control animals. On the other hand, IC NTG pretreatment did not result in enhanced gene transfer efficiency, mRNA or protein levels when compared to control animals. Importantly, the transgene expression was restricted to the heart tissue. In conclusion, we have demonstrated that IV infusion of NTG significantly improves cardiac gene transfer efficiency in porcine hearts.
Temporal Changes of Strain Parameters in the Progress of Chronic Ischemia: with Comparison to Transmural Infarction
The International Journal of Cardiovascular Imaging. Jan, 2012 | Pubmed ID: 22231467
The aim of this study was to reveal the temporal and spatial changes of strain parameters during the progression of chronic coronary ischemia. Fourteen pigs received occluder implantation to create gradual ischemia (CI), while six pigs underwent a sham surgery (Control). Six pigs after myocardial infarction were also studied (MI). Strain analysis was performed using a speckle-tracking algorithm. Eleven of the 14 animals with occluder implantation had total occlusion of the left anterior descending artery with collaterals at 1 month (early occlusion group), whereas three pigs had occlusion at 3 months (late occlusion group). Both radial strain (RS) and circumferential strain (CS) of ischemic area deteriorated at 1 month in the early occlusion group and remained at the same level throughout the remaining 2 months of the experiment. In the late occlusion group, RS gradually declined, while CS took the same course as Control until the 2 month time point. Thereafter, both metrics reached the same level as the early occlusion group at the time of occlusion. Interestingly, RS in the remote area decreased moderately, whereas CS remained normal in CI pigs. The comparison between CI and MI revealed preserved CS at the ischemic area in CI pigs. Both RS and CS deteriorate by the time total coronary occlusion was established and remain at the same level thereafter. Altered RS in the remote area may be an indicator of remodeling in the non-ischemic area, whereas CS may be useful for distinguishing between transmural and non-transmural scar.
Assessing Left Ventricular Systolic Dysfunction After Myocardial Infarction: Are the Ejection Fraction and the DP/dt Maximum Complementary or Redundant?
American Journal of Physiology. Heart and Circulatory Physiology. Feb, 2012 | Pubmed ID: 22307667
Background: Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and dP/dt maximum (dP/dt max) are the simplest and most used. However, these parameters are often reported together and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt max in assessing systolic dysfunction after myocardial infarction (MI) in swine. Methods and Results: A total of 220 measurements were obtained. All the measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of MI revealed a good predictive value for EF (area under the curve (AUC)=0.998), but not by dP/dt max (AUC=0.69, P<0.001 vs. EF). Dividing dP/dt max by the LV end diastolic pressure (EDP) and the heart rate (HR) significantly increased the AUC to 0.87 (p<0.001 vs dP/dt max, p<0.001 vs EF). In naive pigs, the coefficient of variation of dP/dt max was twice than EF (22.5% vs 9.5%, respectively). Furthermore, in n=19 pigs, dP/dt max increased after the MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt max and strain parameters in non-infarct area (circumferential strain: r=0.42, P=0.05, radial strain: r=0.71, P<0.001). Conclusions: EF is a more accurate measure of systolic dysfunction than dP/dt max in a swine model of MI. Despite the variability of dP/dt max both in naive pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.