Constantinos Davos - Academia.edu (original) (raw)

Papers by Constantinos Davos

International Journal of Cardiology, 2016

Prior studies conducted in Greece consistently indicate that dyslipidemia is suboptimally managed... more Prior studies conducted in Greece consistently indicate that dyslipidemia is suboptimally managed, while the burden of cardiovascular disease (CVD) and related risk factors is rising. CHALLENGE was a multicenter, cross-sectional study carried out following the publication of guidelines advocating stricter low-density lipoprotein cholesterol (LDL-C) targets. It primarily aimed to depict LDL-C target attainment, and to assess the cardiovascular risk status and quality of life (QoL) of patients treated in a primary or secondary CVD prevention setting who had received any medical intervention for cardiovascular risk modification within 6months of enrollment. Between December 2012 and April 2013, 500 patients (55% males) aged (mean±SD) 62.0±11.7years, participated in the study. Cardiovascular risk according to the 2011 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines was 'very high', 'high', and 'moderate' in 61.2%, 23.4%, and 15.4%, respectively. Overall, 92.0% of patients were on lipid-lowering treatment, yet only 23.3% had attained their ESC/EAS-defined LDL-C target. LDL-C target attainment was more likely among 'moderate' versus 'very high' cardiovascular risk patients (odds ratio: 4.04; 95% confidence interval: 2.32-7.06; p<0.001). QoL improved as cardiovascular risk decreased (EQ-VAS 71.8±16.2 in the 'very high' versus 78.3±15.1 and 80.3±15.7 in the 'high' and 'moderate' risk groups; p<0.001). Time constraints and difficulties in implementation in daily practice were the investigator's main barriers for guideline utilization. During contemporary management of dyslipidemia in Greece, LDL-C target attainment is suboptimal. There is an undoubted need for improvement and implementation of cardiovascular risk assessment in routine clinical practice.

Background-In patients with chronic heart failure (CHF) and preserved exercise tolerance, the val... more Background-In patients with chronic heart failure (CHF) and preserved exercise tolerance, the value of cardiopulmonary exercise testing for risk stratification is not known. Elevated slope of ventilatory response to exercise (V E/V CO 2 ) predicts poor prognosis in advanced CHF. Derangement of cardiopulmonary reflexes may trigger exercise hyperpnea. We assessed the relationship between cardiopulmonary reflexes and V E/V CO 2 and investigated the prognostic value of V E/V CO 2 in CHF patients with preserved exercise tolerance. Methods and Results-Among 344 consecutive CHF patients, we identified 123 with preserved exercise capacity, defined as a peak oxygen consumption (peak V O 2 ) Ն18 mL · kg Ϫ1 · min Ϫ1 (age 56 years; left ventricular ejection fraction 28%; peak V O 2 23.5 mL · kg Ϫ1 · min Ϫ1 ). Hypoxic and hypercapnic chemosensitivity (nϭ38), heart rate variability (nϭ34), baroreflex sensitivity (nϭ20), and ergoreflex activity (nϭ20) were also assessed. We identified 40 patients (33%) with high V E/V CO 2 (ie, Ͼ34.0). During follow-up (49Ϯ22 months, Ͼ3 years in all survivors), 34 patients died (3-year survival 81%). High V E/V CO 2 (hazard ratio 4.3, PϽ0.0001) but not peak V O 2 (Pϭ0.7) predicted mortality. In patients with high V E/V CO 2 , 3-year survival was 57%, compared with 93% in patients with normal V E/V CO 2 (PϽ0.0001). Patients with high V E/V CO 2 demonstrated impaired reflex control, as evidenced by augmented peripheral (Pϭ0.01) and central (Pϭ0.0006) chemosensitivity, depressed low-frequency component of heart rate variability (PϽ0.0001) and baroreflex sensitivity (Pϭ0.03), and overactive ergoreceptors (Pϭ0.003) compared with patients with normal V E/V CO 2 . Conclusions-In CHF patients with preserved exercise capacity, enhanced ventilatory response to exercise is a simple marker of a widespread derangement of cardiovascular reflex control; it predicts poor prognosis, which peak V O 2 does not. (Circulation. 2001;103:967-972.)

Cancer research, Jan 8, 2015

The potential to heighten the efficacy of antiangiogenic agents was explored in this study based ... more The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogs of a clinically established antiangiogenic compound (sunitinib) from which a lead candidate (SAN1) was conjugated to the targeting peptide [D-Lys6]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared to equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered...

Journal of Cardiac Failure, 2004

Peak oxygen consumption (pVO2) reflects oxygen extraction from the skeletal muscles, but is routi... more Peak oxygen consumption (pVO2) reflects oxygen extraction from the skeletal muscles, but is routinely corrected for body weight. We hypothesized that correcting pVO2 for lean tissue rather than total body weight would improve the prediction of prognosis in patients with chronic heart failure (CHF). A total of 272 CHF outpatients (mean age 61 +/- 12 years, New York Heart Association [NYHA] class 2.3 +/- 0.8) underwent a cardiopulmonary exercise testing and body composition assessment by dual-energy X-ray absorptiometry. During a median follow-up of 608 days (range 8-3656), 75 patients died. Univariate survival analysis showed strong survival prediction from pVO2 adjusted for total weight or lean tissue (chi2 17.7, P < .001; chi2 27.5, P < .0001, respectively). Both predicted survival significantly in bivariate analysis, (chi2 4.6, P = .032; chi2 16.6, P < .0001). The predictive effects were independent of exercise protocol (treadmill versus cycle ergometer) (both P < .001). Multivariate analysis showed that pVO2 adjusted for lean tissue had prognostic importance independently of NYHA class, ejection fraction, and ventilation and carbon dioxide production slope (P < .05 for each). In patients with NYHA class I and II (n = 160), pVO2 adjusted for lean tissue predicted outcome (P = .03). Adjustment for lean tissue instead for body weight increases the prognostic power of pVO2, particularly in patients with mild heart failure.

International Journal of Cardiology, 2011

International Journal of Cardiology, 2009

Background: Tetralogy of Fallot (ToF) patients face an increased risk of sudden cardiac death lat... more Background: Tetralogy of Fallot (ToF) patients face an increased risk of sudden cardiac death late after repair. Heart rate turbulence (HRT) indices are well-known predictors of sudden cardiac death. We aimed to estimate whether HRT is impaired in repaired ToF patients compared to healthy controls and relate those HRT parameters to already recognized prognostic markers. Methods: Continuous ECG recordings were performed in 19 patients late after ToF repair (36.3± 12.4 years, 26.6 ± 7.1 years after repair) and 20 age-matched healthy controls (40.8 ± 8.1 years). Turbulence slope (TS) and onset (TO), frequency and time domain heart rate variability parameters and QRS duration were estimated. Volumes of the right (RV) and left ventricle (LV) and ejection fraction (EF) were assessed by cardiovascular magnetic resonance imaging. Cardiopulmonary exercise testing was used to estimate peak oxygen consumption (VO 2 ) and VE/VCO 2 slope. Results: TS (15.95 ± 9.41 vs 28.73 ± 12.24 ms/RRI, p = 0.0007) and TO (− 0.98 ± 2.06% vs −3.45 ± 3.25%, p = 0.007) were found to be significantly different between ToF patients and controls. TO correlated with LVEF (r = 0.47, p b 0.05), LVSVi (r = 0.50, p = 0.03), RVEF (r = 0.53, p = 0.02), peak VO 2 (r = 0.50, p = 0.05), VE/VCO 2 slope (r = − 0.55, p = 0.03) and with heart rate variability frequency domain indices (log LF, r = 0.47, p = 0.04, log HF, r = 0.56, p = 0.01). Conclusion: HRT indices are impaired in ToF patients late after surgical repair compared to healthy controls and relate to coexisting haemodynamic, ventilatory and autonomic impairment. A clinical prognostic role of HRT may be speculated, which warrants further investigation.

Basic research in cardiology, 2015

Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (ACM). Howeve... more Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (ACM). However, its role in this process is unresolved. Our goal was to delineate the pathogenic role of the complement system in a new animal model of ACM and in human disease. Using cardiac histology, echocardiography, and electrocardiography, we have demonstrated that the desmin-null mouse (Des-/-) recapitulates most of the pathognomonic features of human ACM. Massive complement activation was observed in the Des-/- myocardium in areas of necrotic cells debris and inflammatory infiltrate. Analysis of C5aR-/-Des-/- double-null animals and a pharmaceutical approach using a C5a inhibitor were used to delineate the pathogenic role of the complement system in the disease progression. Our findings indicate that inhibiting C5aR (CD88) signaling improves cardiac function, histopathology, arrhythmias, and survival after endurance. Containment of the inflammatory reaction at the initiation of cardiac tissue...

Respiratory Physiology & Neurobiology, 2015

ABSTRACT Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function ... more ABSTRACT Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function during exercise in COPD patients. COPD patients with (n=25) and without (n=11) exercise-induced DH undertook an incremental (IET) and a constant-load exercise test (CLET) sustained at 75% peak work (WRpeak) prior to and following an interval cycling exercise training regime (set at 100% WRpeak with 30-s work/30-s rest intervals) lasting for 12 weeks. Cardiac output (Q) was assessed by cardio-bio-impedance (PhysioFlow, enduro, PF-O7) to determine Q mean response time (QMRT) at onset (QMRTON) and offset (QMRTOFF) of CLET. Post-rehabilitation only those patients exhibiting exercise-induced DH demonstrated significant reductions in QMRTON (from 82.2±4.3 to 61.7±4.2sec) and QMRTOFF (from 80.5±3.8 to 57.2±4.9sec). These post-rehabilitation adaptations were associated with improvements in inspiratory capacity, thereby suggesting that mitigation of the degree of exercise-induced DH improves central hemodynamic responses in COPD patients. Copyright © 2015. Published by Elsevier B.V.

Archives of Cardiovascular Diseases Supplements, 2015

International Journal of Cardiology, 2012

Background: Coarctation of aorta (CoA) patients present cardiovascular complications late after r... more Background: Coarctation of aorta (CoA) patients present cardiovascular complications late after repair the causes of which are not fully understood. Our study investigates the neurohormonal and immune activation and the elastic properties of the aorta and peripheral vessels in adult patients with coarctation of aorta (CoA), late after repair. Methods: Nineteen adult patients with repaired CoA and 29 matched healthy controls underwent aortic distensibility, stiffness index, a study of the elastic properties of peripheral vessels proximal to the coarctation site and measurement of plasma cytokine and neurohormone levels. Results: Distensibility index was reduced (p = 0.02) and stiffness index was increased (p = 0.005) in CoA patients compared to control. Augmentation index (p = 0.0007) and augmented pressure (p = 0.001) were higher in CoA patients and Forearm Blood Flow (FBF) index was reduced (p = 0.009). Plasma levels of sICAM-1 (p = 0.01), sVCAM-1 (p = 0.05), E-selectin (p = 0.01), sFas-ligand (p = 0.02) and IL-10 (p = 0.01) were also elevated in CoA patients vs control. TNF-a, IL-6, Endothelin-1 and NT-pro-BNP levels were not. Conclusions: Adults with repaired CoA seem to develop a late inflammatory reaction, which reflects a functional problem in all vessels, regardless of the initial lesion. This may explain the late complications of the disease despite early repair and improved surgical procedures.

Cytokine, 2012

Inflammation and neurohormonal activation are considered to be involved in the development of ear... more Inflammation and neurohormonal activation are considered to be involved in the development of earlier and/or later complications in congenital heart disease patients, even after a successful repair of the lesion. It is not yet clarified what is the role of the therapeutic interventions in the occurrence of such a response and how it could be associated with possible postoperative complications. We sought to assess the inflammatory and neurohormonal response to transcatheter closure of secundum type atrial septal defects (ASD) over a six-month follow-up period. We also evaluated the association between the respective markers and catheterization data as well as echocardiographic measurements. Plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), N-terminal-proatrial natriuretic peptide (NT-proANP) and N-terminal-probrain natriuretic peptide (NT-proBNP) were assessed and echocardiographic measurements were performed in twenty-eight patients with atrial septal defect prior to, and at the first, second and sixth months post transcatheter closure. Thirty-three age-matched healthy volunteers were also enrolled. IL-6 plasma levels, although higher preoperatively, [physical logarithm (ln) IL-6: 3.37±0.66 vs 2.92±0.44 pg/ml, p=0.015], reached control levels postoperatively, at the end of the third month, whereas TNF-α and IL-10 were not influenced by the procedure. NT-proANP levels were elevated preoperatively compared to the control group (ln NT-proANP 3.78±0.572 vs 3.48±0.30, p=0.031), with a further significant increase during the 1st month (ln NT-proANP 3.78±0.572 vs 4.2±0.42, p=0.006), following the pattern of the left atrial volume enlargement, and remained high even 6 months after the procedure .On the other hand, the initially normal concentrations of NT-proBNP, after a transient significant increase during the first month postoperatively (ln NT-proBNP 3.56±0.94 vs 4.58±0.91, p<0.0001) returned to the controls' levels at the end of the third month. Preoperative concentrations of NT-proANP positively correlated with NT-proBNP concentrations and pulmonary to systemic flow ratio (Qp/Qs). Transcatheter closure could improve, on a mid- term basis, the inflammatory process but natriuretic peptides' secretion continues in parallel with left atrial volume increase. Further follow up is required to determine the long-term progress of the inflammatory and neurohormonal response to the procedure.

International Cardiovascular Forum Journal, 2015

Archives of Cardiovascular Diseases Supplements, 2015

Scientific Reports, 2015

that modulates endothelial function and integrity. Polycystins (PC)-1/-2 constitute a flow-sensin... more that modulates endothelial function and integrity. Polycystins (PC)-1/-2 constitute a flow-sensing protein complex in endothelial cells, able to respond to WSS and induce cell-proliferation changes leading to atherosclerosis. An endothelial cell-culture system of measurable WSS was established to detect alterations in PCs expression under conditions of low-and high-oscillatory shear stress in vitro. PCs expression and p53 activation as a regulator of cell proliferation were further evaluated in vivo and in 69 advanced human carotid atherosclerotic plaques (AAPs). Increased PC-1/PC-2 expression was observed at 30-60 min of low shear stress (LSS) in endothelial cells. Elevated PC-1 expression at LSS was followed by p53 potentiation. PCs immunoreactivity localizes in areas with macrophage infiltration and neovascularization. PC-1 mRNA and protein levels were significantly higher than PC-2 in stable fibroatherotic (V) and unstable/complicated (VI) AAPs. Elevated PC-1 immunostaining was detected in AAPs from patients with diabetes mellitus, dyslipidemia, hypertension and carotid stenosis, at both arteries (50%) or in one artery (90%). PCs seem to participate in plaque formation and progression. Since PC-1 upregulation coincides with p38 and p53 activation, a potential interplay of these molecules in atherosclerosis induction is posed.

Cardiovascular Research

Background: Desmin null mice (Des-/-) develop a multisystem disorder involving cardiac, skeletal,... more Background: Desmin null mice (Des-/-) develop a multisystem disorder involving cardiac, skeletal, and smooth muscle. Myocardial abnormalities include progressive degeneration, cardiomyocyte death, extensive calcification and fibrosis which lead to a dilated cardiomyopathy pattern. The aim of this study is to investigate the presence of arrhythmias in a Des-/- mouse model as compared to wild type (WT) mice. Methods: Mice lacking desmin were generated by gene targeting via homologous recombination as previously describe. Electrocardiographic (ECG) recordings were obtained in 8-months old Des-/- and WT mice (n=17) using a Data Sciences International Telemetry System (St. Paul, MN, USA). ECG data were collected for 5 min every 30 min for 24 consecutive hour, giving 240 min of recording. Arrhythmias were recorded and heart rate, QRS wave duration and PR and QTc (Bazett's formula) intervals and were measured using Ponemah software. Mice also underwent a swimming stress test protocol o...

PloS one, 2014

The impact of electromagnetic fields on health is of increasing scientific interest. The aim of t... more The impact of electromagnetic fields on health is of increasing scientific interest. The aim of this study was to examine how the Drosophila melanogaster animal model is affected when exposed to portable or mobile phone fields. Two experiments have been designed and performed in the same laboratory conditions. Insect cultures were exposed to the near field of a 2G mobile phone (the GSM 2G networks support and complement in parallel the 3G wide band or in other words the transmission of information via voice signals is served by the 2G technology in both mobile phones generations) and a 1880 MHz cordless phone both digitally modulated by human voice. Comparison with advanced statistics of the egg laying of the second generation exposed and non-exposed cultures showed limited statistical significance for the cordless phone exposed culture and statistical significance for the 900 MHz exposed insects. We calculated by physics, simulated and illustrated in three dimensional figures the c...

The Open Cardiovascular and Thoracic Surgery Journal, 2012

We present a case of acute decompensated heart failure in a patient with congenitally corrected t... more We present a case of acute decompensated heart failure in a patient with congenitally corrected transposition of great arteries treated with levosimendan, an agent with positive inotropic and vasodilatory effects. Levosimendan infusion resulted in symptomatic and functional improvement, improvement of the subpulmonary left ventricular systolic function and amelioration of the diastolic but not the systolic function of the systemic right ventricle. A number of factors may account for the poor response of the systemic right ventricle to levosimendan, such as altered myofibrillar structure and coronary flow together with the particular loading conditions of the systemic right ventricle.

Medicine & Science in Sports & Exercise, 2003

One of the primary neural mechanisms responsible for the cardiovascular adjustments to exercise i... more One of the primary neural mechanisms responsible for the cardiovascular adjustments to exercise is the "exercise pressor reflex"; a reflex arising from activation of chemically and mechanically sensitive afferents in contracting skeletal muscle (4). Numerous human investigations have indicated that the chemically sensitive component of the reflex, termed the muscle metaboreflex, is primarily responsible for exercise-induced sympathoexcitation, which leads to increases in systemic vascular resistance (SVR) and subsequent elevations in blood pressure. These findings have mainly been derived from studies in which static exercise was performed followed by post exercise ischemia (PEI). The latter maneuver traps the metabolic products of contraction in the vicinity of the metaboreceptor afferent endings while eliminating inputs from mechanically sensitive afferents and central command, the central neural drive associated with the volitional component of exercise. During isolation of the metaboreflex with PEI, heart rate has been shown to return to baseline and limited work has demonstrated that stroke volume (SV) is similar to resting values indicating little affect of the metaboreflex on cardiac output (2). In contrast, animal studies have shown that alterations in cardiac output contribute importantly to metaboreflex-mediated increases in blood pressure (1). Whether these differences are solely due to a species related functional variation remains unclear.

Journal of the American College of Cardiology, 2003

We sought to describe the relationship between cholesterol and survival in patients with chronic ... more We sought to describe the relationship between cholesterol and survival in patients with chronic heart failure (CHF). BACKGROUND Increasing lipoprotein levels are a cardiovascular risk factor. In patients with CHF, the prognostic value of endogenous lipoproteins is not fully clarified.

International Journal of Cardiology, 2016

Prior studies conducted in Greece consistently indicate that dyslipidemia is suboptimally managed... more Prior studies conducted in Greece consistently indicate that dyslipidemia is suboptimally managed, while the burden of cardiovascular disease (CVD) and related risk factors is rising. CHALLENGE was a multicenter, cross-sectional study carried out following the publication of guidelines advocating stricter low-density lipoprotein cholesterol (LDL-C) targets. It primarily aimed to depict LDL-C target attainment, and to assess the cardiovascular risk status and quality of life (QoL) of patients treated in a primary or secondary CVD prevention setting who had received any medical intervention for cardiovascular risk modification within 6months of enrollment. Between December 2012 and April 2013, 500 patients (55% males) aged (mean±SD) 62.0±11.7years, participated in the study. Cardiovascular risk according to the 2011 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines was 'very high', 'high', and 'moderate' in 61.2%, 23.4%, and 15.4%, respectively. Overall, 92.0% of patients were on lipid-lowering treatment, yet only 23.3% had attained their ESC/EAS-defined LDL-C target. LDL-C target attainment was more likely among 'moderate' versus 'very high' cardiovascular risk patients (odds ratio: 4.04; 95% confidence interval: 2.32-7.06; p<0.001). QoL improved as cardiovascular risk decreased (EQ-VAS 71.8±16.2 in the 'very high' versus 78.3±15.1 and 80.3±15.7 in the 'high' and 'moderate' risk groups; p<0.001). Time constraints and difficulties in implementation in daily practice were the investigator's main barriers for guideline utilization. During contemporary management of dyslipidemia in Greece, LDL-C target attainment is suboptimal. There is an undoubted need for improvement and implementation of cardiovascular risk assessment in routine clinical practice.

Background-In patients with chronic heart failure (CHF) and preserved exercise tolerance, the val... more Background-In patients with chronic heart failure (CHF) and preserved exercise tolerance, the value of cardiopulmonary exercise testing for risk stratification is not known. Elevated slope of ventilatory response to exercise (V E/V CO 2 ) predicts poor prognosis in advanced CHF. Derangement of cardiopulmonary reflexes may trigger exercise hyperpnea. We assessed the relationship between cardiopulmonary reflexes and V E/V CO 2 and investigated the prognostic value of V E/V CO 2 in CHF patients with preserved exercise tolerance. Methods and Results-Among 344 consecutive CHF patients, we identified 123 with preserved exercise capacity, defined as a peak oxygen consumption (peak V O 2 ) Ն18 mL · kg Ϫ1 · min Ϫ1 (age 56 years; left ventricular ejection fraction 28%; peak V O 2 23.5 mL · kg Ϫ1 · min Ϫ1 ). Hypoxic and hypercapnic chemosensitivity (nϭ38), heart rate variability (nϭ34), baroreflex sensitivity (nϭ20), and ergoreflex activity (nϭ20) were also assessed. We identified 40 patients (33%) with high V E/V CO 2 (ie, Ͼ34.0). During follow-up (49Ϯ22 months, Ͼ3 years in all survivors), 34 patients died (3-year survival 81%). High V E/V CO 2 (hazard ratio 4.3, PϽ0.0001) but not peak V O 2 (Pϭ0.7) predicted mortality. In patients with high V E/V CO 2 , 3-year survival was 57%, compared with 93% in patients with normal V E/V CO 2 (PϽ0.0001). Patients with high V E/V CO 2 demonstrated impaired reflex control, as evidenced by augmented peripheral (Pϭ0.01) and central (Pϭ0.0006) chemosensitivity, depressed low-frequency component of heart rate variability (PϽ0.0001) and baroreflex sensitivity (Pϭ0.03), and overactive ergoreceptors (Pϭ0.003) compared with patients with normal V E/V CO 2 . Conclusions-In CHF patients with preserved exercise capacity, enhanced ventilatory response to exercise is a simple marker of a widespread derangement of cardiovascular reflex control; it predicts poor prognosis, which peak V O 2 does not. (Circulation. 2001;103:967-972.)

Cancer research, Jan 8, 2015

The potential to heighten the efficacy of antiangiogenic agents was explored in this study based ... more The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogs of a clinically established antiangiogenic compound (sunitinib) from which a lead candidate (SAN1) was conjugated to the targeting peptide [D-Lys6]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared to equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered...

Journal of Cardiac Failure, 2004

Peak oxygen consumption (pVO2) reflects oxygen extraction from the skeletal muscles, but is routi... more Peak oxygen consumption (pVO2) reflects oxygen extraction from the skeletal muscles, but is routinely corrected for body weight. We hypothesized that correcting pVO2 for lean tissue rather than total body weight would improve the prediction of prognosis in patients with chronic heart failure (CHF). A total of 272 CHF outpatients (mean age 61 +/- 12 years, New York Heart Association [NYHA] class 2.3 +/- 0.8) underwent a cardiopulmonary exercise testing and body composition assessment by dual-energy X-ray absorptiometry. During a median follow-up of 608 days (range 8-3656), 75 patients died. Univariate survival analysis showed strong survival prediction from pVO2 adjusted for total weight or lean tissue (chi2 17.7, P < .001; chi2 27.5, P < .0001, respectively). Both predicted survival significantly in bivariate analysis, (chi2 4.6, P = .032; chi2 16.6, P < .0001). The predictive effects were independent of exercise protocol (treadmill versus cycle ergometer) (both P < .001). Multivariate analysis showed that pVO2 adjusted for lean tissue had prognostic importance independently of NYHA class, ejection fraction, and ventilation and carbon dioxide production slope (P < .05 for each). In patients with NYHA class I and II (n = 160), pVO2 adjusted for lean tissue predicted outcome (P = .03). Adjustment for lean tissue instead for body weight increases the prognostic power of pVO2, particularly in patients with mild heart failure.

International Journal of Cardiology, 2011

International Journal of Cardiology, 2009

Background: Tetralogy of Fallot (ToF) patients face an increased risk of sudden cardiac death lat... more Background: Tetralogy of Fallot (ToF) patients face an increased risk of sudden cardiac death late after repair. Heart rate turbulence (HRT) indices are well-known predictors of sudden cardiac death. We aimed to estimate whether HRT is impaired in repaired ToF patients compared to healthy controls and relate those HRT parameters to already recognized prognostic markers. Methods: Continuous ECG recordings were performed in 19 patients late after ToF repair (36.3± 12.4 years, 26.6 ± 7.1 years after repair) and 20 age-matched healthy controls (40.8 ± 8.1 years). Turbulence slope (TS) and onset (TO), frequency and time domain heart rate variability parameters and QRS duration were estimated. Volumes of the right (RV) and left ventricle (LV) and ejection fraction (EF) were assessed by cardiovascular magnetic resonance imaging. Cardiopulmonary exercise testing was used to estimate peak oxygen consumption (VO 2 ) and VE/VCO 2 slope. Results: TS (15.95 ± 9.41 vs 28.73 ± 12.24 ms/RRI, p = 0.0007) and TO (− 0.98 ± 2.06% vs −3.45 ± 3.25%, p = 0.007) were found to be significantly different between ToF patients and controls. TO correlated with LVEF (r = 0.47, p b 0.05), LVSVi (r = 0.50, p = 0.03), RVEF (r = 0.53, p = 0.02), peak VO 2 (r = 0.50, p = 0.05), VE/VCO 2 slope (r = − 0.55, p = 0.03) and with heart rate variability frequency domain indices (log LF, r = 0.47, p = 0.04, log HF, r = 0.56, p = 0.01). Conclusion: HRT indices are impaired in ToF patients late after surgical repair compared to healthy controls and relate to coexisting haemodynamic, ventilatory and autonomic impairment. A clinical prognostic role of HRT may be speculated, which warrants further investigation.

Basic research in cardiology, 2015

Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (ACM). Howeve... more Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (ACM). However, its role in this process is unresolved. Our goal was to delineate the pathogenic role of the complement system in a new animal model of ACM and in human disease. Using cardiac histology, echocardiography, and electrocardiography, we have demonstrated that the desmin-null mouse (Des-/-) recapitulates most of the pathognomonic features of human ACM. Massive complement activation was observed in the Des-/- myocardium in areas of necrotic cells debris and inflammatory infiltrate. Analysis of C5aR-/-Des-/- double-null animals and a pharmaceutical approach using a C5a inhibitor were used to delineate the pathogenic role of the complement system in the disease progression. Our findings indicate that inhibiting C5aR (CD88) signaling improves cardiac function, histopathology, arrhythmias, and survival after endurance. Containment of the inflammatory reaction at the initiation of cardiac tissue...

Respiratory Physiology & Neurobiology, 2015

ABSTRACT Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function ... more ABSTRACT Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function during exercise in COPD patients. COPD patients with (n=25) and without (n=11) exercise-induced DH undertook an incremental (IET) and a constant-load exercise test (CLET) sustained at 75% peak work (WRpeak) prior to and following an interval cycling exercise training regime (set at 100% WRpeak with 30-s work/30-s rest intervals) lasting for 12 weeks. Cardiac output (Q) was assessed by cardio-bio-impedance (PhysioFlow, enduro, PF-O7) to determine Q mean response time (QMRT) at onset (QMRTON) and offset (QMRTOFF) of CLET. Post-rehabilitation only those patients exhibiting exercise-induced DH demonstrated significant reductions in QMRTON (from 82.2±4.3 to 61.7±4.2sec) and QMRTOFF (from 80.5±3.8 to 57.2±4.9sec). These post-rehabilitation adaptations were associated with improvements in inspiratory capacity, thereby suggesting that mitigation of the degree of exercise-induced DH improves central hemodynamic responses in COPD patients. Copyright © 2015. Published by Elsevier B.V.

Archives of Cardiovascular Diseases Supplements, 2015

International Journal of Cardiology, 2012

Background: Coarctation of aorta (CoA) patients present cardiovascular complications late after r... more Background: Coarctation of aorta (CoA) patients present cardiovascular complications late after repair the causes of which are not fully understood. Our study investigates the neurohormonal and immune activation and the elastic properties of the aorta and peripheral vessels in adult patients with coarctation of aorta (CoA), late after repair. Methods: Nineteen adult patients with repaired CoA and 29 matched healthy controls underwent aortic distensibility, stiffness index, a study of the elastic properties of peripheral vessels proximal to the coarctation site and measurement of plasma cytokine and neurohormone levels. Results: Distensibility index was reduced (p = 0.02) and stiffness index was increased (p = 0.005) in CoA patients compared to control. Augmentation index (p = 0.0007) and augmented pressure (p = 0.001) were higher in CoA patients and Forearm Blood Flow (FBF) index was reduced (p = 0.009). Plasma levels of sICAM-1 (p = 0.01), sVCAM-1 (p = 0.05), E-selectin (p = 0.01), sFas-ligand (p = 0.02) and IL-10 (p = 0.01) were also elevated in CoA patients vs control. TNF-a, IL-6, Endothelin-1 and NT-pro-BNP levels were not. Conclusions: Adults with repaired CoA seem to develop a late inflammatory reaction, which reflects a functional problem in all vessels, regardless of the initial lesion. This may explain the late complications of the disease despite early repair and improved surgical procedures.

Cytokine, 2012

Inflammation and neurohormonal activation are considered to be involved in the development of ear... more Inflammation and neurohormonal activation are considered to be involved in the development of earlier and/or later complications in congenital heart disease patients, even after a successful repair of the lesion. It is not yet clarified what is the role of the therapeutic interventions in the occurrence of such a response and how it could be associated with possible postoperative complications. We sought to assess the inflammatory and neurohormonal response to transcatheter closure of secundum type atrial septal defects (ASD) over a six-month follow-up period. We also evaluated the association between the respective markers and catheterization data as well as echocardiographic measurements. Plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), N-terminal-proatrial natriuretic peptide (NT-proANP) and N-terminal-probrain natriuretic peptide (NT-proBNP) were assessed and echocardiographic measurements were performed in twenty-eight patients with atrial septal defect prior to, and at the first, second and sixth months post transcatheter closure. Thirty-three age-matched healthy volunteers were also enrolled. IL-6 plasma levels, although higher preoperatively, [physical logarithm (ln) IL-6: 3.37±0.66 vs 2.92±0.44 pg/ml, p=0.015], reached control levels postoperatively, at the end of the third month, whereas TNF-α and IL-10 were not influenced by the procedure. NT-proANP levels were elevated preoperatively compared to the control group (ln NT-proANP 3.78±0.572 vs 3.48±0.30, p=0.031), with a further significant increase during the 1st month (ln NT-proANP 3.78±0.572 vs 4.2±0.42, p=0.006), following the pattern of the left atrial volume enlargement, and remained high even 6 months after the procedure .On the other hand, the initially normal concentrations of NT-proBNP, after a transient significant increase during the first month postoperatively (ln NT-proBNP 3.56±0.94 vs 4.58±0.91, p<0.0001) returned to the controls' levels at the end of the third month. Preoperative concentrations of NT-proANP positively correlated with NT-proBNP concentrations and pulmonary to systemic flow ratio (Qp/Qs). Transcatheter closure could improve, on a mid- term basis, the inflammatory process but natriuretic peptides' secretion continues in parallel with left atrial volume increase. Further follow up is required to determine the long-term progress of the inflammatory and neurohormonal response to the procedure.

International Cardiovascular Forum Journal, 2015

Archives of Cardiovascular Diseases Supplements, 2015

Scientific Reports, 2015

that modulates endothelial function and integrity. Polycystins (PC)-1/-2 constitute a flow-sensin... more that modulates endothelial function and integrity. Polycystins (PC)-1/-2 constitute a flow-sensing protein complex in endothelial cells, able to respond to WSS and induce cell-proliferation changes leading to atherosclerosis. An endothelial cell-culture system of measurable WSS was established to detect alterations in PCs expression under conditions of low-and high-oscillatory shear stress in vitro. PCs expression and p53 activation as a regulator of cell proliferation were further evaluated in vivo and in 69 advanced human carotid atherosclerotic plaques (AAPs). Increased PC-1/PC-2 expression was observed at 30-60 min of low shear stress (LSS) in endothelial cells. Elevated PC-1 expression at LSS was followed by p53 potentiation. PCs immunoreactivity localizes in areas with macrophage infiltration and neovascularization. PC-1 mRNA and protein levels were significantly higher than PC-2 in stable fibroatherotic (V) and unstable/complicated (VI) AAPs. Elevated PC-1 immunostaining was detected in AAPs from patients with diabetes mellitus, dyslipidemia, hypertension and carotid stenosis, at both arteries (50%) or in one artery (90%). PCs seem to participate in plaque formation and progression. Since PC-1 upregulation coincides with p38 and p53 activation, a potential interplay of these molecules in atherosclerosis induction is posed.

Cardiovascular Research

Background: Desmin null mice (Des-/-) develop a multisystem disorder involving cardiac, skeletal,... more Background: Desmin null mice (Des-/-) develop a multisystem disorder involving cardiac, skeletal, and smooth muscle. Myocardial abnormalities include progressive degeneration, cardiomyocyte death, extensive calcification and fibrosis which lead to a dilated cardiomyopathy pattern. The aim of this study is to investigate the presence of arrhythmias in a Des-/- mouse model as compared to wild type (WT) mice. Methods: Mice lacking desmin were generated by gene targeting via homologous recombination as previously describe. Electrocardiographic (ECG) recordings were obtained in 8-months old Des-/- and WT mice (n=17) using a Data Sciences International Telemetry System (St. Paul, MN, USA). ECG data were collected for 5 min every 30 min for 24 consecutive hour, giving 240 min of recording. Arrhythmias were recorded and heart rate, QRS wave duration and PR and QTc (Bazett's formula) intervals and were measured using Ponemah software. Mice also underwent a swimming stress test protocol o...

PloS one, 2014

The impact of electromagnetic fields on health is of increasing scientific interest. The aim of t... more The impact of electromagnetic fields on health is of increasing scientific interest. The aim of this study was to examine how the Drosophila melanogaster animal model is affected when exposed to portable or mobile phone fields. Two experiments have been designed and performed in the same laboratory conditions. Insect cultures were exposed to the near field of a 2G mobile phone (the GSM 2G networks support and complement in parallel the 3G wide band or in other words the transmission of information via voice signals is served by the 2G technology in both mobile phones generations) and a 1880 MHz cordless phone both digitally modulated by human voice. Comparison with advanced statistics of the egg laying of the second generation exposed and non-exposed cultures showed limited statistical significance for the cordless phone exposed culture and statistical significance for the 900 MHz exposed insects. We calculated by physics, simulated and illustrated in three dimensional figures the c...

The Open Cardiovascular and Thoracic Surgery Journal, 2012

We present a case of acute decompensated heart failure in a patient with congenitally corrected t... more We present a case of acute decompensated heart failure in a patient with congenitally corrected transposition of great arteries treated with levosimendan, an agent with positive inotropic and vasodilatory effects. Levosimendan infusion resulted in symptomatic and functional improvement, improvement of the subpulmonary left ventricular systolic function and amelioration of the diastolic but not the systolic function of the systemic right ventricle. A number of factors may account for the poor response of the systemic right ventricle to levosimendan, such as altered myofibrillar structure and coronary flow together with the particular loading conditions of the systemic right ventricle.

Medicine & Science in Sports & Exercise, 2003

One of the primary neural mechanisms responsible for the cardiovascular adjustments to exercise i... more One of the primary neural mechanisms responsible for the cardiovascular adjustments to exercise is the "exercise pressor reflex"; a reflex arising from activation of chemically and mechanically sensitive afferents in contracting skeletal muscle (4). Numerous human investigations have indicated that the chemically sensitive component of the reflex, termed the muscle metaboreflex, is primarily responsible for exercise-induced sympathoexcitation, which leads to increases in systemic vascular resistance (SVR) and subsequent elevations in blood pressure. These findings have mainly been derived from studies in which static exercise was performed followed by post exercise ischemia (PEI). The latter maneuver traps the metabolic products of contraction in the vicinity of the metaboreceptor afferent endings while eliminating inputs from mechanically sensitive afferents and central command, the central neural drive associated with the volitional component of exercise. During isolation of the metaboreflex with PEI, heart rate has been shown to return to baseline and limited work has demonstrated that stroke volume (SV) is similar to resting values indicating little affect of the metaboreflex on cardiac output (2). In contrast, animal studies have shown that alterations in cardiac output contribute importantly to metaboreflex-mediated increases in blood pressure (1). Whether these differences are solely due to a species related functional variation remains unclear.

Journal of the American College of Cardiology, 2003

We sought to describe the relationship between cholesterol and survival in patients with chronic ... more We sought to describe the relationship between cholesterol and survival in patients with chronic heart failure (CHF). BACKGROUND Increasing lipoprotein levels are a cardiovascular risk factor. In patients with CHF, the prognostic value of endogenous lipoproteins is not fully clarified.