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Firat Duru

Publications and source records attributed to Firat Duru.

At least 19 recordsLinked to original sources
PubMed2026

Desmoplakin Mutations in Cardiac Fibroblasts Cause TGFβ1-Mediated Pathological Fibrogenesis in Desmoplakin Cardiomyopathy Via Beclin-1 Regulation.

BACKGROUND: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy. Among arrhythmogenic cardiomyopathies, pathogenic DSP (desmoplakin) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remains unknown. METHODS: Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including the heart. We first used RNA-seq genome-wide analyses to generate cardiac fibroblast-like, induced pluripotent stem cell-derived MSCs from normal donors and patients with arrhythmogenic cardiomyopathy and DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to TGFβ1 (transforming growth factor β1) using Western/Co-IP, autophagy assays, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR. RESULTS: TGFβ1 induced excessive accumulation of VIM (vimentin)/fibrillar collagens and over-activated fibrotic genes in DSP-mutant MSCs when compared with normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. DSP-mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered BECN1 (beclin-1) from activating autophagy and CAV1 (caveolin-1)-mediated endocytosis. Decreased autophagy caused collagen accumulation, and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes (COL1A1, COL3A1, and fibronectin [FN]) via heightened p38 activity after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expression. CONCLUSIONS: Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.

Animals↗
PubMed2024

Desmoplakin mutations in cardiac fibroblasts cause TGFβ1-mediated pathological fibrogenesis in desmoplakin cardiomyopathy via beclin-1 regulation.

BACKGROUND: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy (ACM). Among ACM, pathogenic desmoplakin ( DSP ) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remain unknown. METHODS: Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including hearts. We first used unbiased genome-wide analyses to generate cardiac fibroblasts-like, induced pluripotent stem cell-derived MSCs from normal donors and ACM patients with DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to transforming growth factor beta-1 (TGF-β1) using Western/Co-IP, autophagy assay, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR. RESULTS: TGFβ1 induced excessive accumulations of vimentin (VIM)/fibrillar collagens, and over-activated fibrotic genes in DSP- mutant MSCs when compared to normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. DSP- mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered beclin-1 (BECN1) from activating autophagy and caveolin-1 (CAV1)-mediated endocytosis. Decreased autophagy caused collagen accumulations and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes [ COL1A1, COL3A1, and fibronectin ( FN )] via heightened p38 activities after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expressions. CONCLUSIONS: Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.

Journal Article↗
PubMed2006

Improving SVT discrimination in single-chamber ICDs: a new electrogram morphology-based algorithm.

INTRODUCTION: Wide-spread adoption of ICD therapy has focused efforts on improving the quality of life for patients by reducing "inappropriate" shock therapies. To this end, distinguishing supraventricular tachycardia from ventricular tachycardia remains a major challenge for ICDs. More sophisticated discrimination algorithms based on ventricular electrogram morphology have been made practicable by the increased computational ability of modern ICDs. METHODS AND RESULTS: We report results from a large prospective study (1,122 pts) of a new ventricular electrogram morphology tachycardia discrimination algorithm (Wavelet Dynamic Discrimination, Medtronic, Minneapolis, MN, USA) operating at minimal algorithm setting (RV coil-can electrogram, match threshold of 70%). This is a nonrandomized cohort study of ICD patients using the morphology discrimination of the Wavelet algorithm to distinguish SVT and VT/VF. The Wavelet criterion was required ON in all patients and all other supraventricular tachycardia discriminators were required to be OFF. Spontaneous episodes (N = 2,235) eligible for ICD therapy were adjudicated for detection algorithm performance. The generalized estimating equations method was used to remove bias introduced when an individual patient contributes multiple episodes. Inappropriate therapies for supraventricular tachycardia were reduced by 78% (90% CI: 72.8-82.9%) for episodes within the range of rates where Wavelet was programmed to discriminate. Sensitivity for sustained ventricular tachycardia was 98.6% (90% CI: 97-99.3%) without the use of high-rate time out. CONCLUSIONS: Results from this prospective study of the Wavelet electrogram morphology discrimination algorithm operating as the sole discriminator in the ON mode demonstrate that inappropriate therapy for supraventricular tachycardia in a single-chamber ICD can be dramatically reduced compared to rate detection alone.

Algorithms↗
PubMed2006

Potential interference of small neodymium magnets with cardiac pacemakers and implantable cardioverter-defibrillators.

BACKGROUND: Magnetic fields may interfere with the function of cardiac pacemakers and implantable cardioverter-defibrillators (ICDs). Neodymium-iron-boron (NdFeB) magnets, which are small in size but produce strong magnetic fields, have become widely available in recent years. Therefore, NdFeB magnets may be associated with an emerging risk of device interference. OBJECTIVE: We conducted a clinical study to evaluate the potential of small NdFeB magnets to interfere with cardiac pacemakers and ICDs. METHODS: The effect of four NdFeB magnets (two spherical magnets 8 and 10 mm in diameter, a necklace made of 45 spherical magnets, and a magnetic name tag) was tested in forty-one ambulatory patients with a pacemaker and 29 patients with an ICD. The maximum distance at which the magnetic switch of a device was influenced was observed. RESULTS: Magnetic interference was observed in all patients. The maximum distance resulting in device interference was 3 cm. No significant differences were found with respect to device manufacturer and device types. CONCLUSION: Small NdFeB magnets may cause interference with cardiac pacemakers and ICDs. Patients should be cautioned about the interference risk associated with NdFeB magnets during daily life.

Aged↗
PubMed2006

Integration of B-type natriuretic peptide levels with clinical data and exercise testing for predicting coronary artery disease.

Natriuretic peptides have been shown to be high in patients with myocardial ischemia. We sought to create a diagnostic score using clinical data, stress testing, and B-type natriuretic peptide (BNP) levels to improve noninvasive prediction of coronary artery disease (CAD). Patients with stable angina pectoris and normal systolic left ventricular function were eligible for this prospective cohort study. Patients with arrhythmias, valvular heart disease, impaired left ventricular function, or renal dysfunction were excluded. All patients underwent clinical evaluation, bicycle stress testing, BNP testing, and coronary angiography. Then a diagnostic risk score was derived that combined cardiovascular risk factors, results of exercise testing, and BNP measurements and added 1 point for the presence of each of these variables. Seventy-one patients (52 years of age, range 31 to 61; 46 men) were included in the study. Prevalence of CAD, defined by 50% narrowing of > or =1 coronary artery on coronary angiography, was 45%. For 0 point in the risk score system, the negative predictive value was 93% with a negative likelihood ratio of 0.1 (95% confidence interval [CI] 0.02 to 0.38); for a score of 3 points, the positive predictive value was 93% with a positive likelihood ratio of 15.9 (95% CI 2.19 to 114.7). Serum BNP level >50 ng/L at rest was the best single diagnostic parameter, with 66% sensitivity and 97% specificity, and a positive likelihood ratio of 25.6 (95% CI 3.64 to 180) and a negative likelihood ratio of 0.35 (95% CI 0.22 to 0.57). In conclusion, a diagnostic score combining exercise testing, clinical data, and serum BNP values at rest can distinguish patients with CAD from those without CAD with high accuracy.

Adult↗
PubMed2006

Long-term continuous external electrocardiographic recording: a review.

Ambulatory electrocardiographic (AECG) monitoring is an essential tool in the diagnostic evaluation of patients with cardiac arrhythmias. Recent advances in solid-state technology have improved the quality of the ECG signals and new dedicated algorithms have expanded the clinical application of software-based AECG analysis systems. These advances, in addition to the availability of inexpensive large storage capacities, and very long-term continuous high-quality AECG monitoring, have opened new potential uses for AECG. New digital recorders have the capability of multichannel simultaneous recordings (from 3 to 12 leads) and for telemetred signal transduction. These possibilities will expand the traditional uses of AECG for arrhythmia detection, as arrhythmia monitoring to assess drug and device efficacies has been further defined by new studies. The analysis of transient ST-segment deviation still remains controversial, but considerably more data are now available, especially about the prognostic value of detecting asymptomatic ischaemia. Heart rate variability analysis has shown promise for predicting mortality rates in cardiac patients at high risk. We review recent advances in this field of non-invasive cardiac testing.

Algorithms↗
PubMed2006

Nocturnal overdrive pacing for the treatment of sleep apnea syndrome.

STUDY OBJECTIVES: We investigated the effect of 1 week of nocturnal overdrive pacing (NOP) on the apnea-hypopnea index (AHI) in patients with a chronically implanted pacemaker and diagnosed during a screening phase with sleep apnea. DESIGN: Randomized, single-blind, crossover study. SETTING: University medical centers in Zürich, Switzerland, and Berlin, Germany. PATIENTS: Nineteen patients with mild to severe sleep apnea/hypopnea (16 men, mean age = 68.8 +/- 11.4 years) participated. The individuals did not suffer from permanent atrial arrhythmia, did not use continuous positive airway pressure, and had been implanted with atrial or dual-chamber pacemakers. INTERVENTIONS: Nocturnal lower rates were 45 and 75 beats per minute (bpm) at night for the control and NOP arms, respectively, and daytime lower rates were 60 bpm. Subjects were in each arm for 1 week. MEASUREMENTS AND RESULTS: Heart-rate increase from control (61 +/- 9 bpm) to NOP (78 +/- 4 bpm) followed by significant reduction in circulation time (24.6 seconds control, 20.7 seconds NOP; p = .04) resulted in no significant change in AHI (26.8 +/- 17.1/h control, 23.0 +/- 16.7/h NOP; p = .49). Seven subjects characterized by a higher hypopnea index, less stage 1 and 2 sleep, and less slow-wave sleep improved at least 1 AHI severity level with NOP, mainly attributable to reduction of hypopneas. CONCLUSION: NOP over a period of 1 week followed by a reduction in circulation time did not improve AHI in patients with SA. Whether an improvement by 1 AHI severity level in a specific subset of patients reflects a true response remains to be elucidated by further studies.

Continuous Positive Airway Pressure↗
PubMed2006

Wavelet-based tachycardia discrimination in ICDs: Impact of posture and electrogram configuration.

BACKGROUND: Inappropriate therapy delivery is an important concern in the management of patients with implantable cardioverter defibrillators (ICDs). Recently, a morphology-based algorithm (wavelet feature) has been introduced for differentiation of ventricular and supraventricular tachycardia. In this study, we evaluated the performance of the wavelet algorithm using various electrogram (EGM) configurations during different body positions. METHODS: Patients with a single-chamber Medtronic model 7230 ICD (Minneapolis, MN, USA) and a double-coil lead were included. EGM templates were collected during baseline rhythm in supine position for different EGM sources (right ventricular [RV] coil-can, RV coil-superior vena cava [SVC] coil, tip-ring, SVC coil-can). For each EGM configuration, morphologic similarity (match percentage) of EGMs obtained during different body positions (supine, left and right lateral, sitting, standing, walking) were compared with the templates. RESULTS: Twenty-eight patients (24 males; age 58 +/- 17 years) were studied. A total of 9,775 intracardiac EGMs were analyzed. Median match percentage (interquartile range) was 88% (85-94), 88% (82-94), 82% (76-88), and 73 (58-85) for the RV coil-can, RV coil-SVC coil, tip-ring, and SVC coil-can configurations, respectively. Correct classification rates, as defined by match percentage of 70% or higher, were significantly higher with the RV coil-can, RV coil-SVC coil, and tip-ring EGM configurations, as compared to the SVC coil-can configuration (95, 91, and 91 vs 58% > or =70% match percent, P < 0.001). CONCLUSION: Wavelet-based morphology scores in ICDs may change with various body positions. These variations are relatively minor using the nominal configuration (RV coil-can), as well as by using RV coil-SVC coil and tip-ring. However, morphology scores can vary considerably when SVC coil-can is used; therefore, this configuration should be avoided while using the wavelet algorithm.

Algorithms↗
PubMed2005

3-D CT for cardiovascular treatment planning.

The recently developed 64-slice CT scanner together with the use of 2-D and 3-D reconstructions can aid the cardiovascular surgeon and interventional radiologist in visualizing exact geometric relationships to plan and execute complex procedures via minimally invasive or standard approaches. Cardiac 64-slice CT considerably benefits from the high temporal and spatial resolution allowing the reliable depiction of small coronary segments. Similarly, abdominal vascular 64-slice CT became possible within short examination times and allowing an optimal arterial contrast bolus exploitation. We demonstrate four representative cardiac and abdominal examples using the new 64-slice CT technology which reveal the impact of the new scanner generation for cardiovascular treatment planning.

Cardiovascular Diseases↗
PubMed2005

Automatic impedance monitoring and patient alert feature in implantable cardioverter defibrillators: being alert for the unexpected!

Recent advances in implantable cardioverter defibrillator (ICD) technology have enabled implementation of an automatic monitoring feature in ICDs that provides daily measurements of several technical parameters such as battery status, pacing, and high-voltage impedance. The system alerts the patient with an audible alarm to contact the physician in case the measured parameters are not within normal limits. Early detection of intermittent and potentially serious complications justifies routine use of this feature. This report describes a patient with an ICD who died suddenly due to ventricular fibrillation, which was not appropriately treated by the device. The cause of device malfunction was most likely an intermittent lead fracture that was not detected by the automatic impedance monitoring and alert feature of this device. Based on these data, potential benefits and theoretical pitfalls of automatic impedance monitoring and alert features are discussed.

Adult↗
PubMed2005

Induction ovens and electromagnetic interference: what is the risk for patients with implantable cardioverter defibrillators?

Electromagnetic fields may interfere with normal implantable cardioverter defibrillator (ICD) function. Although the devices are effectively shielded and use exclusively bipolar leads, electromagnetic interference (EMI) remains a concern when patients are exposed to several household appliances. The aim of this study was to evaluate potential EMI risk of induction ovens, which are increasingly common in private households. In vitro measurements of an induction oven for private households GK 43 TI (V-Zug, Inc., Zug, Switzerland) showed that heating is regulated by increasing operating time from level 1 (100 ms/sec) to 5 (continuous operation). From levels 5 to 9 the magnetic field increases. Nineteen patients with left-sided implants of single- and dual-chamber ICD systems (8 Medtronic, 7 Guidant, and 4 St. Jude Medical) (18 males, 1 female), age (mean +/- SEM) 58 +/- 3 years, were included in this study. All patients were examined in standing position, bent over the cooking pot (minimal distance to the induction coil 25 cm), and with the cooking pot put eccentrically over the induction field at three different cooking levels (level 2, 5, and 9). The tests were repeated touching the cooking pot with one hand. Ventricular sensitivity was left unchanged. Ventricular tachycardia therapies were turned off in Medtronic and Guidant devices and ventricular sensing was continuously monitored in St. Jude Medical devices during testing. Interrogation of the devices after exposure did not show any inappropriate tachycardia detection, oversensing, or reprogramming. In conclusion, ICD patients can be reassured that EMI is unlikely to affect their devices if induction ovens are used in their kitchens.

Defibrillators, Implantable↗
PubMed2004

In vivo heating of pacemaker leads during magnetic resonance imaging.

AIMS: Magnetic resonance imaging (MRI) is well established as an important diagnostic tool in medicine. However, the presence of a cardiac pacemaker is usually regarded as a contraindication for MRI due to safety reasons. In this study, heating effects at the myocardium-pacemaker lead tip interface have been investigated in a chronic animal model during MRI at 1.5 Tesla. METHODS AND RESULTS: Pacemaker leads with additional thermocouple wires as temperature sensors were implanted in nine animals. Temperature increases of up to 20 degrees C were measured during MRI of the heart. Significant impedance and minor stimulation threshold changes could be seen. However, pathology and histology could not clearly demonstrate heat-induced damage. CONCLUSIONS: MRI may produce considerable heating at the lead tip. Changes of pacing parameters due to MRI could be seen in chronic experiments. Potential risk of tissue damage cannot be excluded even though no reproducible alterations at the histological level could be found.

Animals↗
PubMed2004

Diagnosis of sleep-related breathing disorders by visual analysis of transthoracic impedance signals in pacemakers.

BACKGROUND: Minute ventilation sensors of cardiac pacemakers measure ventilation by means of transthoracic impedance changes between the pacemaker case and the electrode tip. We investigated whether this technique might detect sleep-related breathing disorders. METHODS AND RESULTS: In 22 patients, analog waveforms of the transthoracic impedance signal measured by the pacemaker minute ventilation sensor over the course of a night were visualized, scored for apnea/hypopnea events, and compared with simultaneous polysomnography. Analysis of transthoracic impedance signals correctly identified the presence or absence of moderate to severe sleep apnea (apnea/hypopnea index, AHI >20 h(-1)) in all patients (receiver operating characteristics, ROC=1.0). The ROC for AHI scores of > or =5 h(-1) and > or =10 h(-1) showed an area under the curve of 0.95, P<0.005, and 0.97, P<0.0001, respectively. Accuracy over time assessed by comparing events per 5-minute epochs was high (Cronbach alpha reliability coefficient, 0.85; intraclass correlation, 0.73). Event-by-event comparison within +/-15 seconds revealed agreement in 81% (kappa, 0.77; P<0.001). CONCLUSIONS: Detection of apnea/hypopnea events by pacemaker minute ventilation sensors is feasible and accurate compared with laboratory polysomnography. This technique might be useful to screen and monitor sleep-related breathing disorders in pacemaker patients.

Aged↗