Publications by authors named "Cinzia Forleo"

44 Publications

Safety of reduced or absent antithrombotic therapy after left atrial appendage closure in patients affected by hereditary haemorrhagic telangiectasia and atrial fibrillation.

Minerva Cardiol Angiol 2021 Mar 11. Epub 2021 Mar 11.

C. Frugoni Internal Medicine Unit, Department of Interdisciplinary Medicine, Center for Rare Diseases, VascERN HHT Reference Center Policlinico University Hospital, University of Bari, Bari, Italy.

Background: Left atrial appendage (LAA) closure represents a novel therapeutic chance for patients with contraindications to long-term anticoagulation therapy, such as those affected by Hereditary Hemorrhagic Telangiectasia (HHT) and atrial fibrillation (AF). Nevertheless, current experts' indications suggest the post-procedural administration of antithrombotic therapies to minimize the residual thromboembolic risk due to AF and to the need for device endothelialization. The aim of our study was to investigate the safety and effectiveness of LAA closure in preventing arterial thromboembolism in a very high-bleeding risk group, such as HHT patients, who are at risk not to tolerate even the mild post-procedural antithrombotic therapy usually recommended.

Methods: Eight HHT-affected patients with non-valvular AF, high-bleeding risk and/or known intolerance to antiplatelet and anticoagulant therapy were treated with interventional LAA occlusion with the Amplatzer™ Cardiac Plug™ and Amplatzer™ Amulet™ devices. Device implantation was successful in all patients.

Results: Post-procedural antiplatelet/anticoagulation therapy was attempted in seven patients: adherence to therapy exceeded six months only for one, while four patients suspended all antithrombotic medications within 30 days from the procedure due to an increase in bleeding frequency and/or severity and the other two discontinued treatment within six months; a single patient was not prescribed any antithrombotic therapy. At a medium follow-up of 22.4±14.3 months no thromboembolic episodes attributable to AF or device related thrombosis were reported. Two deaths were recorded 1231 and 783 days after the procedure which were classified as unrelated to any cerebral or cardiovascular accident.

Conclusions: Our study suggests that the percutaneous LAA closure in HHT patients with AF could be safe and effective in preventing arterial systemic thromboembolism, also in the presence of reduced or absent post-interventional antithrombotic treatment. LAA occluder implantation can represent a valid and potentially life-saving alternative to lifelong anticoagulant therapy in HHT, as in other very high-bleeding risk patients.
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http://dx.doi.org/10.23736/S2724-5683.20.05474-2DOI Listing
March 2021

VINYL: Variant prIoritizatioN by survivaL analysis.

Bioinformatics 2020 Dec 26. Epub 2020 Dec 26.

Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy.

Motivation: Clinical applications of genome re-sequencing technologies typically generate large amounts of data that need to be carefully annotated and interpreted to identify genetic variants potentially associated with pathological conditions. In this context, accurate and reproducible methods for the functional annotation and prioritization of genetic variants are of fundamental importance.

Results: In this paper, we present VINYL, a flexible and fully automated system for the functional annotation and prioritization of genetic variants. Extensive analyses of both real and simulated datasets suggest that VINYL can identify clinically relevant genetic variants in a more accurate manner compared to equivalent state of the art methods, allowing a more rapid and effective prioritization of genetic variants in different experimental settings. As such we believe that VINYL can establish itself as a valuable tool to assist healthcare operators and researchers in clinical genomics investigations.

Availability: VINYL is available at http://beaconlab.it/VINYL and https://github.com/matteo14c/VINYL.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa1067DOI Listing
December 2020

Late gadolinium enhancement role in arrhythmic risk stratification of patients with LMNA cardiomyopathy: results from a long-term follow-up multicentre study.

Europace 2020 12;22(12):1864-1872

Department of Arrhythmology and Cardiac Electrophysiology, IRCCS San Raffaele Hospital, Milan, Italy.

Aims: We aimed at addressing the role of late gadolinium enhancement (LGE) in arrhythmic risk stratification of LMNA-associated cardiomyopathy (CMP).

Methods And Results: We present data from a multicentre national cohort of patients with LMNA mutations. Of 164 screened cases, we finally enrolled patients with baseline cardiac magnetic resonance (CMR) including LGE sequences [n = 41, age 35 ± 17 years, 51% males, mean left ventricular ejection fraction (LVEF) by echocardiogram 56%]. The primary endpoint of the study was follow-up (FU) occurrence of malignant ventricular arrhythmias [MVA, including sustained ventricular tachycardia (VT), ventricular fibrillation, and appropriate implantable cardioverter-defibrillator (ICD) therapy]. At baseline CMR, 25 subjects (61%) had LGE, with non-ischaemic pattern in all of the cases. Overall, 23 patients (56%) underwent ICD implant. By 10 ± 3 years FU, eight patients (20%) experienced MVA, consisting of appropriate ICD shocks in all of the cases. In particular, the occurrence of MVA in LGE+ vs. LGE- groups was 8/25 vs. 0/16 (P = 0.014). Of note, no significant differences between LGE+ and LGE- patients were found in currently recognized risk factors for sudden cardiac death (male gender, non-missense mutations, baseline LVEF <45% and non-sustained VT), all P-value >0.05.

Conclusions: In LMNA-CMP patients, LGE at baseline CMR is significantly associated with MVA. In particular, as suggested by this preliminary experience, the absence of LGE allowed to rule-out MVA at 10 years mean FU.
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http://dx.doi.org/10.1093/europace/euaa171DOI Listing
December 2020

Inflammatory Bowel Disease and Acute Coronary Syndromes: From Pathogenesis to the Fine Line Between Bleeding and Ischemic Risk.

Inflamm Bowel Dis 2021 Apr;27(5):725-731

Cardiovascular Diseases Section, Cardiothoracic Department, University of Bari, Bari, Italy.

Inflammatory bowel disease (IBD) is a pathological condition that first involves the gastrointestinal wall but can also trigger a systemic inflammatory state and thus extraintestinal manifestations. Systemic inflammation is probably secondary to the passage of bacterial products into the bloodstream because of altered intestinal permeability and the consequent release of proinflammatory mediators. Inflammation, through several diverse pathophysiological pathways, determines both a procoagulative state and systemic endothelial dysfunction, which are both deemed to be responsible for venous and arterial thromboembolic adverse events. The management of systemic thrombotic complications is particularly challenging in this category of patients, who also present a high bleeding risk; what is more, both bleeding and thrombotic risks peak during the active phases of the disease. The literature suggests that treating physicians have been, so far, more heavily influenced by concerns about bleeding than by the thrombotic risk. Despite the absence of data provided by large cohorts or randomized studies, the high risk of arterial and venous atherothrombosis in patients with IBD seems unquestionable. Moreover, several reports suggest that when arterial thromboembolism involves the coronary vessels, causing acute coronary syndromes, ischemic complications from antithrombotic drug undertreatment are frequent and severe. This review aims to shed light on the tricky balance between the ischemic and hemorrhagic risks of patients with IBD and to highlight how difficult it is for clinicians to define a tailored therapy based on a case-by-case, careful, and unprejudiced clinical evaluation.
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http://dx.doi.org/10.1093/ibd/izaa160DOI Listing
April 2021

Cardiac and Neuromuscular Features of Patients With LMNA-Related Cardiomyopathy.

Ann Intern Med 2019 10 3;171(7):458-463. Epub 2019 Sep 3.

University of Bari Aldo Moro, Bari, Italy (C.F., N.R., S.F.).

Background: Mutations in the LMNA (lamin A/C) gene have been associated with neuromuscular and cardiac manifestations, but the clinical implications of these signs are not well understood.

Objective: To learn more about the natural history of LMNA-related disease.

Design: Observational study.

Setting: 13 clinical centers in Italy from 2000 through 2018.

Patients: 164 carriers of an LMNA mutation.

Measurements: Detailed cardiologic and neurologic evaluation at study enrollment and for a median of 10 years of follow-up.

Results: The median age at enrollment was 38 years, and 51% of participants were female. Neuromuscular manifestations preceded cardiac signs by a median of 11 years, but by the end of follow-up, 90% of the patients had electrical heart disease followed by structural heart disease. Overall, 10 patients (6%) died, 14 (9%) received a heart transplant, and 32 (20%) had malignant ventricular arrhythmias. Fifteen patients had gait loss, and 6 had respiratory failure. Atrial fibrillation and second- and third-degree atrioventricular block were observed, respectively, in 56% and 51% of patients with combined cardiac and neuromuscular manifestations and 37% and 33% of those with heart disease only.

Limitations: Some of the data were collected retrospectively. Neuromuscular manifestations were more frequent in this analysis than in previous studies.

Conclusion: Many patients with an LMNA mutation have neurologic symptoms by their 30s and develop progressive cardiac manifestations during the next decade. A substantial proportion of these patients will have life-threatening neurologic or cardiologic conditions.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M18-2768DOI Listing
October 2019

Functional study of a KCNH2 mutant: Novel insights on the pathogenesis of the LQT2 syndrome.

J Cell Mol Med 2019 09 30;23(9):6331-6342. Epub 2019 Jul 30.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.

The K voltage-gated channel subfamily H member 2 (KCNH2) transports the rapid component of the cardiac delayed rectifying K current. The aim of this study was to characterize the biophysical properties of a C-terminus-truncated KCNH2 channel, G1006fs/49 causing long QT syndrome type II in heterozygous members of an Italian family. Mutant carriers underwent clinical workup, including 12-lead electrocardiogram, transthoracic echocardiography and 24-hour ECG recording. Electrophysiological experiments compared the biophysical properties of G1006fs/49 with those of KCNH2 both expressed either as homotetramers or as heterotetramers in HEK293 cells. Major findings of this work are as follows: (a) G1006fs/49 is functional at the plasma membrane even when co-expressed with KCNH2, (b) G1006fs/49 exerts a dominant-negative effect on KCNH2 conferring specific biophysical properties to the heterotetrameric channel such as a significant delay in the voltage-sensitive transition to the open state, faster kinetics of both inactivation and recovery from the inactivation and (c) the activation kinetics of the G1006fs/49 heterotetrameric channels is partially restored by a specific KCNH2 activator. The functional characterization of G1006fs/49 homo/heterotetramers provided crucial findings about the pathogenesis of LQTS type II in the mutant carriers, thus providing a new and potential pharmacological strategy.
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http://dx.doi.org/10.1111/jcmm.14521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714209PMC
September 2019

Cardiogenic Shock Following Acute Myocardial Infarction: What's New?

Shock 2020 04;53(4):391-399

Division of Cardiology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Cardiogenic shock (CS) is a state of critical end-organ hypoperfusion primarily due to cardiac dysfunction. This condition is the most common cause of death in patients affected by acute myocardial infarction (AMI). Despite early revascularization, prompt optimal medical therapy, and up-to-date mechanical circulatory supports, mortality of patients with CS remains high.The objective of this review is to summarize epidemiology, pathophysiology, and treatment options of CS in light of the new European Society of Cardiology (ESC) recommendations. The latest European guidelines on myocardial revascularization have reviewed the previous guidelines with respect to early multivessel revascularization and routine use of intra-aortic balloon pump (IABP) in patients with AMI-related CS.Most of the current evidences come partly from randomized trials, but mostly from observational registries because of the difficulty to test different treatments in this life-threatening clinical setting.Some of the latest studies highlight the potential crucial benefit of newly introduced mechanical circulatory support devices, although evidences are not sufficient to definitely assess the benefit/risk ratio of the different systems.Many questions remain unanswered in this field, and further trials are advocated to better elucidate the best medical, reperfusion, and circulatory support approaches aimed to improve the poor prognosis of patients with CS after AMI.
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http://dx.doi.org/10.1097/SHK.0000000000001377DOI Listing
April 2020

Time-dependent benefits of pre-treatment with new oral P2Y -inhibitors in patients addressed to primary PCI for acute ST-elevation myocardial infarction.

Catheter Cardiovasc Interv 2019 03 30;93(4):592-601. Epub 2018 Sep 30.

Division of Cardiology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Objectives: The aim of this observational study was to determine the benefits of the novel, orally delivered P2Y -inhibitors (Is) in terms of angiographic endpoints and in relation to the time of the loading dose (LD) administration.

Background: The goal of ST-elevation myocardial infarction (STEMI) treatment is timely reperfusion. The P2Y -Is prasugrel and ticagrelor have improved the angiographic outcome of primary percutaneous coronary intervention (pPCI) and patients' prognosis. However, their onset of action is impaired in STEMI and delayed by their oral administration.

Methods: The 328 eligible patients with STEMI consecutively referred for pPCI were divided into three groups depending on the interval of "P2Y -I LD administration-to-balloon time": Group 2 included patients that received P2Y -I LD at least 60 min prior to pPCI, Group 1 within 60 min prior to pPCI, and Group 0 at the moment of pPCI. Angiographic, clinical, and biochemical parameters were evaluated. Pre- and post-pPCI TIMI flow grade (TFG) and ST resolution (STR) were used as outcome measures to determine efficacy and optimal timing of pretreatment.

Results: Pre-pPCI TFG improved with increasing P2Y -I LD administration-to-balloon time; pre-PCI TFG 0/1 was 74.5% in Group 0, 65.5% in Group 1 and 54.9% in Group 2 (P < 0.002). Post-pPCI TFG 3 results also differed significantly between the three groups: 85.2% in Group 0, 88.1% in Group 1, 97.6% in Group 2 (P < 0.013). ST resolution rates were also positively associated with longer pretreatment intervals.

Conclusions: This observational study suggests that the angiographic benefit of P2Y -I administration is time-dependent: longer pretreatment improves coronary reperfusion in terms of pre- and post-pPCI TFG and STR.
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http://dx.doi.org/10.1002/ccd.27863DOI Listing
March 2019

Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathies.

PLoS One 2017 27;12(7):e0181842. Epub 2017 Jul 27.

Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.

Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity and mortality. These diseases are genetically diverse and associated with rare mutations in a large number of genes, many of which overlap among the phenotypes. To better investigate the genetic overlap between these three phenotypes and to identify new genotype-phenotype correlations, we designed a custom gene panel consisting of 115 genes known to be associated with cardiomyopathic phenotypes and channelopathies. A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC, was recruited for the study on the basis of more severe phenotypes and family history of cardiomyopathy and/or sudden death. We detected a total of 142 rare variants in 40 genes, and all patients were found to be carriers of at least one rare variant. Twenty-eight of the 142 rare variants were also predicted as potentially pathogenic variants and found in 26 patients. In 23 out of 38 patients, we found at least one novel potential gene-phenotype association. In particular, we detected three variants in OBSCN gene in ARVC patients, four variants in ANK2 gene and two variants in DLG1, TRPM4, and AKAP9 genes in DCM patients, two variants in PSEN2 gene and four variants in AKAP9 gene in HCM patients. Overall, our results confirmed that cardiomyopathic patients could carry multiple rare gene variants; in addition, our investigation of the genetic overlap among cardiomyopathies revealed new gene-phenotype associations. Furthermore, as our study confirms, data obtained using targeted next-generation sequencing could provide a remarkable contribution to the molecular diagnosis of cardiomyopathies, early identification of patients at risk for arrhythmia development, and better clinical management of cardiomyopathic patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181842PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531468PMC
October 2017

The expression of Lamin A mutant R321X leads to endoplasmic reticulum stress with aberrant Ca handling.

J Cell Mol Med 2016 11 15;20(11):2194-2207. Epub 2016 Jul 15.

Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.

Mutations in the Lamin A/C gene (LMNA), which encodes A-type nuclear Lamins, represent the most frequent genetic cause of dilated cardiomyopathy (DCM). This study is focused on a LMNA nonsense mutation (R321X) identified in several members of an Italian family that produces a truncated protein isoform, which co-segregates with a severe form of cardiomyopathy with poor prognosis. However, no molecular mechanisms other than nonsense mediated decay of the messenger and possible haploinsufficiency were proposed to explain DCM. Aim of this study was to gain more insights into the disease-causing mechanisms induced by the expression of R321X at cellular level. We detected the expression of R321X by Western blotting from whole lysate of a mutation carrier heart biopsy. When expressed in HEK293 cells, GFP- (or mCherry)-tagged R321X mislocalized in the endoplasmic reticulum (ER) inducing the PERK-CHOP axis of the ER stress response. Of note, confocal microscopy showed phosphorylation of PERK in sections of the mutation carrier heart biopsy. ER mislocalization of mCherry-R321X also induced impaired ER Ca handling, reduced capacitative Ca entry at the plasma membrane and abnormal nuclear Ca dynamics. In addition, expression of R321X by itself increased the apoptosis rate. In conclusion, R321X is the first LMNA mutant identified to date, which mislocalizes into the ER affecting cellular homeostasis mechanisms not strictly related to nuclear functions.
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http://dx.doi.org/10.1111/jcmm.12926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082401PMC
November 2016

Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.

Int J Mol Med 2016 Oct 7;38(4):1111-24. Epub 2016 Sep 7.

Laboratory of Human Genetics, E.O. Ospedali Galliera, Genova, Italy.

Hypertrophic cardiomyopathy (HCM) is mainly associated with myosin, heavy chain 7 (MYH7) and myosin binding protein C, cardiac (MYBPC3) mutations. In order to better explain the clinical and genetic heterogeneity in HCM patients, in this study, we implemented a target-next generation sequencing (NGS) assay. An Ion AmpliSeq™ Custom Panel for the enrichment of 19 genes, of which 9 of these did not encode thick/intermediate and thin myofilament (TTm) proteins and, among them, 3 responsible of HCM phenocopy, was created. Ninety-two DNA samples were analyzed by the Ion Personal Genome Machine: 73 DNA samples (training set), previously genotyped in some of the genes by Sanger sequencing, were used to optimize the NGS strategy, whereas 19 DNA samples (discovery set) allowed the evaluation of NGS performance. In the training set, we identified 72 out of 73 expected mutations and 15 additional mutations: the molecular diagnosis was achieved in one patient with a previously wild-type status and the pre-excitation syndrome was explained in another. In the discovery set, we identified 20 mutations, 5 of which were in genes encoding non-TTm proteins, increasing the diagnostic yield by approximately 20%: a single mutation in genes encoding non-TTm proteins was identified in 2 out of 3 borderline HCM patients, whereas co-occuring mutations in genes encoding TTm and galactosidase alpha (GLA) altered proteins were characterized in a male with HCM and multiorgan dysfunction. Our combined targeted NGS-Sanger sequencing-based strategy allowed the molecular diagnosis of HCM with greater efficiency than using the conventional (Sanger) sequencing alone. Mutant alleles encoding non-TTm proteins may aid in the complete understanding of the genetic and phenotypic heterogeneity of HCM: co-occuring mutations of genes encoding TTm and non-TTm proteins could explain the wide variability of the HCM phenotype, whereas mutations in genes encoding only the non-TTm proteins are identifiable in patients with a milder HCM status.
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http://dx.doi.org/10.3892/ijmm.2016.2732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029966PMC
October 2016

Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy.

PLoS One 2015 2;10(4):e0121723. Epub 2015 Apr 2.

Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121723PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383583PMC
March 2016

Role of nuclear Lamin A/C in cardiomyocyte functions.

Biol Cell 2014 Oct 20;106(10):346-58. Epub 2014 Aug 20.

Department of Sciences, University of Basilicata, Potenza, Italy; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.

Lamin A/C is a structural protein of the nuclear envelope (NE) and cardiac involvement in Lamin A/C mutations was one of the first phenotypes to be reported in humans, suggesting a crucial role of this protein in the cardiomyocytes function. Mutations in LMNA gene cause a class of pathologies generically named 'Lamanopathies' mainly involving heart and skeletal muscles. Moreover, the well-known disease called Hutchinson-Gilford Progeria Syndrome due to extensive mutations in LMNA gene, in addition to the systemic phenotype of premature aging, is characterised by the death of patients at around 13 typically for a heart attack or stroke, suggesting again the heart as the main site sensitive to Lamin A/C disfunction. Indeed, the identification of the roles of the Lamin A/C in cardiomyocytes function is a key area of exploration. One of the primary biological roles recently conferred to Lamin A/C is to affect contractile cells lineage determination and senescence. Then, in differentiated adult cardiomyocytes both the 'structural' and 'gene expression hypothesis' could explain the role of Lamin A in the function of cardiomyocytes. In fact, recent advances in the field propose that the structural weakness/stiffness of the NE, regulated by Lamin A/C amount in NE, can 'consequently' alter gene expression.
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http://dx.doi.org/10.1111/boc.201400033DOI Listing
October 2014

Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis.

Int J Cardiol 2013 Nov 7;169(4):e49-50. Epub 2013 Sep 7.

Cardiology Unit, Emergency and Organ Transplantation Department, University of Bari, Bari, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2013.08.114DOI Listing
November 2013

Independent role of left ventricular global longitudinal strain in predicting prognosis of chronic heart failure patients.

Echocardiography 2013 Aug 14;30(7):803-11. Epub 2013 Mar 14.

Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Aims: To evaluate the independent prognostic role of two-dimensional (2D) strain measures reflecting global longitudinal left ventricular (LV) systolic function in outpatients affected by chronic heart failure (CHF).

Methods And Results: Global longitudinal LV systolic strain (GLS) was assessed in 308 outpatients affected by CHF, by analyzing standard views with 2D speckle tracking technique. During a mean follow-up of 26 ± 13 months 37 patients died (29 due to cardiovascular causes), 10 patients underwent heart transplantation, and 75 patients experienced at least 1 episode of hospitalization due to acute decompensated heart failure (ADHF). Thirty-one patients without a history of major ventricular arrhythmic events experienced the occurrence of ventricular fibrillation and/or tachycardia or sudden death was observed. Multivariate Cox regression analysis showed that GLS was significantly associated with all-cause mortality (HR: 1.15; 95%CI: 1.02-1.30; P: 0.026), cardiovascular death (HR: 1.20; 95%CI: 1.04-1.39; P: 0.011), cardiovascular death or heart transplantation (HR: 1.24; 95%CI: 1.09-1.41; P: 0.001), ADHF-related hospitalizations (HR: 1.15; 95%CI: 1.05-1.25; P: 0.003), and arrhythmic events (HR: 1.17; 95%CI: 1.03-1.33; P: 0.018).

Conclusions: Quantifying LV longitudinal systolic function in CHF outpatients on the basis of 2D speckle tracking analysis provides a new parameter that independently predicts patient outcome, thus, strengthening its possible role in current clinical practice.
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http://dx.doi.org/10.1111/echo.12142DOI Listing
August 2013

Blood pressure control and treatment adherence in hypertensive patients with metabolic syndrome: protocol of a randomized controlled study based on home blood pressure telemonitoring vs. conventional management and assessment of psychological determinants of adherence (TELEBPMET Study).

Trials 2013 Jan 23;14:22. Epub 2013 Jan 23.

Department of Cardiology, IRCCS Ospedale San Luca, Istituto Auxologico Italiano, Milano, Italy.

Background: Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient's therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated.

Methods/design: The purpose of this open label, parallel group, randomized, controlled study is to assess whether, in patients with high cardiovascular risk (treated or untreated essential arterial hypertension--both in the office and in ambulatory conditions over 24 h--and metabolic syndrome), long-term (48 weeks) blood pressure control is more effective when based on HBPT and on the feedback to patients by their doctor between visits, or when based exclusively on blood pressure determination during quarterly office visits (conventional management (CM)). A total of 252 patients will be enrolled and randomized to usual care (n = 84) or HBPT (n = 168). The primary study endpoint will be the rate of subjects achieving normal daytime ambulatory blood pressure targets (< 135/85 mmHg) 24 weeks and 48 weeks after randomization. In addition, the study will assess the psychological determinants of adherence and persistence to drug therapy, through specific psychological tests administered during the course of the study. Other secondary study endpoints will be related to the impact of HBPT on additional clinical and economic outcomes (number of additional medical visits, direct costs of patient management, number of antihypertensive drugs prescribed, level of cardiovascular risk, degree of target organ damage and rate of cardiovascular events, regression of the metabolic syndrome).

Discussion: The TELEBPMET Study will show whether HBPT is effective in improving blood pressure control and related medical and economic outcomes in hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control of these patients.

Trial Registration: Clinical Trials.gov: NCT01541566.
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http://dx.doi.org/10.1186/1745-6215-14-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576326PMC
January 2013

Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis.

Int J Cardiol 2013 Sep 3;168(1):27-35. Epub 2012 Oct 3.

Cardiology Unit, Emergency and Organ Transplantation Department, University of Bari, Bari, Italy.

Background: A systematic evaluation focused on sensitivity and specificity of head-up tilt testing (HUT) for diagnosing vasovagal syncope has not been previously performed. We conducted a meta-analysis of studies comparing HUT outcome between patients with syncope of unknown origin and control subjects without previous syncope.

Methods: We searched Pubmed and Embase databases for all English-only articles concerning case-control studies estimating the diagnostic yield of HUT, and selected 55 articles, published before March 2012, including 4361 patients and 1791 controls. The influence of age, test duration, tilt angle, and nitroglycerine or isoproterenol stimulation on tilt testing outcome was analyzed.

Results: Head-up tilt testing demonstrated to have a good overall ability to discriminate between symptomatic patients and asymptomatic controls with an area under the summary receiver-operating characteristics curve of 0.84 and an adjusted diagnostic odds ratio of 12.15 (p<0.001). A significant inverse relationship between sensitivity and specificity of tilt testing for each study was observed (p<0.001). At multivariate analysis, advancing age and a 60° tilt angle showed a significant effect in reducing sensitivity and increasing specificity of the test. Nitroglycerine significantly raised tilt testing sensitivity by maintaining a similar specificity in comparison to isoproterenol.

Conclusions: The results from this meta-analysis show the high overall performance of HUT for diagnosing vasovagal syncope. Our findings provide useful information for evaluating clinical and instrumental parameters together with pharmacological stressors influencing HUT accuracy. This could allow the drawing of tilt testing protocols tailored on the diagnostic needs of each patient with unexplained syncope.
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http://dx.doi.org/10.1016/j.ijcard.2012.09.023DOI Listing
September 2013

Incidence and prevalence of hypothyroidism in patients affected by chronic heart failure: role of amiodarone.

Endocr Metab Immune Disord Drug Targets 2012 Mar;12(1):86-94

Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Background: It has been demonstrated that hypothyroidism can lead to significant hemodynamic alterations favoring the onset of chronic heart failure (CHF) as well as its progression. Furthermore, amiodarone, an iodine-containing antiarhythmic drug frequently used in CHF patients, is often the cause of primary hypothyroidism.

Aim Of The Study: To define the prevalence and incidence of hypothyroidism in a group of CHF outpatients in stable clinical conditions, with particular reference to the role of amiodarone therapy.

Results: Among the 422 enrolled patients (326 males, aged 65±12 years), 51 (12%) had a previous diagnosis of hypothyroidism while 21 (5%) were newly diagnosed at the enrolment. Then, the overall prevalence of hypothyroidism at the first evaluation was 17%and, as expected, it was significantly higher in females than males (33% vs 13%; p < 0.001). During follow-up (median 28 months) hypothyroidism occurred in further 19 patients (incidence rate: 26/1000/year) and it was mainly attributable to amiodarone therapy. Considering all together the hypothyroid patients, either those affected by thyroid failure at the enrolment than those developing hypothyroidism during the follow-up, levothyroxine therapy was continued or started in 69% of them; however, normal serum TSH values were obtained only in 76% of treated cases (mean levothyroxine dose: 69±44 mcg/day). In any case, in the group of patients affected by hypothyroidism a significantly greater occurrence of heart failure progression was observed.

Conclusions: Hypothyroidism, especially the subclinical form, frequently occurs in patients affected by CHF receiving amiodarone therapy. Given the unfavorable impact of hypothyroidism on the progression and prognosis of CHF, and the opportunity to adequately manage thyroid failure by means of levothyroxine replacement therapy without the need to withdraw amiodarone, we recommend regular testing of thyroid function in CHF patients, in particular in those submitted to amiodarone therapy, in order to early diagnose a condition of hypothyroidism and titrate substitutive treatment.
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http://dx.doi.org/10.2174/187153012799278947DOI Listing
March 2012

Altered two-dimensional strain measures of the right ventricle in patients with Brugada syndrome and arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Eur J Echocardiogr 2011 Oct 23;12(10):773-81. Epub 2011 Aug 23.

Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.

Aims: Brugada syndrome (BrS) is an inherited channelopathy that can be characterized by mild right ventricular (RV) abnormalities that are not detectable with conventional echocardiography. The aim of this study was to evaluate the presence of RV abnormalities in BrS patients when compared with controls and a group of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using two-dimensional (2D) strain analysis.

Methods And Results: We enrolled 25 BrS, 15 ARVD/C patients, and 25 controls. Right and left ventricular dimension and systo-diastolic function were evaluated by conventional echocardiography. Longitudinal systolic strain (sS) peak, systolic and early diastolic strain rate of lateral RV segments were evaluated by 2D speckle tracking analysis. Left ventricle global and segmental strain measures were also evaluated. A reduced basal or mid-RV lateral sS were the parameters mostly associated with both BrS and ARVD/C. In BrS patients the minimum sS observed in these segments was significantly lower than that of controls (-28.9±3.2% vs. -32.3±3.2%, P: 0.002) but significantly greater than that evaluated in ARVD/C patients (-24.6±6.7%, P<0.001 both vs. BrS and controls). No differences were found between the BrS and the control group when left ventricular strain measures were analysed.

Conclusion: By 2D strain technique it is possible to observe mild abnormalities in RV systolic and diastolic function of BrS patients that are less pronounced than those observed in ARVD/C patients. These results help to better define the phenotypic characteristics of BrS patients and represent the basis for future studies aimed at testing their clinical usefulness in BrS patients.
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http://dx.doi.org/10.1093/ejechocard/jer139DOI Listing
October 2011

Reversibility of the endothelial dysfunction after CPAP therapy in OSAS patients.

Int J Cardiol 2012 Jul 25;158(3):383-6. Epub 2011 Feb 25.

Department of Cardiology, University of Bari, Italy.

Background: The obstructive sleep apnoea syndrome (OSAS) is a common airways disease which often involves cardiovascular structures, causing vessel inflammation as well as hypoxia, induced by difficulties in the passage of air through the upper airways. Aim of our research is to evaluate the effects of Continuous Positive Airway Pressure (CPAP) on the syndrome itself and the patients cardiovascular risk profile, practically adopting Flow-Mediated Vasodilation (FMD) technique to evaluate endothelial function.

Methods And Results: We enrolled 63 patients (49 males and 14 female, mean age: 54 ± 10 years) subdivided into four groups: high cardiovascular risk factors, no CPAP therapy, CPAP therapy started less- and more than 3 months before. The patients underwent FMD of the brachial artery using a high resolution ultrasonograph connected to an image analysis system. The maximum recovery value was calculated as the ratio (maximum-baseline) of the change in diameter over the baseline value. Data obtained from this study demonstrate the significant reversibility of FMD in patients treated for more than 3 months with CPAP therapy (Group 4).

Conclusions: Our study shows the importance of administering CPAP therapy for more than 3 months in patients suffering from OSAS to improve EF to a level equal to high cardiovascular risk subjects probably due to a recovery from the systemic hypoxia. Besides, our work points out the importance of FMD as a "clinical" tool able to point out any improvement or regression after therapies.
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http://dx.doi.org/10.1016/j.ijcard.2011.01.065DOI Listing
July 2012

Independent role of reduced arterial baroreflex sensitivity during head-up tilt testing in predicting vasovagal syncope recurrence.

Europace 2010 Aug 20;12(8):1149-55. Epub 2010 May 20.

Cardiology Unit, Emergency and Organ Transplantation Department, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.

Aims: The involvement of arterial baroreflex function in the pathophysiology of vasovagal syncope (VVS) is controversial, and there are no published data supporting its clinical usefulness. The aim of this study was to evaluate the role of arterial baroreflex sensitivity (BRS) at baseline and during head-up tilt testing (HUT) in predicting the recurrence of VVS.

Methods And Results: The study involved otherwise healthy patients with a history of unexplained syncope who underwent diagnostic HUT by being tilted to 70 degrees after 10 min supine rest; the test was potentiated by the administration of 300 microg of nitroglycerine (NTG) after 20 min. Beat-to-beat heart rate and systolic blood pressure were continuously recorded, and the sequence method was used to measure arterial baroreflex control of heart rate. The 190 enrolled patients were followed up for 18 +/- 6 months, during which 34 experienced a total of 90 episodes of syncope recurrence. In a stepwise multivariate analysis, female gender [hazard ratio (HR): 2.74; P = 0.008], the presence of >or=3 syncope events before HUT (HR: 3.36; P = 0.004), and BRS below median value after the start of HUT or after the administration of NTG (HR: 3.79; P = 0.006) were significantly and independently associated with the recurrence of syncope. Moreover, when a BRS value of less than the median was added to the other independent factors in a stepwise model, a significant increase in discrimination (C-index: 0.77) and model fitting (P = 0.001) was observed.

Conclusion: Reduced BRS during HUT has independent and incremental value in predicting the recurrence of syncope, thus supporting its potential usefulness in the clinical management of patients.
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http://dx.doi.org/10.1093/europace/euq149DOI Listing
August 2010

Nitrate-potentiated head-up tilt testing in older patients: outcomes, hemodynamic responses and prodrome recognition.

Pacing Clin Electrophysiol 2010 Oct;33(10):1210-6

Cardiology Unit, Emergency and Organ Transplantation Department, University of Bari, Piazza Giulio Cesare 11, Bari, Italy.

Background: To compare head-up tilt testing (HUT) outcomes and hemodynamic responses, and the prevalence and correlates of prodromes, in elderly and younger patients with suspected vasovagal syncope (VVS).

Methods: Consecutive outpatients with a history of recurrent unexplained syncope underwent HUT by being tilted to 70°; the test was potentiated by the administration of 300 μg of nitroglycerine after 20 minutes. Occurrence of VVS and hemodynamic responses during passive and nitroglycerine phases of HUT were evaluated; symptoms preceding HUT-induced syncope were recorded, together with heart rate and arterial blood pressure values.

Results: Four hundred and sixty of the 743 patients were HUT positive: 156 fainted during the unmedicated phase and 304 after nitroglycerine administration. The patients aged ≥65 years (n = 102) experienced VVS more frequently during the pharmacological stage of HUT; the overall rate of positive results was similar to that observed in the patients aged 36-64 years (n = 329) and only slightly lower than that observed in those aged ≤ 35 years (n = 312). In the older patients, who experienced fewer and mainly prodrome-free spontaneous syncopal episodes, HUT increased the number of premonitory symptoms, and there were no significant age-related differences in symptom prevalence or timing or the patients' hemodynamic characteristics.

Conclusions: The rate of VVS induced by nitroglycerine-potentiated HUT is similar in elderly and younger patients. In the former, nitroglycerine-potentiated HUT significantly increases the prevalence of prodromes in comparison with spontaneous episodes, which suggests that it may be useful not only for diagnosis but also for patient counseling.
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http://dx.doi.org/10.1111/j.1540-8159.2010.02791.xDOI Listing
October 2010

Lack of association between genetic polymorphisms affecting sympathetic activity and tilt-induced vasovagal syncope.

Auton Neurosci 2010 Jun 2;155(1-2):98-103. Epub 2010 Feb 2.

Department, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.

Although the pathophysiology of vasovagal syncope is not completely understood, the involvement of sympathetic nervous system alterations has been suggested. Since predisposition to fainting during orthostatic challenge may be associated with genetic variations, we sought to explore the role of genetic polymorphisms affecting sympathetic nervous system function in the susceptibility to tilt-induced vasovagal syncope. We genotyped 129 subjects with recurrent unexplained syncope who underwent tilt testing, and investigated the recurrence of syncope. The analysed polymorphisms were Arg492Cys (ADRA1A gene), Ser49Gly and Arg389Gly (ADRB1), Arg16Gly and Gln27Glu (ADRB2), 825C/T (GNB3), -1021C/T (DBH) and S/L (SLC6A4). No association of the aforementioned genetic variants with both tilt test outcomes and new syncopal episodes during follow-up was found. None of the considered polymorphisms influencing sympathetic activity is a major risk factor for vasovagal syncope in Italian patients.
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http://dx.doi.org/10.1016/j.autneu.2010.01.002DOI Listing
June 2010

Prevalence, timing, and haemodynamic correlates of prodromes in patients with vasovagal syncope induced by head-up tilt test.

Europace 2009 Sep 1;11(9):1221-6. Epub 2009 Jul 1.

Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.

Aims: To evaluate the prevalence, timing, and haemodynamic characteristics of prodromal symptoms in patients experiencing vasovagal syncope (VVS) during a head-up tilt test (HUT) potentiated with nitroglycerin, and their relationships with those reported before spontaneous episodes.

Methods And Results: Symptoms preceding HUT-induced syncope were recorded, together with heart rate (HR) and arterial blood pressure (BP) values, in 149 otherwise healthy and drug-free subjects with recurrent unexplained syncope. Head-up tilt test significantly increase the number of patients capable of recognizing the premonitory symptoms of VVS than before spontaneous episodes (96 vs. 79%; P<0.001). The nine most frequent symptoms were stratified into three groups on the basis of their characteristics: headache, hot flashes, and palpitations occurred more than 3 min before syncope, with a very slight reduction in BP; nausea, asthenia, diaphoresis, vertigo, and epigastric discomfort preceded syncope by 1-3 min and were associated with a slight reduction in BP; and blurred vision appeared the last minute before syncope and was characterized by the lowest BP and HR values.

Conclusion: In comparison with spontaneous syncopal episodes, HUT allows the more frequent recognition of prodromes also providing useful information in terms of timing and haemodynamic characteristics of symptoms that may allow more tailored patient counselling.
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http://dx.doi.org/10.1093/europace/eup164DOI Listing
September 2009

Clinical predictors of head-up tilt test outcome during the nitroglycerin phase.

Clin Auton Res 2010 Jun 30;20(3):167-73. Epub 2009 Jun 30.

Cardiology Unit, Emergency and Organ Transplantation Department, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.

Objectives: Nitrate-stimulated head-up tilt testing (HUT) is currently recommended to confirm the diagnosis of vasovagal syncope in subjects with syncope of unknown origin. Given the few data currently available, the aim of this study was to assess correlations between nitrate-induced HUT outcomes and the clinical characteristics of patients.

Methods: Two hundred and thirty consecutive, otherwise healthy subjects with a history of recurrent unexplained syncope underwent HUT. After 10 min supine rest, they were tilted to 70 degrees , and the test was potentiated by the administration of 300 microg of nitroglycerin after 20 min.

Results: Out of 178 subjects who underwent nitroglycerin administration during HUT, 95 fainted. At univariate Cox regression analysis, a reduced probability of VVS occurrence after nitrates was associated with greater systolic blood pressure and body mass index values, to male gender and smoking. At multivariate Cox regression analysis, only male gender (HR = 0.61; P = 0.039) and smoking (HR = 0.18; P = 0.001) remained significantly associated with HUT outcomes during the pharmacological phase of the test.

Interpretation: Smokers and males are less likely to faint after nitrate administration during HUT than non-smokers and females. Further studies should clarify the possibility of improving the diagnostic power of HUT in these patients.
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http://dx.doi.org/10.1007/s10286-009-0020-7DOI Listing
June 2010

Endothelin system polymorphisms in tilt test-induced vasovagal syncope.

Clin Auton Res 2009 Dec 15;19(6):347-54. Epub 2009 Apr 15.

Emergency and Organ Transplantation Department, University of Bari, Italy.

Introduction: Genetics may be involved in the pathophysiology of vasovagal syncope. The 3A/4A polymorphism of the EDN1 gene affects the expression of endothelin-1, and the H323H T/C polymorphism of the EDNRA gene encoding for the endothelin type A receptor has been associated with cardiovascular pathologies. As the endothelin system participates in the regulation of cardiovascular homeostasis, the aim of this study was to analyse the role of these genetic variants in influencing tilt-induced vasovagal syncope.

Materials And Methods: We recorded the cardiovascular parameters of 107 otherwise healthy subjects with recurrent unexplained syncope who underwent a head-up tilt test; 58 (54%) fainted.

Results: In terms of the EDNRA polymorphism, eight subjects (8%) had the T/T genotype, 41 were heterozygous (38%) and 58 homozygous (54%) for the C allele. Sixty subjects (56%) carried homozygosis for the 3A allele of the EDN1 polymorphism and 47 were heterozygous (44%). The 4A allele was significantly more frequent in the patients who responded positively to the tilt test than in those who did not: the relative odds ratios and confidence intervals at univariate and multivariate analyses were respectively 2.37 (1.07-5.26) and 2.41 (1.05-5.49). Comparisons with a control group further supported these data. Among the tilt-positive patients, the carriers of the 4A allele were more likely to have a vasodepressive pattern than those who were homozygous for the 3A variant.

Conclusion: In conclusion, the 3A/4A polymorphism of the EDN1 gene affects susceptibility to syncope, and the 4A variant associated with increased endothhelin-1 expression may promote vasodepressive hemodynamic responses during tilt testing.
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http://dx.doi.org/10.1007/s10286-009-0008-3DOI Listing
December 2009

Endothelin system polymorphisms in tilt test-induced vasovagal syncope.

Clin Auton Res 2009 Apr 19;19(2):123-9. Epub 2009 Feb 19.

Cardiology Unit, Emergency and Organ Transplantation Dept., University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.

Objectives: As the endothelin system participates in the regulation of cardiovascular homeostasis, the aim of this study was to analyse the role of endothelin system polymorphisms in influencing tilt-induced vasovagal syncope.

Methods: We evaluated 107 otherwise healthy subjects with recurrent unexplained syncope who underwent a head-up tilt test. All subjects were genotyped for the 3A/4A polymorphism of the EDN1 gene and the H323H T/C polymorphism of the EDNRA gene.

Results: Fifty-eight patients (54%) fainted. In terms of the EDNRA polymorphism, eight subjects (8%) had the T/T genotype, 41 were heterozygous (38%) and 58 homozygous (54%) for the C allele. Sixty subjects (56%) carried homozygosis for the 3A allele of the EDN1 polymorphism and 47 were heterozygous (44%). The 4A allele was significantly more frequent in the patients who responded positively to the tilt test than in those who did not: the relative odds ratios and confidence intervals at univariate and multivariate analyses were respectively 2.37 (1.07-5.26) and 2.41 (1.05-5.49). Comparisons with a control group further supported these data. Among the tilt-positive patients, the carriers of the 4A allele were more likely to have a vasodepressive pattern than those who were homozygous for the 3A variant.

Interpretation: The 3A/4A polymorphism of the EDN1 gene affects susceptibility to syncope, and the 4A variant associated with increased endothelin-1 expression may promote vasodepressive hemodynamic responses during tilt testing.
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http://dx.doi.org/10.1007/s10286-009-0519-yDOI Listing
April 2009

Impaired arterial baroreflex function before nitrate-induced vasovagal syncope during head-up tilt test.

Europace 2008 Oct 22;10(10):1170-5. Epub 2008 Aug 22.

Cardiology Unit, Emergency and Organ Transplantation Department, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.

Aims: The aim of this study was to evaluate arterial baroreflex control of heart rate immediately before head-up tilt test (HUT)-induced vasovagal syncope (VVS).

Methods And Results: We enrolled 97 otherwise healthy subjects with recurrent unexplained syncope. After 10 min of rest in supine position, they underwent a passive HUT potentiated with nitroglycerin administration after 20 min. Beat-to-beat heart rate and systolic blood pressure were continuously recorded. Sequence method was used to measure two complementary parameters reflecting arterial baroreflex control of heart rate: the baroreflex sensitivity (BRS) and the baroreflex effectiveness index (BEI). Twenty-one patients fainted before nitrate administration (HUT+) and 37 after nitrate administration (NTG+). Immediately before syncope, the NTG+ patients showed significantly lower BRS values than those observed at the end of the test in the patients without syncope (5.5 +/- 2.8 vs. 7.7 +/- 3.4 ms/mmHg; P = 0.004) and a significantly lower BEI (30 +/- 20% vs. 53 +/- 24%; P < 0.001). The HUT+ patients did not show any significant differences in BRS and BEI before syncope from the values observed during the corresponding tilt period in the other groups.

Conclusion: A significant depression in BRS and BEI occurs immediately before syncope in patients who faint after nitrate administration, thus suggesting that arterial baroreflex dysfunction plays a role in mediating nitrate-induced VVS.
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http://dx.doi.org/10.1093/europace/eun217DOI Listing
October 2008

The 212A variant of the APJ receptor gene for the endogenous inotrope apelin is associated with slower heart failure progression in idiopathic dilated cardiomyopathy.

J Card Fail 2007 Sep;13(7):521-9

Department of Internal Medicine, University of Ancona-Politecnica delle Marche, Ancona, Italy.

Background: Idiopathic dilated cardiomyopathy (IDC) has multiple genetic and acquired causes. Apelin is an endogenous peptide that increases cardiac inotropism through his APJ receptor. No data are available concerning the APJ gene mutations responsible for IDC or on the role of APJ receptor gene variants in predicting heart failure (HF) progression.

Methods And Results: We prospectively evaluated 202 consecutive patients with IDC and 202 matched controls: 90 were screened for APJ gene mutations and all 202 were genotyped for G212A and A445C APJ receptor polymorphisms. No mutations were found within the coding or untranslated regions of the APJ receptor, and no differences in allelic or genotype frequencies were observed comparing patients with a healthy control population. The correlations between APJ receptor polymorphisms and HF progression were assessed. During a median follow-up of 37 months, 35 patients experienced HF progression. Univariate analysis showed that patients carrying at least 1 copy of 212A had a significantly lower risk for HF-related events than those who were homozygous for the G212 variant, and multivariate analysis confirmed that it was significantly related to a more favorable prognosis.

Conclusions: APJ is unlikely to be a gene causing IDC, but the independent correlation between the 212A allele and a better prognosis suggests that it might act as a modifier gene.
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http://dx.doi.org/10.1016/j.cardfail.2007.04.002DOI Listing
September 2007