Publications by authors named "Theofilos Kolettis"

102 Publications

Association of non-invasive electrocardiographic risk factors with left ventricular systolic function in post-myocardial infarction patients with mildly reduced or preserved ejection fraction: Insights from the PRESERVE-EF study.

Ann Noninvasive Electrocardiol 2022 Jul 6:e12946. Epub 2022 Jul 6.

First Department of Cardiology, Hippokrateion Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Background: Electrocardiographic non-invasive risk factors (NIRFs) have an important role in the arrhythmic risk stratification of post-myocardial infarction (post-MI) patients with preserved or mildly reduced left ventricular ejection fraction (LVEF). However, their specific relation to left ventricular systolic function remains unclear. We aimed to evaluate the association between NIRFs and LVEF in the patients included in the PRESERVE-EF trial.

Methods: We studied 575 post-MI ischemia-free patients with LVEF≥40% (mean age: 57.0 ± 10.4 years, 86.2% men). The following NIRFs were evaluated: premature ventricular complexes, non-sustained ventricular tachycardia (NSVT), late potentials (LPs), prolonged QTc, increased T-wave alternans, reduced heart rate variability, and abnormal deceleration capacity with abnormal turbulence.

Results: There was a statistically significant relationship between LPs (Chi-squared = 4.975; p < .05), nsVT (Chi-squared = 5.749, p < .05), PVCs (r= -.136; p < .01), and the LVEF. The multivariate linear regression analysis showed that LPs (p = .001) and NSVT (p < .001) were significant predictors of the LVEF. The results of the multivariate logistic regression analysis indicated that LPs (OR: 1.76; 95% CI: 1.02-3.05; p = .004) and NSVT (OR: 2.44; 95% CI: 1.18-5.04; p = .001) were independent predictors of the mildly reduced LVEF: 40%-49% versus the preserved LVEF: ≥50%.

Conclusion: Late potentials and NSVT are independently related to reduced LVEF while they are independent predictors of mildly reduced LVEF versus the preserved LVEF. These findings may have important implications for the arrhythmic risk stratification of post-MI patients with mildly reduced or preserved LVEF.
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http://dx.doi.org/10.1111/anec.12946DOI Listing
July 2022

Autonomic Responses during Labor: Potential Implications for Takotsubo Syndrome.

J Cardiovasc Dev Dis 2021 Nov 7;8(11). Epub 2021 Nov 7.

1st Cardiology Department, University Hospital of Ioannina, 45500 Ioannina, Greece.

Takotsubo syndrome is a serious complication of labor. Although the pathophysiologic role of excessive sympathetic activation is established in this process, concurrent vagal responses have not been adequately described. Moreover, it remains unclear whether autonomic activity depends on the mode of delivery. Here, we explored the hypothesis that the different management of cesarean and vaginal delivery may elicit diverse responses affecting both autonomic arms. For this aim, continuous electrocardiographic recording was performed in 20 women during labor, and non-invasive indices of sympathetic and vagal activity were compared between the two modes of delivery. We report sympathetic prevalence during cesarean delivery, caused by marked vagal withdrawal, whereas autonomic activity was rather stable during vaginal delivery. These differences may be attributed to the effects of anesthesia during cesarean delivery, along with the protective effects of oxytocin administration during vaginal delivery. Our results provide further insights on autonomic responses during labor that may prove useful in the prevention of complications, such as takotsubo syndrome.
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http://dx.doi.org/10.3390/jcdd8110152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620927PMC
November 2021

Myocardial perfusion SPECT as a potential mediator on circulating chromogranin A in patients with old myocardial infarction.

Hell J Nucl Med 2021 May-Aug;24(2):114-121. Epub 2021 Aug 6.

University Hospital of Ioannina, Nuclear Medicine Dept. Stavros Niarchos Avenue, Ioannina 455 00, Greece.

Objective: Chromogranin A (CgA) is a soluble polypeptide stored within and released from secretory granules of endocrine and other cell types (including cardiomyocytes); CgA appears to be a marker of the overall neuroendocrine activity. Increased levels of serum CgA have been found not only in patients with neuroendocrine neoplasms but also with other malignancies, hypertension, myocardial infarction, heart, or renal failure.

Subjects And Methods: A population of 307 patients (202 males, 105 females) was enrolled. The study group consisted of 118 individuals (38.4%) with myocardial infarction more than one year old (MI group); the remaining 189 (61.6%) had no known heart disease (control group). All patients underwent myocardial perfusion scintigraphy (MPS) after blood withdrawal for serum CgA measurement. To test whether a possible effect of old infarction on serum CgA is mediated by MPS findings, we employed analysis of covariance for three distinct categories of left ventricular (LV) perfusion deficits as dichotomous predictors: (1) any-type deficits (abnormal MPS); (2) reversible deficits (ischemia); and (3) fixed deficits (scar).

Results: In all three MPS conditions, the effect of age, gender, and LV ejection fraction (EFLV) on serum CgA was statistically significant: women exhibited higher CgA levels than men (P=0.008-0.023), whereas increasing age and decreasing EFLV were associated with increasing CgA (all P<0.001). Conversely, no statistically significant differences in mean CgA levels were found between MI patients and normal controls with either abnormal MPS, scar, or ischemia, or their degree and extent.

Conclusion: Although serum CgA is significantly associated with age, gender, and EFLV in patients with an old MI, no association was found between CgA levels and either old MI history or MPS findings. The verified involvement of circulating CgA in the acute/subacute phase of infarction appears to be blunted in infarctions older than a year.
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http://dx.doi.org/10.1967/s002449912351DOI Listing
January 2022

Optical Coherence Tomography Facilitating Early Withdrawal of Antiplatelet Agents in a High-Bleeding Risk Patient.

JACC Case Rep 2020 Jul 15;2(8):1186-1191. Epub 2020 Jul 15.

First Cardiology Department, Ioannina University Hospital, Ioannina, Greece.

Optical coherence tomography (OCT) can guide percutaneous coronary interventions to optimize results, thus minimizing the risk of stent thrombosis. We present the case of a cancer patient, paroxysmal atrial fibrillation, and unstable angina who underwent OCT-guided complex percutaneous coronary intervention and who required early discontinuation of antiplatelet therapy because of major bleeding. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.04.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311683PMC
July 2020

Should Deferred Stenting Still Be Considered in ST-Elevation Myocardial Infarction with High Thrombus Burden?

J Cardiovasc Dev Dis 2021 May 21;8(6). Epub 2021 May 21.

1st Cardiology Department, University Hospital of Ioannina, 45500 Ioannina, Greece.

Patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) may demonstrate distal microvascular embolization of thrombotic materials. We retrospectively examined 20 cases displaying extensive thrombus in the infarct-related artery (IRA), treated either with a two-step procedure, with interim tirofiban infusion, or immediate stent implantation. Distal embolization tended to be more common in the latter strategy, but, overall, the outcome was comparable. Thus, a two-staged procedure may be considered in selected cases of primary PCI associated with high thrombus burden.
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http://dx.doi.org/10.3390/jcdd8060059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224060PMC
May 2021

Sympathetic Activation and Arrhythmogenesis after Myocardial Infarction: Where Do We Stand?

J Cardiovasc Dev Dis 2021 May 15;8(5). Epub 2021 May 15.

1st Department of Cardiology, University Hospital of Ioannina, 1 St. Niarxou Avenue, 45500 Ioannina, Greece.

Myocardial infarction often leads to progressive structural and electrophysiologic remodeling of the left ventricle. Despite the widespread use of β-adrenergic blockade and implantable defibrillators, morbidity and mortality from chronic-phase ventricular tachyarrhythmias remains high, calling for further investigation on the underlying pathophysiology. Histological and functional studies have demonstrated extensive alterations of sympathetic nerve endings at the peri-infarct area and flow-innervation mismatches that create a highly arrhythmogenic milieu. Such accumulated evidence, along with the previously well-documented autonomic dysfunction as an important contributing factor, has stirred intense research interest for pharmacologic and non-pharmacologic neuromodulation in post-infarction heart failure. In this regard, aldosterone inhibitors, sacubitril/valsartan and sodium-glucose cotransporter type 2 inhibitors have shown antiarrhythmic effects. Non-pharmacologic modalities, currently tested in pre-clinical and clinical trials, include transcutaneous vagal stimulation, stellate ganglion modulation and renal sympathetic denervation. In this review, we provide insights on the pathophysiology of ventricular arrhythmogenesis post-myocardial infarction, focusing on sympathetic activation.
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http://dx.doi.org/10.3390/jcdd8050057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156099PMC
May 2021

Sympathetic and Vagal Responses Elicited by Acute Stress in Rats.

Cureus 2020 Nov 20;12(11):e11602. Epub 2020 Nov 20.

Cardiology, Cardiovascular Research Institute, Ioannina, GRC.

Introduction Acute emotional stress triggers autonomic responses that affect sympathovagal balance. However, the temporal pattern of changes in each autonomic arm during stress and recovery remains unclear. Therefore, we analyzed separately sympathetic and vagal activity, elicited by acute unpredictable stress in a rat model. Methods Continuous electrocardiographic recording was performed during (32 minutes) and after (two hours) successive use of restraint and air-jet stress in 10 rats, whereas five rats served as controls. Sympathetic and vagal indices were calculated non-invasively after heart rate variability analysis. Voluntary motion was quantified during recovery, as an index of continuing anxiety. Results The sympathetic nervous system index increased during stress and remained elevated during the initial stage of recovery. The parasympathetic nervous system index decreased immediately after the onset of stress and remained low throughout the observational period. During recovery, voluntary activity was more pronounced in the stress group than in the controls. Conclusion Successive restraint and air-jet stress in rats increased sympathetic activity and decreased vagal activity. These changes displayed only partial recovery post-stress and were accompanied by enhanced voluntary motion. Our findings may be important in the evaluation of the cardiac electrophysiologic implications of autonomic changes elicited by acute emotional stress.
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http://dx.doi.org/10.7759/cureus.11602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752793PMC
November 2020

Treatment of Mobile Right Heart Thrombi.

Eur J Case Rep Intern Med 2020 17;7(12):001918. Epub 2020 Sep 17.

1st Cardiology Department, School of Medicine, University of Ioannina, Ioannina. Greece.

Right heart thrombi are detected in approximately 4% of patients with pulmonary embolism. The associated mortality is high, but the optimal strategy remains controversial. We report a case of a large mobile right heart thrombus, complicated by embolism of the right pulmonary artery, which was successfully treated with half-dose alteplase. We briefly review the literature and discuss the therapeutic options, focusing on the advantages of thrombolysis.

Learning Points: Mobile right heart thrombi require rapid therapeutic choices between surgical thrombectomy and thrombolysis.Half-dose alteplase may be effective, even in the presence of an extensive thrombus burden.
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http://dx.doi.org/10.12890/2020_001918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727624PMC
September 2020

Trends in ablation procedures in Greece over the 2008-2018 period: Results from the Hellenic Cardiology Society Ablation Registry.

Hellenic J Cardiol 2021 Jan-Feb;62(1):48-54. Epub 2020 Sep 19.

Metropolitan General, Athens, Greece.

Objective: In 2008, the radiofrequency ablation (RFA) procedures registry of the Hellenic Society of Cardiology was created. This online database allowed electrophysiologists around the country to input data for all performed ablation procedures. The aim of this study is to provide a thorough report and interpretation of the data submitted to the registry between 2008 and 2018.

Methods: In 2008, a total of 27 centers/medical teams in 24 hospitals were licensed to perform RFA in Greece. By 2018, the number had risen to 31. Each center was tasked with inserting their own data into the registry, which included patient demographics (anonymized), type of procedure and technique, complications, and outcomes.

Results: A total of 18587 procedures in 17900 patients were recorded in the period of 2008-2018. By 2018, slightly more than 70% of procedures were performed in 7 high-volume centers (>100 cases/year). The most common procedure since 2014 was atrial fibrillation ablation, followed by atrioventricular nodal reentry tachycardia ablation. Complication rates were low, and success rates remained high, whereas the 6-month relapse rates declined steadily.

Conclusion: This online RFA registry has proved that ablation procedures in Greece have reached a very high standard, with results and complication rates comparable to European and American standards. Ablation procedures for atrial fibrillation are increasing constantly, with it being the most common intervention over the last 6-year period, although the absolute number of procedures still remains low, compared to other European countries.
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http://dx.doi.org/10.1016/j.hjc.2020.09.005DOI Listing
August 2021

Access-site Complications of the Transradial Approach: Rare But Still There.

Curr Cardiol Rev 2021 ;17(3):279-293

1st Cardiology Department, School of Medicine, University of Ioannina, Ioannina, Greece.

In the past decade, the Transradial Approach (TRA) has constantly gained ground among interventional cardiologists. TRA's anatomical advantages, in addition to patients' acceptance and financial benefits, due to rapid patient mobilization and shorter hospital stay, made it the default approach in most catheterization laboratories. Access-site complications of TRA are rare and usually of little clinical impact, thus, they are often overlooked and underdiagnosed. Radial Artery Occlusion (RAO) is the most common, followed by radial artery spasm, perforation, hemorrhagic complications, pseudoaneurysm, arterio-venous fistula, and even rarer complications, such as nerve injury, sterile granuloma, eversion endarterectomy or skin necrosis. Most of them are conservatively treated, but rarely, surgical treatment may be needed and late diagnosis may lead to life-threatening situations, such as hand ischemia or compartment syndrome and tissue loss. Additionally, some complications may eventually lead to TRA failure and switch to a different approach. On the other hand, it is the opinion of the authors that non-occlusive radial artery injury, commonly included in TRA's complications in the literature, should be regarded more as an anticipated functional and anatomical cascade, following radial artery puncture and sheath insertion.
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http://dx.doi.org/10.2174/1573403X16999200819101923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640860PMC
July 2021

Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.

JAMA Netw Open 2020 06 1;3(6):e2013136. Epub 2020 Jun 1.

Department of Cardiology, Ioannina University Hospital, University of Ioannina, Ioannina, Greece.

Importance: Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile.

Objective: To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19).

Design, Setting, And Participants: In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece.

Intervention: Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks.

Main Outcomes And Measures: Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis.

Results: A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003).

Conclusions And Relevance: In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution.

Trial Registration: ClinicalTrials.gov Identifier: NCT04326790.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.13136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315286PMC
June 2020

The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design.

Hellenic J Cardiol 2020 Jan - Feb;61(1):42-45. Epub 2020 Apr 3.

Humanitas Clinical and Research Institute, Rozzano, Milan, Italy; Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Objective: Colchicine has been utilized safely in a variety of cardiovascular clinical conditions. Among its potential mechanisms of action is the non-selective inhibition of NLRP3 inflammasome which is thought to be a major pathophysiologic component in the clinical course of patients with COVID-19. GRECCO-19 will be a prospective, randomized, open-labeled, controlled study to assess the effects of colchicine in COVID-19 complications prevention.

Methods: Patients with laboratory confirmed SARS-CoV-2 infection (under RT PCR) and clinical picture that involves temperature >37.5 oC and at least two out of the: i. sustained coughing, ii. sustained throat pain, iii. Anosmia and/or ageusia, iv. fatigue/tiredness, v. PaO2<95 mmHg will be included. Patients will be randomised (1:1) in colchicine or control group.

Results: Trial results will be disseminated through peer-reviewed publications and conference presentations.

Conclusion: GRECCO-19 trial aims to identify whether colchicine may positively intervene in the clinical course of COVID-19. (ClinicalTrials.gov Identifier: NCT04326790).
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http://dx.doi.org/10.1016/j.hjc.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194546PMC
July 2020

Electrophysiologic Effects of Growth Hormone Post-Myocardial Infarction.

Int J Mol Sci 2020 Jan 30;21(3). Epub 2020 Jan 30.

1st Department of Cardiology, University Hospital of Ioannina, 45500 Ioannina, Greece.

Myocardial infarction remains a major health-related problem with significant acute and long-term consequences. Acute coronary occlusion results in marked electrophysiologic alterations that can induce ventricular tachyarrhythmias such as ventricular tachycardia or ventricular fibrillation, often heralding sudden cardiac death. During the infarct-healing stage, hemodynamic and structural changes can lead to left ventricular dilatation and dysfunction, whereas the accompanying fibrosis forms the substrate for re-entrant circuits that can sustain ventricular tachyarrhythmias. A substantial proportion of such patients present clinically with overt heart failure, a common disease-entity associated with high morbidity and mortality. Several lines of evidence point toward a key role of the growth hormone/insulin-like growth factor-1 axis in the pathophysiology of post-infarction structural and electrophysiologic remodeling. Based on this rationale, experimental studies in animal models have demonstrated attenuated dilatation and improved systolic function after growth hormone administration. In addition to ameliorating wall-stress and preserving the peri-infarct myocardium, antiarrhythmic actions were also evident after such treatment, but the precise underlying mechanisms remain poorly understood. The present article summarizes the acute and chronic actions of systemic and local growth hormone administration in the post-infarction setting, placing emphasis on the electrophysiologic effects. Experimental and clinical data are reviewed, and hypotheses on potential mechanisms of action are discussed. Such information may prove useful in formulating new research questions and designing new studies that are expected to increase the translational value of growth hormone therapy after acute myocardial infarction.
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http://dx.doi.org/10.3390/ijms21030918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037853PMC
January 2020

Endothelin receptors in the brain modulate autonomic responses and arrhythmogenesis during acute myocardial infarction in rats.

Life Sci 2019 Dec 14;239:117062. Epub 2019 Nov 14.

Cardiovascular Research Institute, Ioannina and Athens, Greece; Department of Cardiology, Medical School, University of Ioannina, Greece. Electronic address:

Aims: Endothelin has been implicated in various processes in the brain, including the modulation of sympathetic responses. The present study examined the pathophysiologic role of brain endothelin-receptors in the setting of acute myocardial infarction, characterized by high incidence of ventricular tachyarrhythmias.

Main Methods: We investigated the effects of intracerebroventricular administration of antagonists of endothelin-receptors ET, ET, or both, during a 24 h-observation period post-coronary ligation in (n = 70) rats. Continuous recording was performed via implanted telemetry transmitters, followed by arrhythmia-analysis and calculation of autonomic indices derived from heart rate variability. The regional myocardial electrophysiologic properties were assessed by monophasic action potentials and multi-electrode recordings.

Key Findings: Sympathetic-activity was decreased and vagal-activity was enhanced after intracerebroventricular ET-receptor blockade, thus attenuating regional myocardial repolarization inhomogeneity. As a result, the incidence of ventricular tachyarrhythmias was markedly lower in this group. Such effects were also observed after intracerebroventricular blockade of ET-, or both, ET- and ET-receptors, although to a lesser extent.

Significance: ET-receptors in the brain modulate sympathetic and vagal responses and alter arrhythmogenesis during evolving myocardial necrosis in rats. These findings provide insights into arrhythmogenic mechanisms during acute myocardial infarction and call for further investigation on the role of endothelin in the central autonomic network.
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http://dx.doi.org/10.1016/j.lfs.2019.117062DOI Listing
December 2019

CPVT: Arrhythmogenesis, Therapeutic Management, and Future Perspectives. A Brief Review of the Literature.

Front Cardiovasc Med 2019 12;6:92. Epub 2019 Jul 12.

Heart Rhythm Management Centre, Vrije University, Brussels, Belgium.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a primary electrical disease characterized by a normal resting electrocardiogram and induction of malignant arrhythmias during adrenergic stress leading to syncope or sudden cardiac death (SCD). CPVT is caused by mutations in the cardiac ryanodine receptor (RyR2) or in the sarcoplasmic reticulum protein calsequestrin 2 genes (). The RyR2 mutations are responsible for the autosomal dominant form of CPVT, while mutations are rare and account for the recessive form. These mutations cause a substantial inballance in the homeostasis of intracellular calcium resulting in polymorphic ventricular tachycardia through triggered activity. Beta blockers were for years the cornerstone of therapy in these patients. Sodium channel blockers, especially flecainide, have an additive role in those not responding in beta blockade. Implantation of defibrillators needs a meticulous evaluation since inappropriate shocks may lead to electrical storm. Finally, cardiac sympathetic denervation might also be an alternative therapeutic option. Early identification and risk stratification is of major importance in patients with CPVT. The aim of the present review is to present the arrhythmogenic mechanisms of the disease, the current therapies applied and potential future perspectives.
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http://dx.doi.org/10.3389/fcvm.2019.00092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644488PMC
July 2019

Medium-term Electrophysiologic Effects of a Cellularized Scaffold Implanted in Rats After Myocardial Infarction.

Cureus 2018 Jul 10;10(7):e2959. Epub 2018 Jul 10.

Division of Biomedical Research, Institute of Molecular Biology and Biotechnology - Forth, Ioannina, GRC.

Background Cardiac repair strategies are being evaluated for myocardial infarctions, but the safety issues regarding their arrhythmogenic potential remain unresolved. By utilizing the in-vivo rat model, we have examined the medium-term electrophysiologic effects of a biomaterial scaffold that has been cellularized with spheroids of human adipose tissue, derived from mesenchymal stem cells and umbilical vein endothelial cells. Methods Mesenchymal stem cells, which exhibit adequate differentiation capacity, were co-cultured with umbilical vein endothelial cells and were seeded on an alginate based scaffold. After in-vitro characterization, the cellularized scaffold was implanted in (n=15) adult Wistar rats 15 min post ligation of the left coronary artery, with an equal number of animals serving as controls. Two weeks thereafter, monophasic action potentials were recorded and activation-mapping was performed with a multi-electrode array. An arrhythmia score for inducible ventricular tachyarrhythmias was calculated after programmed electrical stimulation. Results The arrhythmia score was comparable between the treated animals and controls. No differences were detected in the local conduction at the infarct border and in the voltage rise in monophasic action potential recordings. Treatment did not affect the duration of local repolarization, but tended to enhance its dispersion. Conclusions The fabricated bi-culture cellularized scaffold displayed favorable properties after in-vitro characterization. Medium-term electrophysiologic assessment after implantation in the infarcted rat myocardium revealed low arrhythmogenic potential, but the long-term effects on repolarization dispersion will require further investigation.
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http://dx.doi.org/10.7759/cureus.2959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132679PMC
July 2018

Autonomic function and ventricular tachyarrhythmias during acute myocardial infarction.

World J Exp Med 2018 Aug 30;8(1):8-11. Epub 2018 Aug 30.

Department of Cardiology, Cardiovascular Research Institute and University of Ioannina Medical School, Ioannina 45500, Greece.

Most cases of sudden cardiac death are attributed to sustained ventricular tachyarrhythmias (VTs), triggered by acute coronary occlusion. Autonomic dysfunction, an important arrhythmogenic mechanism in this setting, is being actively investigated, aiming at the advent of preventive strategies. Recent experimental studies have shown vagal withdrawal after anterior myocardial infarction, coinciding with high incidence of VTs, followed by more gradual sympathetic activation coinciding with a second arrhythmia peak. This article summarizes recent knowledge on this intriguing topic, generating hypotheses that can be investigated in future experimental and clinical studies.
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http://dx.doi.org/10.5493/wjem.v8.i1.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125141PMC
August 2018

Signal-averaged electrocardiography: Past, present, and future.

J Arrhythm 2018 Jun 28;34(3):222-229. Epub 2018 May 28.

Electrophysiology Laboratory and First University Department of Cardiology Hippokration General Hospital National and Kapodestrian University of Athens Athens Greece.

Signal-averaged electrocardiography records delayed depolarization of myocardial areas with slow conduction that can form the substrate for monomorphic ventricular tachycardia. This technique has been examined mostly in patients with coronary artery disease, but its use has been declined over the years. However, several lines of evidence, derived from hitherto clinical data in patients with healed myocardial infarction, indicate that signal-averaged electrocardiography remains a valuable tool in risk stratification, especially when incorporated into algorithms encompassing invasive and noninvasive indices. Such an approach can aid the more precise identification of candidates for device therapy, in the context of primary prevention of sudden cardiac death. This article reappraises the value of signal-averaged electrocardiography as a predictor of arrhythmic outcome in patients with ischemic heart disease and discusses potential future indications.
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http://dx.doi.org/10.1002/joa3.12062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010001PMC
June 2018

How should we follow-up patients undergoing CRT?

Hellenic J Cardiol 2018 Jul - Aug;59(4):232-233. Epub 2018 Jun 1.

Cardiovascular Research Institute, Ioannina, Greece; Department of Cardiology, Medical School, University of Ioannina, Greece. Electronic address:

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http://dx.doi.org/10.1016/j.hjc.2018.05.004DOI Listing
March 2019

Optimization of Ca content in alginate hydrogel injected in myocardium.

J Biomed Mater Res B Appl Biomater 2019 02 24;107(2):223-231. Epub 2018 Apr 24.

Department of Materials Science and Engineering, University of Ioannina, Ioannina, Greece.

The spontaneous uptake of Ca -ions is a unique property of alginate hydrogels, which, along with their high biocompatibility, disintegration (approximately within 2 weeks), and morphological similarity to heart tissue, makes them attractive as scaffolding materials in therapies in infarct myocardium. To shed light on the aforementioned ability, thorough theoretical calculations were carried out with the density functional theory (DFT) method. The influence of Ca-content οn the molecular structure and the thermodynamic stability of the alginate hydrogel was determined; what is more, these results effectively interpreted the experimental findings, as well. This analysis suggests that in Ca-free or Ca-deficient alginates spontaneous Ca cations uptake can occur from the biological environment and develop, via chelation reaction, a well-formed and thermodynamically stable hydrogel in situ inside the tissue. The highest degree of cross linking results in viscosity peak. Nevertheless, further increase of Ca-content in alginate structure beyond this peak results in products with poorer thermodynamic stability. Structural optimization DFT calculations revealed that the destabilization of the Ca-rich alginate hydrogels is attributed to changes of the alginate chain molecule, which are relaxation, weakening, and eventually total collapse of the bond between the units of the alginate chain. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 223-231, 2019.
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http://dx.doi.org/10.1002/jbm.b.34113DOI Listing
February 2019

Autonomic responses during acute myocardial infarction in the rat model: implications for arrhythmogenesis.

J Basic Clin Physiol Pharmacol 2018 Jul;29(4):339-345

National and Kapodistrian University of Athens, Athens, Greece.

Background Autonomic responses participate in the pathophysiology of acute myocardial infarction, but their precise time course remains unclear. Here, we investigated the autonomic activity and ventricular tachyarrhythmias in conscious, unrestrained rats post-infarction. Methods The left coronary artery was ligated in 12 Wistar rats, and six rats were sham operated, followed by 24-h electrocardiographic recording via implanted telemetry transmitters. Sympathetic activity was assessed by detrended fluctuation analysis and vagal activity by time- and frequency-domain analysis of heart rate variability. The duration of the ventricular tachyarrhythmias was measured, and voluntary motion served as a marker of heart failure. Results In sham-operated rats, heart rate and sympathetic activity remained low, whereas vagal activity rose progressively after the fourth hour. Post-ligation, medium-sized antero-septal necrosis was observed, reaching ~20% of the left ventricular volume; tachyarrhythmias were frequent, displaying a bimodal curve, and motion counts were low. Vagal activity decreased early post-ligation, coinciding with a high incidence of tachyarrhythmias, but tended to rise subsequently in rats with higher motion counts. Sympathetic activity increased after the third hour, along with a second tachyarrhythmia peak, and remained elevated throughout the 24-h period. Conclusions Vagal withdrawal, followed by gradual sympathetic activation, may participate in arrhythmogenesis during acute myocardial infarction.
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http://dx.doi.org/10.1515/jbcpp-2017-0202DOI Listing
July 2018

Local conduction during acute myocardial infarction in rats: Interplay between central sympathetic activation and endothelin.

J Arrhythm 2017 Apr 31;33(2):144-146. Epub 2016 Aug 31.

Cardiovascular Research Institute, 1 Stavrou Niarxou Ave., 45500 Ioannina, Greece.

We investigated the effects of autonomic dysfunction and endothelin on local conduction and arrhythmogenesis during myocardial infarction. We recorded ventricular tachyarrhythmias, monophasic action potentials, and activation sequences in wild-type and ET-deficient rats displaying high endothelin levels. Central sympathetic inputs were examined after clonidine administration. Clonidine mitigated early and delayed arrhythmogenesis in ET-deficient and wild-type rats, respectively. The right ventricular activation delay increased in clonidine-treated ET-deficient rats and slightly decreased in wild-type rats. The left ventricular voltage rise decreased in all groups, whereas the activation delay increased mainly in clonidine-treated ET-deficient rats. Central sympathetic activation and endothelin modulate ischemia-induced arrhythmogenesis. Ischemia alters excitability, whereas endothelin impairs local conduction, an action partly counterbalanced by central sympathetic activity.
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http://dx.doi.org/10.1016/j.joa.2016.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388042PMC
April 2017

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

Growth Factors 2017 02 6;35(1):1-11. Epub 2017 Mar 6.

a Department of Cardiology , Medical School, University of Ioannina , Greece.

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study.
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http://dx.doi.org/10.1080/08977194.2017.1297432DOI Listing
February 2017

Arrhythmic risk stratification in heart failure: Time for the next step?

Ann Noninvasive Electrocardiol 2017 Mar 3;22(2). Epub 2017 Feb 3.

Department of Cardiology, University General Hospital of Ioannina, Ioannina, Greece.

Background: Primary prevention of sudden cardiac death by means of implantable cardioverter-defibrillators constitutes the holy grail of arrhythmology. However, current risk stratification algorithms lead to suboptimal outcomes, by both allocating ICDs to patients not deriving any meaningful survival benefit and withholding them from those erroneously considered as low-risk for arrhythmic mortality.

Methods: In the present review article we will attempt to present shortcomings of contemporary guidelines regarding sudden death prevention in ischemic and dilated cardiomyopathy patients and present available data suggesting encouraging results following implementation of multifactorial approaches, by using multiple modalities, both noninvasive and invasive. Invasive electrophysiological testing, namely programmed ventricular stimulation, will be discussed in greater length to highlight both its potential usefulness and currently ongoing multicenter studies aiming to provide evidence necessary to make the next step in sudden death risk stratification.

Results: Promising findings have been reported by multiple study groups regarding novel strategies for both negative selection of low and positive selection of relatively preserved ejection fraction patients as candidates for ICD implantation.

Conclusions: The era of ejection fraction as the sole risk stratifier for arrhythmic risk in heart failure appears to be drawing to an end, especially if current underway large studies validate previous findings.
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http://dx.doi.org/10.1111/anec.12430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931804PMC
March 2017

Isolation of an ES-Derived Cardiovascular Multipotent Cell Population Based on VE-Cadherin Promoter Activity.

Stem Cells Int 2016 22;2016:8305624. Epub 2016 Dec 22.

Laboratory of Biology, Medical School, University of Ioannina, Ioannina, Greece; Department of Biomedical Research, Institute of Molecular Biology & Biotechnology, Foundation of Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece.

Embryonic Stem (ES) or induced Pluripotent Stem (iPS) cells are important sources for cardiomyocyte generation, targeted for regenerative therapies. Several in vitro protocols are currently utilized for their differentiation, but the value of cell-based approaches remains unclear. Here, we characterized a cardiovascular progenitor population derived during ES differentiation, after selection based on VE-cadherin promoter (Pvec) activity. ESCs were genetically modified with an episomal vector, allowing the expression of puromycin resistance gene, under Pvec activity. Puromycin-surviving cells displayed cardiac and endothelial progenitor cells characteristics. Expansion and self-renewal of this cardiac and endothelial dual-progenitor population (CEDP) were achieved by Wnt/-catenin pathway activation. CEDPs express early cardiac developmental stage-specific markers but not markers of differentiated cardiomyocytes. Similarly, CEDPs express endothelial markers. However, CEDPs can undergo differentiation predominantly to cTnT (~47%) and VE-cadherin (~28%) cells. Transplantation of CEDPs in the left heart ventricle of adult rats showed that CEDPs-derived cells survive and differentiate in vivo for at least 14 days after transplantation. A novel, dual-progenitor population was isolated during ESCs differentiation, based on Pvec activity. This lineage can self-renew, permitting its maintenance as a source of cardiovascular progenitor cells and constitutes a useful source for regenerative approaches.
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http://dx.doi.org/10.1155/2016/8305624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215608PMC
December 2016

Intra-myocardial growth hormone administration ameliorates arrhythmogenesis during ischemia-reperfusion in rats.

J Electrocardiol 2017 Mar - Apr;50(2):207-210. Epub 2016 Oct 18.

Department of Cardiology, Medical School, University of Ioannina, Greece; Cardiovascular Research Institute, Ioannina, Greece. Electronic address:

Growth hormone, currently under evaluation for the prevention of left ventricular remodeling post-myocardial infarction, displays antiarrhythmic properties in the acute setting. However, it is uncertain whether these actions are retained after ischemia/reperfusion. Using implanted telemetry transmitters, we examined the effects of prolonged, intra-myocardial growth hormone administration in conscious rats. During a 24-h observation period, ventricular tachyarrhythmias and sympathetic activation were attenuated in treated rats, whereas infarct-size was unchanged. These findings call for further study on the antiarrhythmic effects of growth hormone and on the underlying mechanisms.
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http://dx.doi.org/10.1016/j.jelectrocard.2016.10.004DOI Listing
November 2017
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