Publications by authors named "Francesca Graziani"

38 Publications

Right ventricular strain in Anderson-Fabry disease.

Int J Cardiol 2021 May 15;330:84-90. Epub 2021 Feb 15.

Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy.

Background: 2D speckle tracking echocardiography (2DSTE) is superior to standard echocardiography in the assessment of subtle right ventricle (RV) systolic dysfunction. In this study we aimed to: 1) test the hypothesis that 2DSTE may unveil subtle RV systolic dysfunction in patients with Fabry disease; 2) investigate whether the physiologic difference between the 3-segment (RV-FWS) and the 6-segment (RV-GLS) RV strain (∆RV strain) is preserved in Fabry patients.

Methods And Results: Standard echocardiography and 2DSTE were performed in 49 Fabry patients and 49 age- and sex-matched healthy controls. Fabry patients were divided in two groups according to the presence/absence of left ventricular hypertrophy (LVH+: left ventricular wall thickness > 12 mm, 49% of total Fabry patients). RV systolic function assessed by standard echocardiography was normal in the majority of Fabry patients (92%) while RV-GLS and RV-FWS were impaired in about 40%. RV-GLS and RV-FWS were significantly worse in patients LVH+ vs LVH- and vs controls (RV-GLS: LVH+ vs LVH-: -18.4 ± -4.3% vs -23.8 ± -3.1% p<0.001; LVH+ vs controls: -18.4 ± -4.3% vs -23.9 ± -2.8% p<0.001; RV-FWS: LVH+ vs LVH-: -21.8 ± -5.3% vs -26.7 ± -3.8% p = 0.002, LVH+ vs controls -21.8 ± -5.3% vs -26.8 ± -3.9% p<0.001). No difference was found between LVH- patients and controls in both RV-GLS (p = 0.65) and RV-FWS (p = 0.79). ∆RV strain was similar among the groups.

Conclusions: In Fabry cardiomyopathy impaired RV-GLS and RV-FWS is a common finding, while RV strain is preserved in Fabry patients without overt cardiac involvement. The physiologic difference between RV-FWS and RV-GLS is maintained in Fabry patients, regardless of the presence of cardiomyopathy.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.038DOI Listing
May 2021

Standard ECG for differential diagnosis between Anderson-Fabry disease and hypertrophic cardiomyopathy.

Heart 2021 Feb 9. Epub 2021 Feb 9.

Cardiology Unit, IRCCS, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola Hospital, University of Bologna, Bologna, Emilia-Romagna, Italy

Objectives: To evaluate the role of the ECG in the differential diagnosis between Anderson-Fabry disease (AFD) and hypertrophic cardiomyopathy (HCM).

Methods: In this multicentre retrospective study, 111 AFD patients with left ventricular hypertrophy were compared with 111 patients with HCM, matched for sex, age and maximal wall thickness by propensity score. Independent ECG predictors of AFD were identified by multivariate analysis, and a multiparametric ECG score-based algorithm for differential diagnosis was developed.

Results: Short PR interval, prolonged QRS duration, right bundle branch block (RBBB), R in augmented vector left (aVL) ≥1.1 mV and inferior ST depression independently predicted AFD diagnosis. A point-by-point ECG score was then derived with the following diagnostic performances: c-statistic 0.80 (95% CI 0.74 to 0.86) for discrimination, the Hosmel-Lemeshow χ 6.14 (p=0.189) for calibration, sensitivity 69%, specificity 84%, positive predictive value 82% and negative predictive value 72%. After bootstrap resampling, the mean optimism was 0.025, and the internal validated c-statistic for the score was 0.78.

Conclusions: Standard ECG can help to differentiate AFD from HCM while investigating unexplained left ventricular hypertrophy. Short PR interval, prolonged QRS duration, RBBB, R in aVL ≥1.1 mV and inferior ST depression independently predicted AFD. Their systematic evaluation and the integration in a multiparametric ECG score can support AFD diagnosis.
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http://dx.doi.org/10.1136/heartjnl-2020-318271DOI Listing
February 2021

Trabecular complexity as an early marker of cardiac involvement in Fabry disease.

Eur Heart J Cardiovasc Imaging 2021 Jan 22. Epub 2021 Jan 22.

Multimodality Cardiac Imaging Section, IRCCS Policlinico San Donato, San Donato Milanese, Via Morandi 30, Milan 20097, Italy.

Aims: Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy.

Methods And Results: Study population included 20 healthy controls (12 males, age 32±9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28±13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33±9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5±9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27±0.02 controls vs. 1.29±0.02 Group 1 vs. 1.30±0.02 Group 2 vs. 1.34±0.02 Group 3; P<0.001). Group 3 showed significantly higher values of all Dfs compared to the other Groups. Both basal and total Dfs were significantly higher in Group 1 compared with controls (basal: 1.30±0.03 vs. 1.26±0.04, P =0.010; total: 1.29±0.02 vs. 1.27±0.02, P=0.044). Total Df showed significant correlations with: (i) T1 value (r=-0.569; P<0.001); (ii) LV mass (r=0.664, P<0.001); (iii) trabecular mass (r=0.676; P <0.001); (iv) Mainz Severity Score Index (r=0.638; P<0.001).

Conclusion: Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement.
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http://dx.doi.org/10.1093/ehjci/jeaa354DOI Listing
January 2021

Evidence of evolution towards left midventricular obstruction in severe Anderson-Fabry cardiomyopathy.

ESC Heart Fail 2021 Feb 19;8(1):725-728. Epub 2020 Nov 19.

Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy.

Aims: In Fabry cardiomyopathy, left ventricular outflow tract obstruction mimicking hypertrophic cardiomyopathy is a very rare finding, with few cases reported and successfully treated with cardiac surgery. In our population of patients with Fabry disease and severe left ventricular hypertrophy (LVH) at the time of diagnosis, we observed an evolution towards a midventricular obstructive phenotype.

Methods And Results: We present a case series of three classically affected Fabry male patients with significant diagnostic delay and severe cardiac involvement (maximal wall thickness >20 mm) at first evaluation. All patients developed midventricular obstructive form over time despite prompt initiation and optimal compliance to enzyme replacement therapy. The extension and distribution of the LVH, involving the papillary muscles, was the main mechanism of obstruction, unlike the asymmetric septal basal hypertrophy and the mitral valve abnormalities commonly seen as substrate of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

Conclusions: Fabry cardiomyopathy can evolve over time towards a midventricular obstructive form due to massive LVH in classically affected men with significant diagnostic delay and severe LVH before enzyme replacement therapy initiation. This newly described cardiac phenotype could represent an adverse outcome of the disease.
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http://dx.doi.org/10.1002/ehf2.13101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835588PMC
February 2021

Successful Transcatheter Treatment of Left Pulmonary Artery to Left Atrium Communication Diagnosed in Adulthood.

Circ Cardiovasc Imaging 2020 11 6;13(11):e010668. Epub 2020 Nov 6.

Department of Cardiovascular and Thoracic Sciences (R.L., F.G., F.B., G.L., C.A., E.R., M.G., E.P., R.S., F.I., M.M., C.T.) Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

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http://dx.doi.org/10.1161/CIRCIMAGING.120.010668DOI Listing
November 2020

Undiagnosed Severe Late Complications of Repaired Tetralogy of Fallot.

Circ Cardiovasc Imaging 2020 06;13(6):e010273

Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (R.L., E.P., F.G., A.M.L., M.G., F.C., M.M.).

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http://dx.doi.org/10.1161/CIRCIMAGING.119.010273DOI Listing
June 2020

Prognostic significance of right ventricular hypertrophy and systolic function in Anderson-Fabry disease.

ESC Heart Fail 2020 08 20;7(4):1605-1614. Epub 2020 May 20.

Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, Rome, 00168, Italy.

Aims: Right ventricular hypertrophy (RVH) is a common finding in Anderson-Fabry disease (AFD), but the prognostic role of right ventricular (RV) involvement has never been assessed. The aim of our study was to evaluate the prognostic significance of RVH and RV systolic function in AFD.

Methods And Results: Forty-five AFD patients (56% male patients) with extensive baseline evaluation, including assessment of RVH and RV systolic function, were followed-up for an average of 51.2 ± 11.4 months. RV systolic function was assessed by standard and tissue Doppler echocardiography. Cardiovascular events were defined as new-onset atrial fibrillation (AF), sustained ventricular arrhythmias, heart failure, or pacemaker/implantable cardioverter defibrillator implantation; renal events were defined as progression to dialysis and/or renal transplantation or significant worsening of glomerular filtration rate; and cerebrovascular events were defined as transient ischaemic attack or stroke. Fourteen patients (31.1%) presented RVH, while RV systolic function was normal in all cases. During the follow-up period, 13 patients (28.8%, 11 male) experienced 18 major events, including two deaths. Cardiovascular events occurred in eight patients (17.7%). The most common event was pacemaker/implantable cardioverter defibrillator implantation (six patients, 13.3%), followed by AF (three cases, 6.6%). Only one case of worsening New York Heart Association class (from II to III and IV) was observed. Ischaemic stroke occurred in three cases (6.6%). Renal events were recorded in three patients (6.6%). At univariate analysis, several variables were associated with the occurrence of events, including RVH (HR: 7.09, 95% CI: 2.17 to 23.14, P = 0.001) and indexes of RV systolic function (tricuspid annular plane systolic excursion HR: 0.77, 95% CI: 0.62 to 0.96, P = 0.02; and RV tissue Doppler systolic velocity HR: 0.76, 95% CI: 0.61 to 0.93, P = 0.01). At multivariate analysis, proteinuria (HR:8.3, 95% CI: 2.88 to 23.87, P < 0.001) and left ventricular mass index (HR: 1.02, 95% CI: 1.00 to 1.03, P = 0.03) emerged as the only independent predictors of outcome.

Conclusions: RVH and RV systolic function show significant association with clinical events in AFD, but only proteinuria and left ventricular mass index emerged as independent predictors of outcome. Our findings suggest that RV involvement does not influence prognosis in AFD and confirm that renal involvement and left ventricular hypertrophy are the main determinant of major cardiac and non-cardiac events.
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http://dx.doi.org/10.1002/ehf2.12712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373914PMC
August 2020

Pregnancy outcome and left ventricular ejection fraction in women with history of myocardial infarction.

Eur J Obstet Gynecol Reprod Biol 2020 Jul 29;250:74-75. Epub 2020 Apr 29.

Dipartimento Scienze della Salute della Donna, del Bambino, e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, Roma, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ejogrb.2020.04.052DOI Listing
July 2020

The Effects of Granulocyte Colony-Stimulating Factor in Patients with a Large Anterior Wall Acute Myocardial Infarction to Prevent Left Ventricular Remodeling: A 10-Year Follow-Up of the RIGENERA Study.

J Clin Med 2020 Apr 23;9(4). Epub 2020 Apr 23.

Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Background: the RIGENERA trial assessed the efficacy of granulocyte-colony stimulating factor (G-CSF) in the improvement of clinical outcomes in patients with severe acute myocardial infarction. However, there is no evidence available regarding the long-term safety and efficacy of this treatment.

Methods: in order to evaluate the long-term effects on the incidence of major adverse events, on the symptom burden, on the quality of life and the mean life expectancy and on the left ventricular (LV) function, we performed a clinical and echocardiographic evaluation together with an assessment using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Seattle Heart Failure Model (SHFM) at 10-years follow-up, in the patients cohorts enrolled in the RIGENERA trial.

Results: thirty-two patients were eligible for the prospective clinical and echocardiography analyses. A significant reduction in adverse LV remodeling was observed in G-CSF group compared to controls, 9% vs. 48% ( = 0.030). The New York Heart Association (NYHA) functional class was lower in G-CSF group vs. controls ( = 0.040), with lower burden of symptoms and higher quality of life ( = 0.049). The mean life expectancy was significantly higher in G-CSF group compared to controls (15 ± 4 years vs. 12 ± 4 years, = 0.046. No difference was found in the incidence of major adverse events.

Conclusions: this longest available follow-up on G-CSF treatment in patients with severe acute myocardial infarction (AMI) showed that this treatment was safe and associated with a reduction of adverse LV remodeling and higher quality of life, in comparison with standard-of-care treatment.
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http://dx.doi.org/10.3390/jcm9041214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230316PMC
April 2020

Massive Coronary Microvascular Dysfunction in Severe Anderson-Fabry Disease Cardiomyopathy.

Circ Cardiovasc Imaging 2019 06 10;12(6):e009104. Epub 2019 Jun 10.

Department of Cardiovascular and Thoracic Sciences (F.G., R.L., E.P., F.C.), Fondazione Policlinico Universitario A. Gemelli IRCSS, Rome, Italy.

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http://dx.doi.org/10.1161/CIRCIMAGING.119.009104DOI Listing
June 2019

Predictors of Clinical Evolution in Prehypertrophic Fabry Disease.

Circ Cardiovasc Imaging 2019 04;12(4):e008424

Multimodality Cardiac Imaging Section (A.C., S.P., M.L.), IRCCS Policlinico San Donato, San Donato Milanese, Milano, Italy.

Background: In prehypertrophic Fabry disease, low myocardial T1 values, reflecting sphingolipid storage, are associated with early structural and ECG changes. The correlations between T1 values and functional parameters have not been explored. Furthermore, the potential prognostic role of T1 in predicting disease worsening is still unknown.

Methods: ECG, 2D echocardiography, cardiopulmonary test, and cardiac magnetic resonance were performed in 44 Fabry patients without left ventricular hypertrophy (35.7±14.5 years, 68.2% females). After a 12-month follow-up, clinical stability was evaluated using Fabry Stabilization Index.

Results: At baseline, T1 values showed a negative correlation with left ventricular mass ( r=-0.79; P<0.0001), maximum wall thickness ( r=-0.79; P<0.0001), Sokolow-Lyon Index ( r=-0.54; P<0.0001), left atrial volume ( r=-0.49; P<0.0002), and Mainz Severity Score Index ( r=-0.61; P<0.0001). No significant differences in systo-diastolic function and exercise capacity were observed comparing normal and low T1 Fabry patients. Arrhythmias were reported in 2 females with low T1 and late gadolinium enhancement. Five patients (40.0±12.4 years, 2 females) showed clinical worsening (Fabry Stabilization Index >20%) at follow-up. Higher left ventricular wall thickness (odds ratio, 2.61; CI, 1.04-6.57; P=0.04), left atrial volume (odds ratio, 1.24; CI, 1.02-1.51; P=0.03), and lower T1 values (odds ratio, 0.98; CI, 0.96-0.99; P=0.03) at baseline were independently associated with clinical worsening at follow-up.

Conclusions: In prehypertrophic Fabry disease, low T1 values correlate with early electrocardiographic, morphological cardiac changes, and worsening of global disease severity but are not associated with functional abnormalities. The presence of low T1 values is a risk factor for disease worsening, thus representing a potential new tool in prognostic stratification and therapeutic approach.
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http://dx.doi.org/10.1161/CIRCIMAGING.118.008424DOI Listing
April 2019

Severe silent myocardial ischemia during echocardiographic examination in a patient during cardiac screening for a kidney transplant intervention.

J Cardiovasc Med (Hagerstown) 2019 05;20(5):361-362

Dipartimento di Scienze Cardiovascolari e Toraciche, Fondazione Policlinico Universitario A. Gemelli IRCCS.

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http://dx.doi.org/10.2459/JCM.0000000000000784DOI Listing
May 2019

Treating heart failure with preserved ejection fraction: learning from pulmonary fibrosis.

Eur J Heart Fail 2018 10 7;20(10):1385-1391. Epub 2018 Aug 7.

Department of Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Heart failure with preserved ejection fraction (HFpEF) has a poor prognosis, and an effective treatment is currently lacking. Increasing evidence suggests a prevailing pathogenic role of cardiac fibrosis in HFpEF, which generates the possibility of a mechanistic overlap with pulmonary fibrosis. Indeed, cardiac and pulmonary fibrosis share some characteristics and molecular pathways, such as that of transforming growth factor-β. If pulmonary and cardiac fibrosis share common pathways, we can hypothesize a beneficial effect of anti-fibrotic drugs used in idiopathic pulmonary fibrosis on cardiac outcomes. Of note, pirfenidone has been tested in animal models of cardiac fibrosis and was found to be effective in reducing ventricular remodelling. Yet, no results are hitherto available for humans. In this review article, we discuss the potential benefit of anti-fibrotic treatment in HFpEF. In particular, we propose to reappraise safety data collected in placebo-controlled trials of anti-fibrotic drugs in idiopathic pulmonary fibrosis, to explore the hypothesis that these might reduce cardiac fibrosis.
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http://dx.doi.org/10.1002/ejhf.1286DOI Listing
October 2018

Inflammasome, T Lymphocytes and Innate-Adaptive Immunity Crosstalk: Role in Cardiovascular Disease and Therapeutic Perspectives.

Thromb Haemost 2018 Aug 10;118(8):1352-1369. Epub 2018 Jul 10.

Department of Cardiovascular and Thoracic Sciences, IRCCS-Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart, Rome, Italy.

Over the past few decades, lot of evidences have shown atherosclerosis as a chronic progressive disease with an exquisite inflammatory feature. More recently, the role of innate immune response in the onset and progression of coronary artery disease (CAD) and an adaptive immunity imbalance, mostly involving T cell sub-sets, have been documented. Therefore, like in many other inflammatory and autoimmune disorders, an altered innate-adaptive immunity crosstalk could represent the key of the inflammatory burden leading to atherosclerotic plaque formation and progression and to the breakdown of plaque stability. In this review, we will address the role of inflammasome in innate immunity and in the imbalance of adaptive immunity. We will discuss how this altered immune crosstalk is related to CAD onset and progression. We will also discuss how unravelling the key molecular mechanisms is of paramount importance in the development of therapeutic tools to delay the chronic progression and prevent the acute destabilization of atherosclerotic plaque.
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http://dx.doi.org/10.1055/s-0038-1666860DOI Listing
August 2018

When is compassionate appropriate for end-stage aortic valve stenosis?

Minerva Cardioangiol 2018 04 25;66(2):221-222. Epub 2017 Oct 25.

Institute of Cardiology, Catholic University of the Sacred Heart, Policlinico A. Gemelli, Rome, Italy.

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http://dx.doi.org/10.23736/S0026-4725.17.04484-XDOI Listing
April 2018

Anderson-Fabry's Disease: A Rare but Treatable Case of Fever of Unknown Origin.

Eur J Case Rep Intern Med 2017 3;4(7):000645. Epub 2017 Jul 3.

Periodic Fever Research Centre, A. Gemelli Policlinic, Catholic University of the Sacred Heart, Rome, Italy.

Anderson-Fabry's disease (AFD) is a rare, X-linked lysosomal storage disorder caused by the complete deficiency or attenuated activity of the enzyme α-galactosidase A, leading to progressive systemic intracellular accumulation of glycosphingolipids and subsequent cellular dysfunction, inflammation and fibrosis. Fever is a frequently misinterpreted symptom in the early stages of the disease, leading to diagnostic delay. We present the case of a 35-year-old man admitted to our Periodic Fever Research Centre for long-lasting recurrent episodes of fever of unknown origin. After extensive assessment, we diagnosed AFD associated with a novel GLA mutation. We started enzyme replacement therapy with clinical benefit and complete remission of fever.

Learning Points: Anderson-Fabry's Disease (AFD) is an inherited lysosomal storage disorder, in which progressive multi-organ glycosphingolipid accumulation leads to multi-systemic dysfunction. Diagnosis requires a high level of suspicion as the clinical presentation can be very heterogeneous.As fever is an early uncommon symptom causing diagnostic delay, it is important to consider AFD in the differential diagnosis of recurrent fevers, particularly when febrile episodes are not associated with an increase in acute phase reactants and when other signs or symptoms suggestive of AFD are present.Prognosis depends on an early diagnosis because promptly initiation of enzyme replacement therapy (ERT) can prevent the progression of organ damage. In our case fever disappeared after ERT initiation, a finding not previously reported to our knowledge. Therefore, fever remission could be an early marker of response to ERT.
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http://dx.doi.org/10.12890/2017_000645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346910PMC
July 2017

Right Ventricular Hypertrophy, Systolic Function, and Disease Severity in Anderson-Fabry Disease: An Echocardiographic Study.

J Am Soc Echocardiogr 2017 Mar 6;30(3):282-291. Epub 2017 Jan 6.

Department of Cardiovascular Sciences, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.

Background: Right ventricular (RV) involvement has been described in Anderson-Fabry disease (AFD), especially in patients with established Fabry cardiomyopathy (FC). However, few and controversial data on RV systolic function are available, and there are no specific tissue Doppler studies.

Methods: Detailed echocardiographic examinations were performed in 45 patients with AFD. FC, defined as maximal left ventricular wall thickness ≥ 15 mm, was present in 12. The Mainz Severity Score Index was calculated for each patient. Pulsed tissue Doppler was applied to the RV free wall at the tricuspid annular level and at the septal and lateral corners at the mitral annular level to obtain systolic tissue Doppler velocities (RV S, septal S, and lateral S, respectively). Twelve patients with amyloid light-chain cardiac amyloidosis were studied as a control group.

Results: Echocardiography revealed RV hypertrophy (RVH) in 31% of patients with AFD, all but one of whom were male and all of whom had concomitant left ventricular hypertrophy (LVH). All patients with AFD had normal RV fractional area change (47.9 ± 6.5%) and tricuspid annular plane systolic excursion (21.7 ± 3.2 mm) and all but one also had normal RV S (13.2 ± 2.2 cm/sec). RVH positively correlated with indices of LVH (r = 0.8, P = .0001, for all parameters evaluated), as well as with Mainz Severity Score Index (r = 0.70, P = .0001). Septal and lateral S were decreased in almost all patients (means, 7.7 ± 1.8 and 7.9 ± 1.9 cm/sec, respectively), irrespective of the presence of LVH. Compared with control subjects with cardiac amyloidosis, patients with FC showed better indices of RV systolic function (P < .001 for all: tricuspid annular plane systolic excursion, RV fractional area change, and RV S) despite similar RV wall thickness (6.2 ± 1.2 vs 6.9 ± 1.9 mm, P = NS).

Conclusions: RVH is common in patients with AFD and correlates with disease severity and LVH. RVH, however, does not significantly affect RV systolic function. Patients with FC have better RV systolic function compared with those with cardiac amyloidosis with similar levels of RV thickness. The combination of low LV S values and normal RV S values might be helpful in the differential diagnosis of infiltrative heart disease.
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http://dx.doi.org/10.1016/j.echo.2016.11.014DOI Listing
March 2017

Pharmacological characterization of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro-1H-inden-2-yl]-2-propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator.

Br J Pharmacol 2017 03 31;174(5):370-385. Epub 2017 Jan 31.

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.

Background And Purpose: AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application.

Experimental Approach: [N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro 1H-inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent.

Key Results: We demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native hetero-oligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor-mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay-induced deficit in novel object recognition in rats after both acute and sub-chronic dosing. Sub-chronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg·kg . UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine-impaired rats and water maze learning and retention in aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold test at doses below 10 mg·kg .

Conclusion And Implications: We conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation.
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http://dx.doi.org/10.1111/bph.13696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301047PMC
March 2017

Evaluation of Adults With Congenital Heart Disease.

World J Pediatr Congenit Heart Surg 2016 Mar;7(2):185-91

Department of Pediatrics, Pediatric Cardiology Unit, Catholic University of the Sacred Heart, Rome, Italy

The clinical approach to adults with congenital heart diseases (ACHDs) is unique in cardiovascular medicine because these patients encompass a broad range of presentations. Each patient, despite having similar diagnosis, will be anatomically and physiologically unlike others within ACHD population, in relation to the type of repair, age at repair, associated defects, with specific long-term risk factors and complications. Furthermore, as many patients will not complain of symptoms, clinical evaluation and diagnostic testing must also be based on the underlying main diagnostic category, with complete standardized lesion-specific clinical protocols, investigating all known risk factors specific for each congenital heart disease and performed as part of screening for significant long-term complications. The first part of this review will focus on clinical history, physical examination, and the most important diagnostic testing in ACHD population. The second part of the article will focus on some clinical issues we have to face in our daily practice, such as heart failure, cyanosis, and pulmonary hypertension. Furthermore, as survival rates of ACHD population continue to improve and patients with this condition live longer, we will briefly report on a new clinical concern regarding the impact of acquired morbidities like coronary artery disease that appear to be of greater importance in defining outcome in older patients with ACHD.
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http://dx.doi.org/10.1177/2150135115623285DOI Listing
March 2016

The combined effect of subcutaneous granulocyte- colony stimulating factor and myocardial contrast echocardiography with intravenous infusion of sulfur hexafluoride on post-infarction left ventricular function, the RIGENERA 2.0 trial: study protocol for a randomized controlled trial.

Trials 2016 Feb 19;17:97. Epub 2016 Feb 19.

Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy.

Background: Several clinical trials and recent meta-analyses have demonstrated that administration of recombinant human granulocyte-colony stimulating factor (G-CSF) is safe and, only in patients with large acute myocardial infarction (AMI), is associated with an improvement in left ventricular ejection fraction. Moreover, the mobilization and engraftment of the bone marrow-derived cells may differ significantly among patients, interfering with the restoration of left ventricular function after treatment. Therefore, the clinical potential application of the G-CSF has not yet been fully elucidated.

Methods/design: The RIGENERA 2.0 trial is a multicenter, phase II, placebo-controlled, randomized, open-label, with blinded evaluation of endpoints (PROBE) trial in which 120 patients with an acute ST-elevation myocardial infarction (STEMI) undergoing successful revascularization but with residual myocardial dysfunction will be enrolled. In cases where there is a left ventricular ejection fraction (LVEF) ≤ 45% the patient will be electronically randomized (1:1 ratio) to receive either subcutaneous recombinant human G-CSF (group 1) or placebo (group 2) both added on top of optimal standard of care. Both groups will undergo myocardial contrast echocardiography with intravenous infusion of sulfur hexafluoride (MCE) whilst undergoing the echocardiogram. The primary efficacy endpoint is the evaluation of the LVEF at 6 months after AMI assessed by cardiac magnetic resonance. Secondary efficacy endpoints are the evaluation of LVEF at 6 months after AMI assessed by echocardiography, left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) assessed by cardiac magnetic resonance and echocardiography at 6 months, together with the incidence of major adverse clinical events (MACE) defined as death, myocardial infarction, sustained cardiac arrhythmias, cardiogenic shock, stroke and re-hospitalization due to heart failure at 1 year.

Discussion: The RIGENERA 2.0 trial will test whether G-CSF administration and MCE, through the enhancement of the bone marrow-derived cells homing in the myocardium, determines an improvement in regional and global contractile function, myocardial perfusion and infarct extension in patients with large AMI. The results of the present study are expected to envision routine clinical use of this safe, affordable and reproducible approach in patients with successful revascularization after AMI.

Trial Registration: ClinicalTrials.gov: NCT02502747 (29 June 2015); EudraCT: 2015-002189-21 (10 July 2015).
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http://dx.doi.org/10.1186/s13063-016-1172-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759781PMC
February 2016

A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons.

J Pharmacol Exp Ther 2015 Sep 17;354(3):251-60. Epub 2015 Jun 17.

Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.)

Kv3.1 and Kv3.2 high voltage-activated potassium channels, which display fast activation and deactivation kinetics, are known to make a crucial contribution to the fast-spiking phenotype of certain neurons. Pharmacological experiments show that the blockade of native Kv3 currents with low concentrations of tetraethylammonium or 4-aminopyridine impairs the expression of this firing phenotype. In particular, Kv3 channels are highly expressed by fast-spiking, parvalbumin-positive interneurons in corticolimbic brain circuits, which modulate the synchronization of cortical circuits and the generation of brain rhythms. Here, we describe a novel small molecule, (5R)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione (AUT1), which modulates Kv3.1 and Kv3.2 channels in human recombinant and rodent native neurons. AUT1 increased whole currents mediated by human Kv3.1b and Kv3.2a channels, with a concomitant leftward shift in the voltage dependence of activation. A less potent effect was observed on hKv3.3 currents. In mouse somatosensory cortex slices in vitro, AUT1 rescued the fast-spiking phenotype of parvalbumin-positive-fast-spiking interneurons following an impairment of their firing capacity by blocking a proportion of Kv3 channels with a low concentration of tetraethylammonium. Notably, AUT1 had no effect on interneuron firing when applied alone. Together, these data confirm the role played by Kv3 channels in the regulation of the firing phenotype of somatosensory interneurons and suggest that AUT1 and other Kv3 modulators could represent a new and promising therapeutic approach to the treatment of disorders associated with dysfunction of inhibitory feedback in corticolimbic circuits, such as schizophrenia.
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http://dx.doi.org/10.1124/jpet.115.225748DOI Listing
September 2015

Endothelial progenitor cells in morbid obesity.

Circ J 2014 27;78(4):977-85. Epub 2014 Feb 27.

Department of Cardiovascular Medicine, Catholic University of the Sacred Heart.

Background:  The aim of this study was to assess the relationship among anthropometric indexes of adiposity (body mass index [BMI], waist circumference [WC]), endothelial progenitor cells (EPC) and carotid intima-media thickness (IMT) in patients with morbid obesity, and the effect of diabetes and weight loss.

Methods And Results:  BMI, WC, IMT and circulating EPC (defined as CD34+/KDR+/CD45- cells) were assessed in 100 patients (37 with diabetes). Fifty patients underwent bariatric surgery, and in 48 of them a complete re-assessment after an average follow-up of 252±108 days was carried out. In 29 of them subcutaneous and visceral adipose tissue samples were obtained at the time of intervention and analyzed for the presence and number of EPC. EPC were directly correlated with weight, BMI, WC and insulin level, and inversely with mean IMT. All correlations were confined to non-diabetic patients. EPC were found in both subcutaneous and visceral adipose tissue specimens. Circulating EPC significantly decreased after weight loss (P=0.002).

Conclusions:  EPC are positively related to markers of adiposity in severe obesity, when not complicated by diabetes. Weight loss is associated with decrease in EPC level. EPC are inversely correlated with IMT, confirming their protective role also in severe obesity. Diabetes has a negative modulating action. 
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http://dx.doi.org/10.1253/circj.cj-13-0976DOI Listing
October 2014

Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery.

Circulation 2014 Jan 18;129(2):157-72. Epub 2013 Nov 18.

Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy (D.D'A., A.M.L., A.I., N.L., M.G., M. Manchi, A. Severino, F.G., G.B., A.M., C.S., G.L.D.M., C.C., A. Siracusano, L.O., M. Massetti, F.C.); and Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.D'A., R.K., S.H.S., P.G., A.L., P.A.).

Background: The efficacy of bypass surgery in patients with ischemic cardiomyopathy is not easily predictable; preoperative clinical conditions may be similar, but the outcome may differ significantly. We hypothesized that the growth reserve of cardiac stem cells (CSCs) and circulating cytokines promoting CSC activation are critical determinants of ventricular remodeling in this patient population.

Methods And Results: To document the growth kinetics of CSCs, population-doubling time, telomere length, telomerase activity, and insulin-like growth factor-1 receptor expression were measured in CSCs isolated from 38 patients undergoing bypass surgery. Additionally, the blood levels of insulin-like growth factor-1, hepatocyte growth factor, and vascular endothelial growth factor were evaluated. The variables of CSC growth were expressed as a function of the changes in wall thickness, chamber diameter and volume, ventricular mass-to-chamber volume ratio, and ejection fraction, before and 12 months after surgery. A high correlation was found between indices of CSC function and cardiac anatomy. Negative ventricular remodeling was not observed if CSCs retained a significant growth reserve. The high concentration of insulin-like growth factor-1 systemically pointed to the insulin-like growth factor-1-insulin-like growth factor-1 receptor system as a major player in the adaptive response of the myocardium. hepatocyte growth factor, a mediator of CSC migration, was also high in these patients preoperatively, as was vascular endothelial growth factor, possibly reflecting the vascular growth needed before bypass surgery. Conversely, a decline in CSC growth was coupled with wall thinning, chamber dilation, and depressed ejection fraction.

Conclusions: The telomere-telomerase axis, population-doubling time, and insulin-like growth factor-1 receptor expression in CSCs, together with a high circulating level of insulin-like growth factor-1, represent a novel biomarker able to predict the evolution of ischemic cardiomyopathy following revascularization.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.006591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969331PMC
January 2014

Infections, immunity and atherosclerosis: pathogenic mechanisms and unsolved questions.

Int J Cardiol 2013 Jul 22;166(3):572-83. Epub 2012 Jun 22.

Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy.

The role of inflammation and immunity in the pathogenesis and clinical manifestations of atherosclerotic disease has been widely studied. Common infectious diseases can be associated with a chronic inflammatory state which is the hallmark of atherosclerosis, thus suggesting a possible link between the two pathological conditions. Therefore, a great number of studies have tested the "infection hypothesis", but their results are conflicting. Nevertheless, several molecular and biological mechanisms possibly involved in the complex relationship between infections, immune response, vascular wall damage and atherosclerosis onset and progression have been described. The purpose of this article is to offer an overview of the principal mechanisms and molecular pathways that probably constitute the most relevant biological substrate on which the infection hypothesis is founded; some of these mechanisms are not fully understood yet. Nevertheless, their comprehension could be essential for the development of new preventive and therapeutic strategies.
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http://dx.doi.org/10.1016/j.ijcard.2012.05.098DOI Listing
July 2013

Cardiovascular risk in obesity: different activation of inflammation and immune system between obese and morbidly obese subjects.

Eur J Intern Med 2011 Aug 26;22(4):418-23. Epub 2011 May 26.

Institute of Cardiology, Catholic University, Largo Gemelli 8, 00168 Rome, Italy.

Background: Both inflammation and immunity are involved in the development and progression of atherosclerosis. Obesity is considered a major modifiable cardiovascular risk factor, however, the correlation between increasing degrees of obesity and cardiovascular risk is not clear yet. Aim of our study was to investigate how different degrees of obesity are associated with inflammation and immune system responses.

Methods: One-hundred healthy individuals were divided into 3 groups according to body mass index (BMI): 22 overweight (OW), 26 obese (O) and 52 morbidly obese (MO). High-sensitivity C-Reactive Protein (hs-CRP, immunonephelometry), leptin (radio-immunoassay) and CD4+CD28nullT-lymphocytes (flow-cytometry), a particular subset of T-lymphocytes with pro-atherogenic and plaque-destabilizing properties, were assessed.

Results: hs-CRP levels were significantly higher in O vs OW (p=0.036), in MO vs OW (p<0.001) and in MO vs O (p=0.012). Similarly, leptin levels were higher in O vs OW (p=0.02), in MO vs OW (p<0.001) and in MO vs O (p<0.001). CD4+CD28nullT-lymphocytes were higher in O vs OW (p<0.001), in O vs MO (p=0.03) and in MO vs OW (p=0.01). hs-CRP and leptin levels significantly correlated each other (r=0.39; p<0.001) and with waist circumference (r=0.52; p<0.001; r=0.64; p<0.001) and BMI (r=0.60; p<0.001; r=0.74; p<0.001).

Conclusions: Our study demonstrates that, notwithstanding higher levels of inflammation, MO are characterized by less detrimental immune activation, as shown by the reduced CD4+CD28nullT-cells expansion as compared to OW and O, which might translate in less immune vascular injury. These findings suggest that MO might represent a particular population, in which different pathophysiological mechanisms take part if compared with "classic" obesity.
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http://dx.doi.org/10.1016/j.ejim.2011.04.010DOI Listing
August 2011