Dennis Ladage | University of Cologne (original) (raw)

Papers by Dennis Ladage

Circulation, Nov 20, 2012

ISRN cardiology, 2011

Cardiac gene therapy is one of the most promising approaches to cure patients with cardiac dysfun... more Cardiac gene therapy is one of the most promising approaches to cure patients with cardiac dysfunctions. Many ways of efficient gene transfer using viral vectors are tested, and some of them are already used in clinical settings. However, it is always important to be keenly alert to the possible complications when a new therapy is introduced. We present a case of myocardial sterile abscess in a swine model associated with a direct myocardial injection.

American journal of physiology. Heart and circulatory physiology, Jan 15, 2014

Large animal studies are an important step toward clinical translation of novel therapeutic appro... more Large animal studies are an important step toward clinical translation of novel therapeutic approaches. We aimed to establish an ischemic heart failure (HF) model with a larger myocardial infarction (MI) relative to previous studies, and characterize the functional and structural features of this model. An MI was induced by occluding the proximal left anterior descending artery (LAD; n = 15) or the proximal left circumflex artery (LCx; n = 6) in Yorkshire pigs. Three pigs with sham procedures were also included. All pigs underwent hemodynamic and echocardiographic assessments before MI, at 1 mo, and 3 mo after MI. Analyses of left ventricular (LV) myocardial mechanics by means of strains and torsion were performed using speckle-tracking echocardiography and compared between the groups. The proximal LAD MI approach induced larger infarct sizes (14.2 ± 3.2% vs. 10.6 ± 1.9%, P = 0.03), depressed systolic function (LV ejection fraction; 39.8 ± 7.5% vs. 54.1 ± 4.6%, P < 0.001), and mo...

Methods in Molecular Biology, 2010

Cardiovascular disease is a major cause of morbidity and mortality in contemporary societies. Whi... more Cardiovascular disease is a major cause of morbidity and mortality in contemporary societies. While progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, which was initially envisioned as a treatment strategy for inherited monogenic disorders, has been found to hold broader potential that also includes acquired polygenic diseases, such as atherosclerosis, arrhythmias, and heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, have placed some cardiovascular pathophysiologies within the reach of gene-based therapy. In fact, gene therapy holds great promise as a targeted treatment for cardiovascular diseases. One of the major hurdles for effective cardiovascular gene therapy is the delivery of the viral vectors to the heart. In this chapter, we will present the various types of delivery techniques in preclinical, large animal models of cardiovascular diseases.

American journal of physiology. Heart and circulatory physiology, Jan 15, 2015

Journal of Visualized Experiments, 2011

Various emerging technologies are being developed for patients with heart failure. Well-establish... more Various emerging technologies are being developed for patients with heart failure. Well-established preclinical evaluations are necessary to determine their efficacy and safety. Gene therapy using viral vectors is one of the most promising approaches for treating cardiac diseases. Viral delivery of various different genes by changing the carrier gene has immeasurable therapeutic potential. In this video, the full process of an animal model of heart failure creation followed by gene transfer is presented using a swine model. First, myocardial infarction is created by occluding the proximal left anterior descending coronary artery. Heart remodeling results in chronic heart failure. Unique to our model is a fairly large scar which truly reflects patients with severe heart failure who require aggressive therapy for positive outcomes. After myocardial infarct creation and development of scar tissue, an intracoronary injection of virus is demonstrated with simultaneous nitroglycerine infusion. Our injection method provides simple and efficient gene transfer with enhanced gene expression. This combination of a myocardial infarct swine model with intracoronary virus delivery has proven to be a consistent and reproducible methodology, which helps not only to test the effect of individual gene, but also compare the efficacy of many genes as therapeutic candidates.

Cardiology Research and Practice, 2011

Although ischemic cardiomyopathy is commonly caused by chronic obstructive coronary disease, the ... more Although ischemic cardiomyopathy is commonly caused by chronic obstructive coronary disease, the mechanism of the cause is still under investigation. We present echocardiographic strain, magnetic resonance, and histology findings in a chronic ischemia model in preclinical study. This case illustrates the features of multimodality imaging in chronic obstructive coronary disease and gives us great insight into understanding the mechanism of ischemic cardiomyopathy.

Circulation. Heart failure, 2013

Heart failure is characterized by impaired function and disturbed Ca2+ homeostasis. Transgenic in... more Heart failure is characterized by impaired function and disturbed Ca2+ homeostasis. Transgenic increases in inhibitor-1 activity have been shown to improve Ca2 cycling and preserve cardiac performance in the failing heart. The aim of this study was to evaluate the effect of activating the inhibitor (I-1c) of protein phosphatase 1 (I-1) through gene transfer on cardiac function in a porcine model of heart failure induced by myocardial infarction. Myocardial infarction was created by a percutaneous, permanent left anterior descending artery occlusion in Yorkshire Landrace swine (n=16). One month after myocardial infarction, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 9 carrying I-1c (n=8) or saline (n=6) as control. One month after myocardial infarction was created, animals exhibited severe heart failure demonstrated by decreased ejection fraction (46.4±7.0% versus sham 69.7±8.5%) and impaired (dP/dt)max and (dP/dt)min. Intracoronary injecti...

PLoS ONE, 2013

Aims: Mammalian myocardium has a finite but limited capacity to regenerate. Experimentally stimul... more Aims: Mammalian myocardium has a finite but limited capacity to regenerate. Experimentally stimulating proliferation of cardiomyocytes with extracellular regeneration factors like periostin enhances cardiac repair in rodents. The aim of this study was to develop a safe method for delivering regeneration factors to the heart and to test the functional and structural effects of periostin peptide treatment in a large animal model of myocardial infarction (MI).

Molecular Therapy, 2010

Congestive heart failure (HF) is associated with impaired endothelium-dependent nitric oxide-medi... more Congestive heart failure (HF) is associated with impaired endothelium-dependent nitric oxide-mediated vasodilatation. The aim of this study was to examine the effects of sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2a ( SERCA2a) gene transfer on endothelial function in a swine HF model. Two months after the creation of mitral regurgitation to induce HF, the animals underwent intra coronary injection of adeno-associated virus (AAV) carrying SER-CA2a (n = 7) or saline (n = 6). At 4 months, coronary flow (CF) was measured in the mid-portion of the left anterior descending (LAD) artery. In the failing animals, CF was decreased significantly; SERCA2a gene transfer rescued CF to levels observed in sham-group [ml/min/g, 0.47 ± 0.064 saline versus 0.89 ± 0.116, SERCA2a; P < 0.05; 1.00 ± 0. 185 sham P = NS (nonsignificant)]. In coronary arteries from HF animals, SERCA2a and endothelial isoform of nitric oxide synthase (eNOS) protein expression were decreased, but restored to normal levels by SER-CA2a gene transfer. In human coronary artery endothelial cells (HCAECs), SERCA2a over expression increased eNOS expression, phosphorylation, eNOS promoter activity, Ca 2+ storage capacity, and enhanced histamine-induced calcium oscillations, eNOS activity, and cyclic guanosine monophosphate (cGMP) production. Thus, SERCA2a gene transfer increases eNOS expression and activity by modulating calcium homeostasis to improve CF. These findings suggest that SERCA2a gene transfer improves vascular reactivity in the setting of HF.

Molecular Therapy, 2012

Adeno-associated virus (AAV)-based vectors are promising gene delivery vehicles for human gene tr... more Adeno-associated virus (AAV)-based vectors are promising gene delivery vehicles for human gene transfer. One significant obstacle to AAV-based gene therapy is the high prevalence of neutralizing antibodies in humans. Until now, it was thought that, except for nonhuman primates, pre-existing neutralizing antibodies are not a problem in small or large animal models for gene therapy.

Journal of the American College of Cardiology, 2011

Congestive heart failure is a major cause of morbidity and mortality in the US. While progress in... more Congestive heart failure is a major cause of morbidity and mortality in the US. While progress in conventional treatments is making steady and incremental gains to reduce heart failure mortality, there is a critical need to explore new therapeutic approaches. Gene therapy was initially applied in the clinical setting for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as congestive heart failure. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. Furthermore, the recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) along with the start of more recent phase 1 trials usher a new era for gene therapy for the treatment of heart failure.

Journal of Cardiac Failure, 2009

The International Journal of Cardiovascular Imaging, 2012

The aim of this study was to reveal the temporal and spatial changes of strain parameters during ... more 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.

International Journal of Cardiology, 2011

Background: Aldosterone plays a role in hypertension, the pathogenesis of heart failure and vascu... more Background: Aldosterone plays a role in hypertension, the pathogenesis of heart failure and vascular injury. However, little information exists about the possible influence of aldosterone on bone marrow derived endothelial progenitor cells (EPC), which are involved in the repair of damaged endothelium. This study was designed to determine the long-term in vivo influence of aldosterone on the number of EPC. Methods: Male Wistar rats were equipped with a subcutaneous pump which released aldosterone (n = 20) or placebo (n = 20) over 28 days. The animals were either fed with or without the aldosterone antagonist spironolactone (each n = 10). EPC were identified by the uptake of ac-LDL and BS-1. The expression of VEGF-2 receptor, VEGF, HGF, SDF1 and the mineralocorticoid receptor (MR) in EPC was assessed by quantitative PCR. Finally, VEGF concentration was measured in the serum of all animals by ELISA. Results: The total number of EPC was significantly lowered by chronic aldosterone treatment. Spironolactone compensated the effect and lead to a 2-fold increase. While the SDF1 mRNA was not affected by aldosterone, HGF, MR2 and VEGF receptor mRNA were significantly downregulated in EPC. Strikingly spironolactone not only leads to increases in the mRNA expression in hyper-aldosteronemic animals but also exhibited significant increases above the control levels. Conclusion: The present data indicate that high levels of aldosterone impair the function and reduce the numbers of EPC and lead to a downregulation of VEGF and the VEGF receptor in vivo. Spironolactone antagonized these effects. MR blockade by spironolactone may therefore represent a future tool to enhance the response to cell based therapy.

International Journal of Cardiology, 2013

Treatment of heart failure patients with aldosterone antagonists has been shown to reduce the occ... more Treatment of heart failure patients with aldosterone antagonists has been shown to reduce the occurrence of sudden cardiac death. Therefore we aimed at determining the consequences of chronic exposure to aldosterone and the aldosterone antagonists eplerenone and spironolactone on the electrophysiological properties of the heart in a rat model. Male Wistar rats were chronically treated (4weeks) with aldosterone (ALD) via an osmotic minipump. Spironolactone (SPI) or eplerenone (EPL) was administered with the rat chow. ALD treated animals developed left ventricular hypertrophy, prolonged QT-intervals, a higher rate of ventricular premature beats and non-sustained ventricular tachycardia despite normal blood pressure values. Spironolactone and eplerenone were both able to inhibit the alterations. Left-ventricular mRNA expressions of Kv4.2 and Kv4.3 (Ito), Kv1.5 (IKur), Kir2.1 and Kir2.3 (IK1) and of Cav1.2 (L-type Ca(2+) channel) were significantly down-regulated in ALD. Correspondingly, the protein expressions of subunits Kv1.5, Kir2.3 and Cav1.2 were significantly decreased. A diminished calcineurin activity and mRNA expression of the Aß subunit of calcineurin were found in ALD, which was insensitive to aldosterone antagonists. Chronic aldosterone-overload induces blood pressure independent structural and electrical remodeling of the myocardium resulting in an increased risk for malignant ventricular arrhythmias.