Paige Brlecic
Heidelberg University
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Featured researches published by Paige Brlecic.
American Journal of Physiology-heart and Circulatory Physiology | 2016
Mihály Ruppert; Sevil Korkmaz-Icöz; Shiliang Li; Balázs Tamás Németh; Péter Hegedűs; Paige Brlecic; Csaba Mátyás; Markus Zorn; Béla Merkely; Matthias Karck; Tamás Radovits; Gábor Szabó
Pressure unloading represents the only effective therapy in increased afterload-induced left ventricular hypertrophy (LVH) as it leads to myocardial reverse remodeling (reduction of increased left ventricular mass, attenuated myocardial fibrosis) and preserved cardiac function. However, the effect of myocardial reverse remodeling on cardiac mechanoenergetics has not been elucidated. Therefore, we aimed to provide a detailed hemodynamic characterization in a rat model of LVH undergoing pressure unloading. Pressure overload was induced in Sprague-Dawley rats by abdominal aortic banding for 6 (AB 6th wk) or 12 wk (AB 12th wk). Sham-operated animals served as controls. Aortic debanding procedure was performed after the 6th experimental week (debanded 12th wk) to investigate the regression of LVH. Pressure unloading resulted in significant reduction of LVH (heart weight-to-tibial length ratio: 0.38 ± 0.01 vs. 0.58 ± 0.02 g/mm, cardiomyocyte diameter: 18.3 ± 0.1 vs. 24.1 ± 0.8 μm debanded 12th wk vs. AB 12th wk, P < 0.05), attenuated the extracellular matrix remodeling (Massons score: 1.37 ± 0.13 vs. 1.73 ± 0.10, debanded 12th wk vs. AB 12th wk, P < 0.05), provided protection against the diastolic dysfunction, and reversed the maladaptive contractility augmentation (slope of end-systolic pressure-volume relationship: 1.39 ± 0.24 vs. 2.04 ± 0.09 mmHg/μl, P < 0.05 debanded 12th wk vs. AB 6th wk, P < 0.05). In addition, myocardial reverse remodeling was also associated with preserved ventriculoarterial coupling and increased mechanical efficiency (50.6 ± 2.8 vs. 38.9 ± 2.5%, debanded 12th wk vs. AB 12th wk, P < 0.05), indicating a complete functional and mechanoenergetic recovery. According to our best knowledge, this is the first study demonstrating that the regression of LVH is accompanied by maintained cardiac mechanoenergetics.
Experimental Diabetes Research | 2015
Sevil Korkmaz-Icöz; Alice Lehner; Shiliang Li; Adrian Vater; Tamás Radovits; Péter Hegedűs; Mihály Ruppert; Paige Brlecic; Markus Zorn; Matthias Karck; Gábor Szabó
Despite clinical studies indicating that diabetic hearts are more sensitive to ischemia/reperfusion injury, experimental data is contradictory. Although mild diabetes prior to ischemia/reperfusion may induce a myocardial adaptation, further research is still needed. Nondiabetic Wistar (W) and type 2 diabetic Goto-Kakizaki (GK) rats (16-week-old) underwent 45 min occlusion of the left anterior descending coronary artery and 24 h reperfusion. The plasma glucose level was significantly higher in diabetic rats compared to the nondiabetics. Diabetes mellitus was associated with ventricular hypertrophy and increased interstitial fibrosis. Inducing myocardial infarction increased the glucose levels in diabetic compared to nondiabetic rats. Furthermore, the infarct size was smaller in GK rats than in the control group. Systolic and diastolic functions were impaired in W + MI and did not reach statistical significance in GK + MI animals compared to the corresponding controls. Among the 125 genes surveyed, 35 genes showed a significant change in expression in GK + MI compared to W + MI rats. Short-term diabetes promotes compensatory mechanisms that may provide cardioprotection against ischemia/reperfusion injury, at least in part, by increased antioxidants and the upregulation of the prosurvival PI3K/Akt pathway, by the downregulation of apoptotic genes, proinflammatory cytokine TNF-α, profibrogenic TGF-β, and hypertrophic marker α-actin-1.
Journal of Physiological Sciences | 2016
Sevil Korkmaz-Icöz; Ayhan Atmanli; Tamás Radovits; Shiliang Li; Peter Hegedüs; Mihály Ruppert; Paige Brlecic; Yutaka Yoshikawa; Hiroyuki Yasui; Matthias Karck; Gábor Szabó
We recently demonstrated that the pre-treatment of rats with zinc and acetylsalicylic acid complex in the form of bis(aspirinato)zinc(II) [Zn(ASA)2] is superior to acetylsalicylic acid in protecting the heart from acute myocardial ischemia. Herein, we hypothesized that Zn(ASA)2 treatment after the onset of an acute myocardial injury could protect the heart. The rats were treated with a vehicle or Zn(ASA)2 after an isoproterenol injection. Isoproterenol-induced cardiac damage [inflammatory infiltration into myocardial tissue, DNA-strand breakage evidenced by TUNEL-assay, increased 11-dehydro thromboxane (TX)B2-levels, elevated ST-segment, widened QRS complex and prolonged QT-interval] was prevented by the Zn(ASA)2 treatment. In isoproterenol-treated rats, load-independent left ventricular contractility parameters were significantly improved after Zn(ASA)2. Furthermore, Zn(ASA)2 significantly increased the myocardial mRNA-expression of superoxide dismutase-1, glutathione peroxidase-4 and decreased the level of Na+/K+/ATPase. Postconditioning with Zn(ASA)2 protects the heart from acute myocardial ischemia. Its mechanisms of action might involve inhibition of pro-inflammatory prostanoids and upregulation of antioxidant enzymes.
American Journal of Physiology-heart and Circulatory Physiology | 2016
Sevil Korkmaz-Icöz; Alice Lehner; Shiliang Li; Adrian Vater; Tamás Radovits; Maik Brune; Mihály Ruppert; Xiaoxin Sun; Paige Brlecic; Markus Zorn; Matthias Karck; Gábor Szabó
The Goto-Kakizaki (GK) rat, a non-obese model of type 2 diabetes mellitus (T2DM), was generated by the selective inbreeding of glucose-intolerant Wistar rats. This is a convenient model for studying diabetes-induced cardiomyopathy independently from the effects of the metabolic syndrome. We investigated the myocardial functional and structural changes and underlying molecular pathomechanisms of short-term and mild T2DM. The presence of DM was confirmed by an impaired oral glucose tolerance in the GK rats compared with the age-matched nondiabetic Wistar rats. Data from cardiac catheterization showed that in GK rats, although the systolic indexes were not altered, the diastolic stiffness was increased compared with nondiabetics (end-diastolic-pressure-volume-relationship: 0.12 ± 0.04 vs. 0.05 ± 0.01 mmHg/μl, P < 0.05). Additionally, DM was associated with left-ventricular hypertrophy and histological evidence of increased myocardial fibrosis. The plasma pro-B-type natriuretic peptide, the cardiac troponin-T, glucose, and the urinary glucose concentrations were significantly higher in GK rats. Among the 125 genes surveyed using PCR arrays, DM significantly altered the expression of five genes [upregulation of natriuretic peptide precursor-A and connective tissue growth factor, downregulation of c-reactive protein, interleukin-1β, and tumor necrosis factor (TNF)-α mRNA-level]. Of the altered genes, which were evaluated by Western blot, only TNF-α protein expression was significantly decreased. The ECG recordings revealed no significant differences. In conclusion, while systolic dysfunction, myocardial inflammation, and abnormal electrical conduction remain absent, short-term and mild T2DM induce the alteration of cardiac TNF-α at both the mRNA and protein levels. Further assessments are required to reveal if TNF-α plays a role in the early stage of diabetic cardiomyopathy development.
The Journal of Thoracic and Cardiovascular Surgery | 2018
Gábor Veres; Harald Schmidt; Péter Hegedűs; Sevil Korkmaz-Icöz; Tamás Radovits; Sivakkanan Loganathan; Paige Brlecic; Shiliang Li; Matthias Karck; Gábor Szabó
Objectives The in situ internal thoracic artery (ITA) is recognized as the best conduit for coronary artery bypass surgery. The ITA—if it is used as an in situ graft—has a much higher late patency rate than any other arterial graft, including a free ITA graft. We sought to determine if the use of the ITA as an in situ/free graft and its storage in preservation solutions, have an effect on endothelial function. Methods The ITA was harvested as either a free or in situ graft in a porcine model. Free grafts were stored in different preservation solutions (saline, Custodiol and Tiprotec [both Köhler Chemie GmbH, Bensheim, Germany]). The ITA was anastomosed off pump to the left anterior descending artery (as in situ/free graft). Freshly harvested ITA served as a control. After 2 hours of reperfusion, the implanted grafts were harvested. The assessment of endothelial function, histopathological analysis, and gene expression were performed. Results Endothelial function and integrity were severely impaired after reperfusion in the free ITA groups, however, it was partially preserved in the Tiprotec group. Reperfusion injury resulted in increased nitro‐oxidative stress, DNA breakage, vascular cell adhesion protein 1, intercellular adhesion molecule‐1, and caspase‐3 scores, and a decreased endothelial nitric oxide synthase score in the free ITA groups. The in situ ITA graft showed no signs of injury. mRNA levels were significantly altered among the groups. Conclusions An early, severe endothelial dysfunction of the stored, free ITA as described, could be completely prevented by the use of an in situ ITA graft. Tiprotec might be a feasible option for storage of free arterial grafts during coronary artery bypass grafting.
American Journal of Transplantation | 2017
S. Li; Sevil Korkmaz-Icöz; Tamás Radovits; Mihály Ruppert; R. Spindler; Sivakkanan Loganathan; Péter Hegedűs; Paige Brlecic; B. Theisinger; S. Theisinger; S. Höger; Maik Brune; Felix Lasitschka; Matthias Karck; Benito A. Yard; Gábor Szabó
Heart transplantation is the therapy of choice for end‐stage heart failure. However, hemodynamic instability, which has been demonstrated in brain‐dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n‐octanoyl‐dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham‐operated (n = 9). In BDD, decreased left‐ventricular contractility (ejection fraction; maximum rate of rise of left‐ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left‐ventricular pressure; Tau), and increased end‐diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD‐treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin‐6, tumor necrosis factor TNF‐α, NF‐kappaB‐p65, and nuclear factor (NF)‐kappaB‐p105 gene expression, and increased caspase‐3, TNF‐α and NF‐kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro‐apoptotic factor caspase‐3, pro‐inflammatory cytokines, and NF‐kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion.
Journal of Diabetes and Its Complications | 2015
Sevil Korkmaz-Icöz; Adrian Vater; Shiliang Li; Alice Lehner; Tamás Radovits; Péter Hegedűs; Mihály Ruppert; Paige Brlecic; Markus Zorn; Matthias Karck; Gábor Szabó
AIMS Myocardial infarction (MI) is a common cause of mortality in patients with diabetes mellitus (DM) and vascular dysfunction is a major component of diabetic cardiomyopathy. We investigated the systemic influence of acute MI on the diabetes-induced pathogenic changes in the rat aorta. METHODS Nondiabetic Wistar (W) and type-2 diabetic Goto-Kakizaki (GK) rats underwent 45min of left anterior descending coronary artery occlusion followed by 24h of reperfusion. Isometric force was measured using organ bath. RESULTS Plasma glucose-levels were significantly higher in diabetic rats (GK+sham: 13±2mM; GK+MI: 19±2mM) compared to nondiabetic rats (W+sham: 8±0mM; W+MI: 8±1mM). Acetylcholine-induced relaxation was significantly weaker in rings from W+MI and GK+MI rats compared to corresponding sham-operated animals. Myocardial reperfusion injury was smaller in GK+MI than W+MI rats, and the concentration-response curves to acetylcholine were significantly enhanced in rings from GK+MI than W+MI rats. Nevertheless, the relaxation response to acetylcholine was similar in W+sham and GK+sham. Densitometric analysis of bands for endothelial nitric oxide synthase showed a significant decrease in W+MI rats compared to W+sham and GK+sham animals. Aortas from both GK+sham and GK+MI rats showed impaired contractile responses to phenylephrine in comparison with the nondiabetics. CONCLUSIONS For the first time we showed that short-term and mild type-2 DM improved remote endothelial dysfunction after reperfused acute MI.
European Journal of Cardio-Thoracic Surgery | 2017
Sevil Korkmaz-Icöz; Tamás Radovits; Sivakkanan Loganathan; Shiliang Li; Mihály Ruppert; Kálmán Benke; Paige Brlecic; Csaba Szabó; Matthias Karck; Gábor Szabó
OBJECTIVES Heart transplantation is the standard treatment in end-stage heart failure and at shortage of cardiac allografts is its major limiting factor. Striving to optimize the use of this limited resource, the aspect that long distance procurement may increase the available donor pool must be taken into consideration. As poly(ADP-ribose)polymerase (PARP)-activation has been identified as a key pathway of reperfusion injury, we assessed the hypothesis that its inhibition would allow an extension of cold preservation time and protect the graft against ischaemia/reperfusion injury. METHODS Hearts from donor rats were explanted, stored in a preservation solution (Custodiol) at 4 °C for 4 h or 8 h, and heterotopically transplanted. A vehicle or the PARP-inhibitor, INO-1001 (5 mg/kg), was administered during the reperfusion period. We evaluated post-transplant graft function with a Millar micromanometer at different left-ventricular volumes. Additionally, in organ bath experiments the effect of PARP-inhibition on endothelium-dependent and -independent vasorelaxation was evaluated after long-term cold ischaemic storage/warm reperfusion. RESULTS PARP-inhibition resulted in a better systolic functional recovery of grafts submitted to 4 h and 8 h ischaemia. Furthermore, INO-1001 decreased the left-ventricular end-diastolic pressure after 8 h of ischaemia. Coronary blood flow was significantly higher after PARP-inhibition in comparison to controls. Endothelium-dependent vasorelaxation was significantly better in the INO-1001-groups than in the vehicle-treated transplant groups. After 24-h hypothermic storage, treatment of aortic ring with INO-1001 during reoxygenation significantly improved endothelial dysfunction. CONCLUSIONS By inhibiting the PARP activation, INO-1001 can protect the graft and endothelium from the injury that is caused by prolonged cold myocardial ischaemia/reperfusion, thereby improving post-transplant graft function.
Journal of Heart and Lung Transplantation | 2016
Péter Hegedűs; Shiliang Li; Sevil Korkmaz-Icöz; Tamás Radovits; Tobias Mayer; Samer Al Said; Paige Brlecic; Matthias Karck; Béla Merkely; Gábor Szabó
Cardiovascular Diabetology | 2016
Sevil Korkmaz-Icöz; Samer Al Said; Tamás Radovits; Shiliang Li; Maik Brune; Péter Hegedűs; Ayhan Atmanli; Mihály Ruppert; Paige Brlecic; Lorenz H. Lehmann; Bernd Lahrmann; Niels Grabe; Yutaka Yoshikawa; Hiroyuki Yasui; Patrick Most; Matthias Karck; Gábor Szabó