Jozef Bartunek

Charles University in Prague, Praha, Praha, Czech Republic

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Publications (281)

  • [Show abstract] [Hide abstract] ABSTRACT: Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg IP) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC α1-subunit (sGCα1-/-CM). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCα1-/-CM than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGCα1 mutant (DNsGCα1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCα1tg/+ but not WT mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCα1tg/+ and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCα1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species (ROS) generation was higher in sGCα1-deficient than WT hearts. Innovation and conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice, and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use, and may represent a promising approach to limit doxorubicin-associated cardiotoxicity.
    Article · Aug 2016 · Antioxidants and Redox Signaling
  • Article · Aug 2016 · EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology
  • [Show abstract] [Hide abstract] ABSTRACT: Myocarditis is a polymorphic disease characterized by great variability in clinical presentation and evolution. Patients presenting with severe left ventricular dysfunction and life-threatening arrhythmias represent a demanding challenge for the clinician. Modern techniques of cardiovascular imaging and the exhaustive molecular evaluation of the myocardium with endomyocardial biopsy have provided valuable insight into the pathophysiology of this disease, and several clinical registries have unraveled the disease's long-term evolution and prognosis. However, uncertainties persist in crucial practical issues in the management of patients. This article critically reviews current information for evidence-based management, offering a rational and practical approach to patients with myocarditis. For this review, we searched the PubMed and MEDLINE databases for articles published from January 1, 1980, through December 31, 2015, using the following terms: myocarditis, inflammatory cardiomyopathy, and endomyocardial biopsy. Articles were selected for inclusion if they represented primary data or were review articles published in high-impact journals. In particular, a risk-oriented approach is proposed. The different patterns of presentation of myocarditis are classified as low-, intermediate-, and high-risk syndromes according to the most recent evidence on prognosis, clinical findings, and both invasive and noninvasive testing, and appropriate management strategies are proposed for each risk class.
    Article · Jul 2016 · Mayo Clinic Proceedings
  • Article · Jul 2016 · Journal of the American College of Cardiology
  • Tomas Ondrus · Jozef Bartunek · Marc Vanderheyden · [...] · Martin Penicka
    [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVES To compare the outcomes of MitraClip versus minimally invasive surgical mitral valve repair in high-risk patients with significant functional mitral regurgitation (FMR) and severe heart failure in a centre having pilot versus extensive experience with the MitraClip and the minimally invasive surgical approach, respectively. METHODS The MitraClip group consisted of 24 high-surgical-risk patients [age 75 ± 9 years, 75% males, NYHA III/IV 88%, left ventricular (LV) ejection fraction 31 ± 9%, EuroSCORE II 18 ± 14%], while the surgical group consisted of 48 patients matched for age, NYHA class and LV ejection fraction. RESULTS Patients undergoing MitraClip versus those undergoing surgical repair showed higher prevalence of ischaemic LV dysfunction and larger LV end-diastolic diameter (both P < 0.05). Both the MitraClip and the surgical repair groups had similar 30-day mortality rates (4 vs 13%, P= 0.41) and prevalence of serious adverse events (25 vs 38%, P= 0.43). The median follow-up was 1028 days (IQR: 272–1564 days) in the MitraClip group and 890 days (IQR: 436–1381 days) in the surgical group (P= 0.95). Total all-cause mortality (54 vs 60%, log-rank P= 0.64) and rates of rehospitalizations for heart failure (42 vs 29%, log-rank P= 0.68) did not differ significantly between groups. Both techniques were associated with significant decrease in NYHA class and severity of FMR (P< 0.001 for all) and with a similar degree of stabilization of LV remodelling (P= NS). CONCLUSION Despite the significant baseline differences in accumulated expertise and risk profile between the surgical and the MitraClip groups, both minimally invasive techniques were associated with similar 30-day and long-term outcomes.
    Article · Jun 2016 · Interactive Cardiovascular and Thoracic Surgery
  • Marko Banovic · Bernard Iung · Jozef Bartunek · [...] · Svetozar Putnik
    Article · Jun 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Elevated serum levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and atherogenesis. In patients with suspected coronary artery disease (CAD), we assessed the correlation of serum ADMA levels with extent and functional significance of coronary atherosclerosis. Methods: We enrolled 281 patients with suspected CAD undergoing coronary angiogram. Angiographic CAD severity was evaluated by Bogaty score. In patients with angiographic evidence of at least one intermediate coronary stenosis (≥50% diameter stenosis), functional significance was assessed by fractional flow reserve (FFR). Blood samples were collected in all patients prior to coronary angiography for measurement of serum ADMA levels. Results: We observed across tertiles of ADMA levels increasingly higher values of both Stenosis Score (2.25±1.70 vs. 2.89±1.99 vs. 2.95±1.82, p=0.016) and Extent Index (0.52±0.32 vs. 0.61±0.39 vs. 0.72±0.47, p=0.003). The association between ADMA levels and Extent Index remained significant after multivariate adjustment (p=0.005). Patients with FFR ≤0.80 in at least one vessel (n=113) had significantly higher ADMA levels compared with patients without functionally significant CAD (0.51 [0.43-0.64] vs. 0.46 [0.39-0.58]μmol/L, p=0.005). Serum ADMA levels were independent predictors of abnormal FFR after adjustment for extent score (odds ratio 7.35, 95% confidence interval 1.05-56.76, p=0.046). Conclusions: Serum ADMA levels are independent predictors of coronary atherosclerosis extent and functional significance of CAD.
    Article · Jun 2016 · International journal of cardiology
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    [Show abstract] [Hide abstract] ABSTRACT: Aims: Cardiac resynchronization therapy (CRT) in heart failure is limited by many non-responders. This study explores whether degree of wasted left ventricular (LV) work identifies CRT responders. Methods and results: Twenty-one patients who received CRT according to guidelines were studied before and after 8 ± 3 months. By definition, segments that shorten in systole perform positive work, whereas segments that lengthen do negative work. Work was calculated from non-invasive LV pressure and strain by speckle tracking echocardiography. For each myocardial segment and for the entire LV, wasted work was calculated as negative work in percentage of positive work. LV wall motion score index (WMSI) was assessed by echocardiography. Response to CRT was defined as ≥15% reduction in end-systolic volume (ESV). Responder rate to CRT was 71%. In responders, wasted work for septum was 117 ± 102%, indicating more negative than positive work, and decreased to 14 ± 12% with CRT (P < 0.01). In the LV free wall, wasted work was 19 ± 16% and showed no significant change. Global LV wasted work decreased from 39 ± 21 to 17 ± 7% with CRT (P < 0.01). In non-responders, there were no significant changes. In multiple linear regression analysis, septal wasted work and WMSI were the only significant predictors of ESV reduction (β = 0.14, P = 0.01; β = 1.25, P = 0.03). Septal wasted work together with WMSI showed an area under the curve of 0.86 (95% confidence interval 0.71-1.0) for CRT response prediction. Conclusion: Wasted work in the septum together with WMSI was a strong predictor of response to CRT. This novel principle should be studied in future larger studies.
    Full-text Article · Feb 2016 · European Heart Journal Cardiovascular Imaging
  • [Show abstract] [Hide abstract] ABSTRACT: Objectives: This study sought to assess the impact of a wide range of mean right atrial pressure (Pra) on fractional flow reserve (FFR) measurements. Background: FFR invasively assesses the ischemic potential of coronary stenoses. FFR is calculated as the ratio of mean distal coronary pressure (Pd) to mean aortic pressure (Pa) during maximal hyperemia. The Pra is considered to have little impact if it is within normal range, so it is neglected in the formula. Methods: In 1,676 stenoses of 1,235 patients undergoing left-right heart catheterization for ischemic (642 [52%]) or valvular heart disease (593 [48%]), the authors compared the FFR values calculated without accounting for Pra (FFR= Pd/Pa) to the corresponding myocardial fractional flow reserve (FFRmyo) values accounting for Pra (FFRmyo = Pd - Pra/Pa - Pra). Results: The median Pra was 7 (5; 10) mm Hg with a maximum of 27 mm Hg. The correlation and agreement between FFR and FFRmyo was excellent (R(2) = 0.987; slope 1.096 ± 0.003). The median FFR (0.85; interquartile range [IQR]: 0.78 to 0.91) was slightly but statistically significantly higher than the median FFRmyo (0.83; IQR: 0.76 to 0.90; p < 0.001) with a median difference of 0.01 (IQR: 0.01 to 0.02). Values of FFR above the cutoff of 0.80 provided an FFRmyo ≤0.80 in 110 (9%) stenoses. No FFR value above 0.80 provided an FFRmyo ≤0.75. Conclusions: The difference between FFR and FFRmyo was minimal even in patients with markedly increased Pra. FFR values above the gray zone (i.e., >0.80) did not yield values below the gray zone (i.e., ≤0.75) in any case, which suggests that the impact of right atrial pressure on FFR measurement is indeed negligible.
    Article · Feb 2016 · JACC. Cardiovascular Interventions
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    Marko Banovic · Bernard Iung · Jozef Bartunek · [...] · Svetozar Putnik
    [Show abstract] [Hide abstract] ABSTRACT: Aortic valve replacement (AVR) therapy is an obvious choice for symptomatic severe aortic stenosis (AS) patients as it improves symptoms, LV function and survival. The treatment decisions and indication for AVR in asymptomatic patients with severe AS and normal left ventricular ejection fraction (LVEF) are less well established and the subject of ongoing debate. Many efforts have been made to define the best treatment option in asymptomatic AS patients with normal LVEF. Retrospective and observational data imply that elective AVR for asymptomatic severe AS may lead to improvement in outcomes in comparison to surgery performed after onset of symptoms.
    Full-text Article · Feb 2016 · American heart journal
  • [Show abstract] [Hide abstract] ABSTRACT: Fractional flow reserve (FFR) has never been investigated in patients with aortic stenosis (AS). From 2002 to 2010, we identified 106 patients with AS and coronary artery disease (CAD) with at least 1 intermediate lesion treated according to FFR guidance. We matched 212 contemporary control patients with AS in which revascularization was decided on angiography only. More patients in the FFR-guided group underwent percutaneous coronary intervention (PCI) (24% vs 13%; p=0.019), while there was a trend towards less coronary artery bypass grafting (CABG) performed. After FFR, the number of diseased vessels was downgraded within the FFR-guided group (from 1.85 ± 0.97 to 1.48 ± 1; p<0.01) and compared to the angio-guided group (1.48 ± 1 vs 1.8 ± 0.97; p<0.01). Less aortic valve replacement (AVR) was reported in the FFR-guided group (46% vs. 57%; p=0.056). In patients undergoing CABG, less venous conduits (0.5 ± 0.69 vs 0.73 ± 0.76; p=0.05) and anastomoses (0.61 ± 0.85 vs 0.94 ± 1; p=0.032) were necessary in the FFR-guided group. Up to 5 years, we found no difference in MACE (38% vs 39%; p=0.98), overall death (32% vs 31%; p=0.68), nonfatal MI (2% vs 2%; p=0.79) and revascularization (8% vs 7%; p=0.76) between the 2 groups. In conclusion, FFR guidance impacts the management of selected patients with moderate or severe AS and CAD by resulting into deferral of AVR, more patients treated with PCI, and in patients treated with CABG, into less venous grafts and anastomoses without increasing adverse event rates up to 5 years.
    Article · Feb 2016 · The American journal of cardiology
  • [Show abstract] [Hide abstract] ABSTRACT: Background: -The fractional flow reserve (FFR) value of 0.75 has been validated against ischemic testing, while the FFR value of 0.80 has been widely accepted to guide clinical decision-making. However, revascularization when FFR is 0.76-0.80, within the so-called "gray zone", is still debatable. Methods and results: -From February 1997 to June 2013, all patients with single-segment disease and an FFR value within the gray zone or within the two neighboring FFR strata (0.70-0.75 and 0.81-0.85) were included. Study endpoints consisted of major adverse cardiovascular events (MACE: death, myocardial infarction and any revascularization) up to 5 years. Out of 17380 FFR measurements, 1459 patients were included. Of them, 449 were treated with revascularization (Rev), and 1010 with medical therapy (MT). In the gray zone, MACE rate was similar (37[13.9%] vs. 21[11.2%], respectively, p=0.3) between MT and Rev, while a strong trend toward higher rate of death or myocardial infarction (25[9.4] vs. 9[4.8], p=0.06) and overall death (20[7.5] vs. 6[3.2], p=0.059) was observed in the MT group. Among MT patients, a significant step-up increase in MACE rate was observed across the 3 FFR strata, especially with proximal lesion location. In Rev patients, MACE rate was not different across the 3 FFR strata. Conclusions: -FFR in and around the "gray zone" bears a major prognostic value especially in proximal lesions. These data confirm that FFR ≤ 0.80 is valid to guide clinical decision-making.
    Article · Jan 2016 · Circulation
  • Gabor G Toth · Marc Vanderheyden · Jozef Bartunek
    [Show abstract] [Hide abstract] ABSTRACT: While heart failure is one of the leading causes of mortality and morbidity, our tools to provide ultimate treatment solutions are still limited. Recent developments in new devices are designed to fill this therapeutic gap. The scope of this review is to focus on two particular targets, namely (1) left ventricular geometric restoration and (2) atrial depressurization. (1) Reduction of the wall stress by shrinking the ventricular cavity has been traditionally attempted surgically. Recently, the Parachute device (CardioKinetix Inc., Menlo Park, CA, USA) has been introduced to restore ventricular geometry and cardiac mechanics. The intervention aims to partition distal dysfunctional segments that are non-contributory to the ventricular mechanics and forward cardiac output. (2) Diastolic heart failure is characterized by abnormal relaxation and chamber stiffness. The main therapeutic goal achieved should be the reduction of afterload and diastolic pressure load. Recently, new catheter-based approaches were proposed to reduce left atrial pressure and ventricular decompression: the InterAtrial Shunt Device (IASD™) (Corvia Medical Inc., Tewksbury, MA, USA) and the V-Wave Shunt (V-Wave Ltd, Or Akiva, Israel). Both are designed to create a controlled atrial septal defect in symptomatic patients with heart failure. While the assist devices are aimed at end-stage heart failure, emerging device-based percutaneous or minimal invasive techniques comprise a wide spectrum of innovative concepts that target ventricular remodeling, cardiac contractility or neuro-humoral modulation. The clinical adoption is in the early stages of the initial feasibility and safety studies, and clinical evidence needs to be gathered in appropriately designed clinical trials.
    Article · Jan 2016 · Postepy w Kardiologii Interwencyjnej / Advances in Interventional Cardiology
  • Jozef Bartunek · Beth Davison · Warren Sherman · [...] · Andre Terzic
    [Show abstract] [Hide abstract] ABSTRACT: Aims: Cardiopoiesis is a conditioning programme that aims to upgrade the cardioregenerative aptitude of patient-derived stem cells through lineage specification. Cardiopoietic stem cells tested initially for feasibility and safety exhibited signs of clinical benefit in patients with ischaemic heart failure (HF) warranting definitive evaluation. Accordingly, CHART-1 is designed as a large randomized, sham-controlled multicentre study aimed to validate cardiopoietic stem cell therapy. Methods: Patients (n = 240) with chronic HF secondary to ischaemic heart disease, reduced LVEF (<35%), and at high risk for recurrent HF-related events, despite optimal medical therapy, will be randomized 1:1 to receive 600 × 10(6) bone marrow-derived and lineage-directed autologous cardiopoietic stem cells administered via a retention-enhanced intramyocardial injection catheter or a sham procedure. The primary efficacy endpoint is a hierarchical composite of mortality, worsening HF, Minnesota Living with Heart Failure Questionnaire score, 6 min walk test, LV end-systolic volume, and LVEF at 9 months. The secondary efficacy endpoint is the time to cardiovascular death or worsening HF at 12 months. Safety endpoints include mortality, readmissions, aborted sudden deaths, and serious adverse events at 12 and 24 months. Conclusion: The CHART-1 clinical trial is powered to examine the therapeutic impact of lineage-directed stem cells as a strategy to achieve cardiac regeneration in HF populations. On completion, CHART-1 will offer a definitive evaluation of the efficacy and safety of cardiopoietic stem cells in the treatment of chronic ischaemic HF. Trial registration: NCT01768702.
    Article · Dec 2015 · European Journal of Heart Failure
  • Article · Dec 2015 · Vascular Pharmacology
  • [Show abstract] [Hide abstract] ABSTRACT: Aims: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI), along with optimal medical therapy, improves clinical outcome by targeting ischemia-inducing stenosis. Yet, plaque progression or stent failure may cause recurring cardiac events. We assessed the potential prognostic role of different inflammatory biomarkers, known to be associated with plaque progression or stent failure, in patients undergoing FFR-guided PCI. Methods: We prospectively enrolled 169 stable angina patients with intermediate coronary stenosis at angiography undergoing FFR-guided PCI. PCI was performed if FFR was 0.80 or less, deferred if FFR was more than 0.80. Serum baseline levels of high-sensitivity C-reactive protein (hs-CRP), eosinophil cationic protein (ECP), cystatin-C (Cys-C), and thromboxane A2 (TXA2) were assessed. Rate of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, recurrent myocardial infarction, and target vessel revascularization (TVR), was evaluated. Results: PCI was performed in 78 patients (46%) (mean age 69 ± 10 years, men 73%) and deferred in 91 patients (54%) (mean age 64 ± 11 years, men 53%). Mean clinical follow-up was 31 ± 11 months. Within the PCI group, patients with MACE (n = 14 [18%]) had significantly higher ECP levels than those without (14.4 [9.3-19.5] vs. 4.9 [2.8-10.9] mg/l, P < 0.001), and ECP was a significant predictor of MACE (hazard ratio: 1.05, 95% confidence interval [1.01-1.09], P = 0.021). Within the deferred group, patients with MACE (n = 8 [9%]) had significantly higher CRP levels than those without (15 [6.5-31.9] vs. 1.6 [0.9-2.9] mg/l, P < 0.001) and CRP was a significant predictor of MACE (hazard ratio: 1.04, 95% confidence interval [1.01-1.07], P = 0.015). Cys-C and TXA2 were not significantly different between the two groups. Conclusion: Assessing inflammatory biomarkers allows the identification of patients remaining at residual higher risk of MACE after FFR-guided PCI.
    Article · Nov 2015 · Journal of Cardiovascular Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: In the past decade, novel cell-based products have been studied in patients with acute and chronic cardiac disease to assess whether these therapies are efficacious in improving heart function and preventing the development of end-stage heart failure. Cardiac indications studied include acute myocardial infarction (AMI), refractory angina, and chronic heart failure (CHF). Increased clinical activity, experience, and multiple challenges faced by developers have been recognized at the regulatory level. In May 2014, the Committee for Advanced Therapies (CAT) discussed in an expert meeting various cell-based medicinal products developed for cardiac repair, with a focus on non-manipulated bone marrow cells, sorted bone marrow or apheresis, and expanded cells, applied to patients with AMI or CHF. The intention was to share information, both scientific and regulatory, and to examine the challenges and opportunities in this field. These aspects were considered from the quality, and non-clinical and clinical perspectives, including current imaging techniques, with a focus on AMI and CHF. The scope of this overview is to present the European regulatory viewpoint on cell-based therapies for cardiac repair in the context of scientific observations.
    Full-text Article · Oct 2015 · European Journal of Heart Failure
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    Emanuele Barbato · Paul J Barton · Jozef Bartunek · [...] · Jennifer L Hall
    [Show abstract] [Hide abstract] ABSTRACT: The goal of this paper is to provide an updated review for scientists and clinicians on the major areas in cardiovascular medicine published in the Journal. Leading topics in regenerative and personalized medicine are presented along with a critical overview of the field. New standards in large preclinical animal models of pulmonary hypertension and left bundle branch block are highlighted. Finally, clinical care in the areas of atherosclerosis, the aortic valve, platelet biology, and myocarditis is discussed as well as autonomic modulation therapies.
    Full-text Article · Oct 2015 · Journal of Cardiovascular Translational Research
  • Article · Oct 2015 · Journal of the American College of Cardiology
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    Jozef Bartunek · Marc Vanderheyden · Atta Behfar
    [Show abstract] [Hide abstract] ABSTRACT: The traditional cardiac regenerative paradigm using non-modified adult stem cells with various routes of delivery into the myocardial target has thus far yielded unconvincing clinical outcomes. Besides factors related to heterogeneity in trial methodology, inter-patient variability and the rare incidence of adult stem cells with intrinsic repair potency underscore the importance of further optimization and standardization of regenerative platforms. Cardiac tissue engineering seizing upon the advances of cellular, molecular, and biomaterial development is shaping the next generation of the regenerative paradigm and thereby fostering disruptive curative treatments in heart failure.
    Full-text Article · Sep 2015 · Stem Cell Research & Therapy

Publication Stats

9k Citations

Institutions

  • 2006
    • Charles University in Prague
      Praha, Praha, Czech Republic
  • 2003
    • Catharina Hospital
      Eindhoven, North Brabant, Netherlands
    • The Catholic University of America
      Washington, Washington, D.C., United States
  • 1994-2003
    • OLV Ziekenhuis Aalst
      Alost, Flanders, Belgium
  • 1997-2002
    • Beth Israel Deaconess Medical Center
      • Department of Medicine
      Boston, Massachusetts, United States