Publications by authors named "Eloisa Arbustini"

228 Publications

On the Shades of Coronary Calcium and Plaque Instability.

J Am Coll Cardiol 2021 Apr;77(13):1612-1615

Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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http://dx.doi.org/10.1016/j.jacc.2021.02.011DOI Listing
April 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur Heart J 2021 Mar 3. Epub 2021 Mar 3.

Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.

Aims : Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.

Methods And Results : We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

Conclusion : This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehab030DOI Listing
March 2021

Myths to debunk: the non-compacted myocardium.

Eur Heart J Suppl 2020 Nov 18;22(Suppl L):L6-L10. Epub 2020 Nov 18.

Centre for Inherited Cardiovascular Diseases, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.

Left ventricular non-compaction (LVNC) is defined by the triad: prominent trabecular anatomy, thin compacted layer, and deep inter-trabecular recesses. No person, sick or healthy, demonstrates identical anatomy of the trabeculae; their configuration represents a sort of individual dynamic 'cardiac fingerprinting'. LVNC can be observed in healthy subjects with normal left ventricular (LV) size and function, in athletes, in pregnant women, as well as in patients with haematological disorders, neuromuscular diseases, and chronic renal failure; it can be acquired and potentially reversible. When LVNC is observed in patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy, restrictive cardiomyopathy, or arrhythmogenic cardiomyopathy, the risk exists of misnaming the cardiomyopathy as 'LVNC cardiomyopathy' rather than properly describe, i.e. a 'DCM associated with LVNC'. In rare infantile CMPs (the paradigm is tafazzinopathy or Barth syndrome), the non-compaction (NC) is intrinsically part of the cardiac phenotype. The LVNC is also common in congenital heart disease (CHD) as well as in chromosomal disorders with systemic manifestations. The high prevalence of LVNC in healthy athletes, its possible reversibility or regression, and the increasing detection in healthy subjects suggest a cautious use of the term 'LVNC cardiomyopathy', which describes the morphology, but not the functional profile of the cardiac disease. Genetic testing, when positive, usually reflects the genetic causes of an underlying cardiomyopathy rather than that of the NC, which often does not segregate with CMP phenotype in families. Therefore, when associated with LV dilation and dysfunction, hypertrophy, or CHD, the leading diagnosis is cardiomyopathy or CHD followed by the descriptor LVNC.
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http://dx.doi.org/10.1093/eurheartj/suaa124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904063PMC
November 2020

Epidemiology of cardiomyopathies: essential context knowledge for a tailored clinical work-up.

Eur J Prev Cardiol 2020 Nov 7. Epub 2020 Nov 7.

Department of Clinical Cardiology, Policlinico di Monza, Via Carlo Amati, 111, 20900 Monza, Italy.

Cardiomyopathies (CMPs) are primary disorders of myocardial structure and function in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease. Knowledge of the incidence and prevalence of CMPs may help clinicians to compare their observations in clinical practice with expected cases per person-year and to avoid under-reporting in clinical context. Currently, available estimates of prevalence and incidence of CMPs are based on clinical data, collected with a wide variability in population-source, and before the genetic testing evolved as a standard diagnostic tool. This review focuses on the epidemiology of CMPs in subjects aged between 18 and 55 years. A structured up-to-date diagnostic flow-chart for CMPs diagnosis and assessment is proposed to avoid misdiagnosis of CMPs in the young population and in subjects with unexplained cardiac disorders.
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http://dx.doi.org/10.1093/eurjpc/zwaa035DOI Listing
November 2020

Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week.

J Am Coll Cardiol 2021 Feb;77(7):922-936

Hôpitaux Universitaires de Genève, Genève, Switzerland.

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.
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http://dx.doi.org/10.1016/j.jacc.2020.12.024DOI Listing
February 2021

Potential of an Approach Based on the Identification and Treatment of Vulnerable Coronary Plaques.

JACC Cardiovasc Interv 2021 Feb;14(4):468-473

Department of Cardiology, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, IIS-IP, CIBER-CV, Madrid, Spain.

In this viewpoint paper, the authors are tackling criticism to the limits of invasive imaging modalities for identification and treatment of vulnerable plaques. They believe in the clinical usefulness of invasive imaging modalities for identification of vulnerable plaques, and are suggesting an explanation for the suboptimal results of past studies, that failed to demonstrate a correlation between interventional treatment of vulnerable plaques, and reduction of hard clinical endpoints. Vulnerability studies have been based, so far, on the detection and measurement of plaques lipid content, because of its ease. However, the search for lipid "lakes" as a single common causal feature of acute coronary syndromes does not seem sufficient to identify patients at risk of adverse events. New imaging studies provided the rationale for improving clinical outcomes, adopting a more comprehensive assessment of target plaque morphology. There is little rationale in pursuing a functional assessment of coronary lesions to predict myocardial infarction. Recent studies are further confirming this hypothesis, suggesting that the clinical benefit of the fractional flow reserve-guided strategy is simply due to a significant reduction in the rate of repeated revascularizations, with no significant differences in the incidence of hard endpoints. There is a need to develop new randomized studies, requiring a feasible number of patients, to test the superiority of an approach based on vulnerable plaque sealing and treatment.
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http://dx.doi.org/10.1016/j.jcin.2020.12.033DOI Listing
February 2021

Multivessel endovascular therapy for undiagnosed vascular type Ehlers-Danlos syndrome. Successful percutaneous transcatheter coil embolization of hepatic artery pseudoaneurysm with stenting of right renal and iliac arteries in emergency setting.

BJR Case Rep 2020 Dec 6;6(4):20200025. Epub 2020 Jul 6.

Centre for Inherited Cardiovascular Diseases of Cardio-Thoracic-Vascular Surgery Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

Among Ehlers-Danlos syndromes, the vascular type is the most severe because of its vascular complications. Transcatheter embolization of medium-sized arteries has become the first-line therapy for life-threatening hemorrhage. Ongoing multiple lesions causing hemorrhagic or ischemic complications in the acute phase can challenge patient management. Multivessel endovascular treatment has never been reported. In this study, we report successful single-session treatment by coiling of a ruptured pseudoaneurysm of the hepatic artery with stenting of dissected right renal and iliac arteries in a 46-year-old female. Percutaneous transfemoral approach was gained and sealed with a plug-based closure device. Genetic disease was subsequently confirmed by molecular analysis.
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http://dx.doi.org/10.1259/bjrcr.20200025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709055PMC
December 2020

Broncho-alveolar inflammation in COVID-19 patients: a correlation with clinical outcome.

BMC Pulm Med 2020 Nov 16;20(1):301. Epub 2020 Nov 16.

University of Pavia and Pneumology Unit, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19.

Methods: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels.

Results: ICU patients showed a marked increase in neutrophils (1.24 × 10 ml, 0.85-2.07), lower lymphocyte (0.97 × 10 ml, 0.024-0.34) and macrophages fractions (0.43 × 10 ml, 0.34-1.62) compared to IMW patients (0.095 × 10 ml, 0.05-0.73; 0.47 × 10 ml, 0.28-1.01 and 2.14 × 10 ml, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05).

Conclusions: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.
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http://dx.doi.org/10.1186/s12890-020-01343-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668012PMC
November 2020

Analysis of the SARS-CoV-2 epidemic in Italy: The role of local and interventional factors in the control of the epidemic.

PLoS One 2020 12;15(11):e0242305. Epub 2020 Nov 12.

Laboratorio Genetica-Trapiantologia e Malattie Cardiovascolari, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Containment measures have been applied in several countries in order to limit the diffusion of the SARS-CoV-2 epidemic. The scope of this study is to analyze the evolution of the first wave of the SARS-CoV-2 epidemic throughout Italy and factors associated to the different way it spread in the Italian Regions, starting from the day that the first indigenous cases were detected through day 81 (6 days after the end of the strict lockdown). Data were obtained from daily reports and are represented as number (and percentage) of cases/100,000 persons. A lockdown with movement restrictions, especially across Regions, was declared at day 20. At day 81, 219,070 cases (363/100,000 persons) were diagnosed. A regression analysis based on the Gompertz model predicts a total number 233,606 cases (386/100,000 persons) at the end of the epidemic. The 21 areas, divided into Italian Regions and autonomous Provinces, showed a wide range in the frequency of cases at day 81 (58-921, median 258/100,000 persons) and total predicted cases (58-946, median 267/100,000 persons). Similarly, the predicted time for the end of the wave of the epidemic (considering as surrogate marker the time at which 99% of the total cases are predicted to occur) was highly variable, ranging from 64 to 136 (median 99) days. We analyzed the impact of local and interventional variables on the epidemic curve in each Region. The number of cases correlated inversely with the distance from the area in which first cases were detected and directly also with the gross domestic product pro capite (as a marker of industrial activity) of the Region. Moreover, an earlier start of the lockdown (i.e. in the presence of a lower number of cases) and wider testing were associated with a lower final number of total cases. In conclusion, this analysis shows that population-wide testing and early lockdown enforcement appear effective in limiting the spreading of the SARS-CoV-2 epidemic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242305PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660511PMC
November 2020

Molecular Imaging of Apoptosis in Atherosclerosis by Targeting Cell Membrane Phospholipid Asymmetry.

J Am Coll Cardiol 2020 10;76(16):1862-1874

Icahn School of Medicine at Mount Sinai, New York, New York.

Background: Apoptosis in atherosclerotic lesions contributes to plaque vulnerability by lipid core enlargement and fibrous cap attenuation. Apoptosis is associated with exteriorization of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell membrane. Although PS-avid radiolabeled annexin-V has been employed for molecular imaging of high-risk plaques, PE-targeted imaging in atherosclerosis has not been studied.

Objectives: This study sought to evaluate the feasibility of molecular imaging with PE-avid radiolabeled duramycin in experimental atherosclerotic lesions in a rabbit model and compare duramycin targeting with radiolabeled annexin-V.

Methods: Of the 27 rabbits, 21 were fed high-cholesterol, high-fat diet for 16 weeks. Nine of the 21 rabbits received Tc-duramycin (test group), 6 received Tc-linear duramycin (duramycin without PE-binding capability, negative radiotracer control group), and 6 received Tc-annexin-V for radionuclide imaging. The remaining normal chow-fed 6 animals (disease control group) received Tc-duramycin. In vivo microSPECT/microCT imaging was performed, and the aortas were explanted for ex vivo imaging and for histological characterization of atherosclerosis.

Results: A significantly higher duramycin uptake was observed in the test group compared with that of disease control and negative radiotracer control animals; duramycin uptake was also significantly higher than the annexin-V uptake. Quantitative duramycin uptake, represented as the square root of percent injected dose per cm (√ID/cm) of abdominal aorta was >2-fold higher in atherosclerotic lesions in test group (0.08 ± 0.01%) than in comparable regions of disease control animals (0.039 ± 0.0061%, p = 3.70·10). Mean annexin uptake (0.060 ± 0.010%) was significantly lower than duramycin (p = 0.001). Duramycin uptake corresponded to the lesion severity and macrophage burden. The radiation burden to the kidneys was substantially lower with duramycin (0.49% ID/g) than annexin (5.48% ID/g; p = 4.00·10).

Conclusions: Radiolabeled duramycin localizes in lipid-rich areas with high concentration of apoptotic macrophages in the experimental atherosclerosis model. Duramycin uptake in atherosclerotic lesions was significantly greater than annexin-V uptake and produced significantly lower radiation burden to nontarget organs.
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http://dx.doi.org/10.1016/j.jacc.2020.08.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654709PMC
October 2020

Prospective follow-up in various subtypes of cardiomyopathies: insights from the ESC EORP Cardiomyopathy Registry.

Eur Heart J Qual Care Clin Outcomes 2021 Mar;7(2):134-142

Sorbonne Université, Centre de Référence des Maladies Cardiaques Héréditaires, Assistance Publique-Hôpitaux de Paris, ICAN, Inserm, UMR1166, Hôpital Pitié-Salpêtrière, Paris, France.

Aims: The European Society of Cardiology (ESC) European Observational Research Programme (EORP) Cardiomyopathy Registry is a prospective multinational registry of consecutive patients with cardiomyopathies. The objective of this report is to describe the short-term outcomes of adult patients (≥18 years old).

Methods And Results: Out of 3208 patients recruited, follow-up data at 1 year were obtained in 2713 patients (84.6%) [1420 with hypertrophic (HCM); 1105 dilated (DCM); 128 arrhythmogenic right ventricular (ARVC); and 60 restrictive (RCM) cardiomyopathies]. Improvement of symptoms (dyspnoea, chest pain, and palpitations) was globally observed over time (P < 0.05 for each). Additional invasive procedures were performed: prophylactic implantation of implantable cardioverter-defibrillator (ICD) (5.2%), pacemaker (1.2%), heart transplant (1.1%), ablation for atrial or ventricular arrhythmia (0.5% and 0.1%). Patients with atrial fibrillation increased from 28.7% to 32.2% of the cohort. Ventricular arrhythmias (VF/ventricular tachycardias) in ICD carriers (primary prevention) at 1 year were more frequent in ARVC, then in DCM, HCM, and RCM (10.3%, 8.2%, 7.5%, and 0%, respectively). Major cardiovascular events (MACE) occurred in 29.3% of RCM, 10.5% of DCM, 5.3% of HCM, and 3.9% of ARVC (P < 0.001). MACE were more frequent in index patients compared to relatives (10.8% vs. 4.4%, P < 0.001), more frequent in East Europe centres (13.1%) and least common in South Europe (5.3%) (P < 0.001). Subtype of cardiomyopathy, geographical region, and proband were predictors of MACE on multivariable analysis.

Conclusions: Despite symptomatic improvement, patients with cardiomyopathies remain prone to major clinical events in the short term. Outcomes were different not only according to cardiomyopathy subtypes but also in relatives vs. index patients, and according to European regions.
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http://dx.doi.org/10.1093/ehjqcco/qcaa075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962774PMC
March 2021

Prevalence and quantitative assessment of macrophages in coronary plaques.

Int J Cardiovasc Imaging 2021 Jan 10;37(1):37-45. Epub 2020 Aug 10.

Centro per la Lotta Contro L'Infarto - CLI Foundation, Rome, Italy.

Although optical coherence tomography (OCT) proved to be able to identify macrophage clusters, there are no available data on the possibility to obtain reproducible measurements of their circumferential extension and location. The purpose of the present post-hoc analysis of the CLIMA study was to revise the clinical and demographic variables of patients having coronary plaques with macrophages and to investigate the reproducibility of their quantitative assessment. A total of 577 patients out of 1003 undergoing OCT showed macrophage accumulation. Three groups were identified; group 1 (426 patients) without macrophages, group 2 (296) patients with low macrophage content (less than median value [67°] of circumferential arc) and group 3 (281) with high macrophage content arc [> 67°]. Patients with macrophages (groups 2 and 3) showed a higher prevalence of family history for coronary artery disease and hypercholesterolemia and had a significantly larger body mass index. Furthermore, group 3 had more commonly triple vessel disease and higher value of LDL cholesterol levels compared to the two other groups. The inter-observer agreement for macrophage interpretation was good: R values were 0.97 for the circumferential arc extension, 0.95 for the minimum distance and 0.98 for the mean distance. A non-significant correlation between circumferential extension of macrophages and hsCRP values was found (R = 0.013). Quantitative assessment of macrophage accumulations can be obtained with high reproducibility by OCT. The presence and amount of macrophages are poorly correlated with hsCRP and identify patients with more advanced atherosclerosis and higher LDL cholesterol levels.
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http://dx.doi.org/10.1007/s10554-020-01957-8DOI Listing
January 2021

Rare exon 10 deletion in POLH gene in a family with xeroderma pigmentosum variant correlating with protein expression by immunohistochemistry.

G Ital Dermatol Venereol 2020 Jun;155(3):349-354

Laboratories of Experimental Research in Transplantation, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by severe cutaneous and ocular sensitivity to sunlight, leading to skin cancer. Most XP patients belong to the XP complementation groups (XP-A to XP-G), due to mutations in genes involved in nucleotide excision repair (NER). On the other hand, the XP Variant type (XP-V, OMIM#278750), which accounts for about 20% of all XP patients, is associated with normal NER function. The disease gene is POLH, which encodes polymerase η (pol η) allowing translesion synthesis in regions of DNA damage. We observed an Italian family presenting with photosensitivity, freckling since childhood and multiple skin cancers. Complete sequence analysis of XPA, XPC, XPD/ERCC2 genes and exons 1-9 and 11 of POLH gene did not reveal pathological mutations. No PCR product was observed for exon 10 in POLH gene. By RT-PCR analysis followed by POLH exon 10 sequencing, all affected members were found to harbor a homozygous 170-nucleotide deletion. The same deletion was previously described in 3 XP-V families, one of southern Italian descent and two from Algeria, suggesting a possible founder mutation. The deletion determines a severe protein truncation and defective pol η activity. Immunohistochemical study showed markedly reduced pol η expression in skin lesions of the affected siblings compared to the normal control skin.
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http://dx.doi.org/10.23736/S0392-0488.16.05158-0DOI Listing
June 2020

A Multidimensional Approach of Surgical Mortality Assessment and Stratification (Smatt Score).

Sci Rep 2020 07 3;10(1):10964. Epub 2020 Jul 3.

Medical Direction, Foundation IRCCS San Matteo Hospital, Viale Golgi 19, 27100, Pavia, Italy.

Surgical mortality is the most significant measure of outcome in surgical healthcare. The objective was to assess surgical 30 days mortality and improve the identification of predictors for personalized risk stratification of patients undergoing elective and emergency surgery. The study was conducted as a single-center cohort retrospective observational study, based on the analysis of data collected from patients surgically treated from 2002 to 2014 in a multi-disciplinary research and care referral hospital with global case mix of 1.27. The overall in-hospital mortality rate was 1.89% (95% CI 1.82-1.95). In the univariable analysis, numerous predictors were significantly associated with in-hospital death following surgery. In the multivariable model, age, BMI (Body Mass Index), ASA score, department, planned surgical complexity, surgical priority, previous surgeries in the same hospitalization, cardiovascular, pulmonary, hepato-renal comorbidities, drug intolerance, cancer and AIDS were independently associated with mortality after surgery. At logistic regression, the computed SMATT score (graded 0-100), generated on the basis of multivariate analysis, demonstrated a good discrimination (10-fold cross-validated AUC-ROC 0.945, 95%CI 0.941-0.948) and correctly classified 98.5% of those admissions with a probability of death >50%. The novel SMATT score, based on individual preoperative and surgical factors, accurately predicts mortality and provides dynamic information of the risk in redo/reoperative surgery.
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http://dx.doi.org/10.1038/s41598-020-67164-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335058PMC
July 2020

Pathologic substrate of gastropathy in Anderson-Fabry disease.

Orphanet J Rare Dis 2020 06 22;15(1):156. Epub 2020 Jun 22.

Center for Inherited Cardiovascular Diseases, Transplant Research Area, Fondazione IRCCS Policlinico San Matteo, Piazzale Golgi 19, 27100, Pavia, Italy.

In both classic and late-onset AFD, mutations of the GLA gene cause deficient activity of the alpha-galactosidase enzyme resulting in intracellular accumulation of the undigested substrate. Gastrointestinal symptoms (GI) are common but non-specific and imputed to the AFD, irrespective of the demonstration of substrate accumulation in GI cells. We demonstrate substrate accumulation in gastric epithelial, vascular, and nerve cells of patients with classic AFD and, vice versa, absence of accumulation in late-onset AFD and controls.
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http://dx.doi.org/10.1186/s13023-020-01436-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310490PMC
June 2020

POPDC2 a novel susceptibility gene for conduction disorders.

J Mol Cell Cardiol 2020 08 11;145:74-83. Epub 2020 Jun 11.

Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior MCMBB, Philipps-University of Marburg, Marburg, Germany. Electronic address:

Despite recent progress in the understanding of cardiac ion channel function and its role in inherited forms of ventricular arrhythmias, the molecular basis of cardiac conduction disorders often remains unresolved. We aimed to elucidate the genetic background of familial atrioventricular block (AVB) using a whole exome sequencing (WES) approach. In monozygotic twins with a third-degree AVB and in another, unrelated family with first-degree AVB, we identified a heterozygous nonsense mutation in the POPDC2 gene causing a premature stop at position 188 (POPDC2), deleting parts of its cAMP binding-domain. Popeye-domain containing (POPDC) proteins are predominantly expressed in the skeletal muscle and the heart, with particularly high expression of POPDC2 in the sinoatrial node of the mouse. We now show by quantitative PCR experiments that in the human heart the POPDC-modulated two-pore domain potassium (K) channel TREK-1 is preferentially expressed in the atrioventricular node. Co-expression studies in Xenopus oocytes revealed that POPDC2 causes a loss-of-function with impaired TREK-1 modulation. Consistent with the high expression level of POPDC2 in the murine sinoatrial node, POPDC2 knock-in mice displayed stress-induced sinus bradycardia and pauses, a phenotype that was previously also reported for POPDC2 and TREK-1 knock-out mice. We propose that the POPDC2 loss-of-function mutation contributes to AVB pathogenesis by an aberrant modulation of TREK-1, highlighting that POPDC2 represents a novel arrhythmia gene for cardiac conduction disorders.
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http://dx.doi.org/10.1016/j.yjmcc.2020.06.005DOI Listing
August 2020

Hereditary muscle diseases and the heart: the cardiologist's perspective.

Eur Heart J Suppl 2020 Jun 29;22(Suppl E):E13-E19. Epub 2020 Mar 29.

Centre for Inherited Cardiovascular Diseases, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.

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http://dx.doi.org/10.1093/eurheartj/suaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270924PMC
June 2020

A New Pathway Promotes Adaptation of Human Glioblastoma Cells to Glucose Starvation.

Cells 2020 05 18;9(5). Epub 2020 May 18.

Neurosurgery, Dipartimento di Scienze Clinico-Chirurgiche e Pediatriche, Università degli Studi di Pavia, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.

Adaptation of glioblastoma to caloric restriction induces compensatory changes in tumor metabolism that are incompletely known. Here we show that in human glioblastoma cells maintained in exhausted medium, SHC adaptor protein 3 (SHC3) increases due to down-regulation of SHC3 protein degradation. This effect is reversed by glucose addition and is not present in normal astrocytes. Increased SHC3 levels are associated to increased glucose uptake mediated by changes in membrane trafficking of glucose transporters of the solute carrier 2A superfamily (GLUT/SLC2A). We found that the effects on vesicle trafficking are mediated by SHC3 interactions with adaptor protein complex 1 and 2 (AP), BMP-2-inducible protein kinase and a fraction of poly ADP-ribose polymerase 1 (PARP1) associated to vesicles containing GLUT/SLC2As. In glioblastoma cells, PARP1 inhibitor veliparib mimics glucose starvation in enhancing glucose uptake. Furthermore, cytosol extracted from glioblastoma cells inhibits PARP1 enzymatic activity in vitro while immunodepletion of SHC3 from the cytosol significantly relieves this inhibition. The identification of a new pathway controlling glucose uptake in high grade gliomas represents an opportunity for repositioning existing drugs and designing new ones.
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http://dx.doi.org/10.3390/cells9051249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290719PMC
May 2020

Clinical outcomes of calcified nodules detected by optical coherence tomography: a sub-analysis of the CLIMA study.

EuroIntervention 2020 Aug;16(5):380-386

Cardiovascular Sciences Department, San Giovanni Addalorata Hospital, Rome, Italy.

Aims: The goal of the present post hoc analysis of the CLIMA registry was to establish the relationship between calcified nodules (CNs) with (CND) or without (CNWD) disruption of the superficial intimal fibrous layer and one-year occurrence of target lesion myocardial infarction (MI) and/or cardiac death.

Methods And Results: CND and CNWD were identified based on the presence or absence of superficial irregularities indicative of disruption of the intimal fibrous layer, with possible overlying local thrombus. In total, 222 CNs were found in the 1,776 non-culprit LAD plaques. CND had larger maximum calcific arc and smaller lumen area. Cardiac death and MI occurred in 20% of patients in the CND group versus 2.7% in the CNWD group and 3.3% in the group without CN (p<0.001). This figure was mainly due to the 13.3% incidence of cardiac death in the CND group versus 2.0% in the CNWD group and versus 2.2% in the group without CN (p<0.001). The presence of CND was confirmed as an independent predictor of events (HR 6.58, 95% CI: 2.7-15.8, p<0.001).

Conclusions: The presence of CND was associated with a high one-year incidence of cardiac death and/or target lesion MI.
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http://dx.doi.org/10.4244/EIJ-D-19-01120DOI Listing
August 2020

Myocardial localization of coronavirus in COVID-19 cardiogenic shock.

Eur J Heart Fail 2020 05 11;22(5):911-915. Epub 2020 Apr 11.

Transplant Research Area and Centre for Inherited Cardiovascular Diseases, Department of Medical Sciences and Infectious Diseases, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.

We describe the first case of acute cardiac injury directly linked to myocardial localization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a 69-year-old patient with flu-like symptoms rapidly degenerating into respiratory distress, hypotension, and cardiogenic shock. The patient was successfully treated with venous-arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation. Cardiac function fully recovered in 5 days and ECMO was removed. Endomyocardial biopsy demonstrated low-grade myocardial inflammation and viral particles in the myocardium suggesting either a viraemic phase or, alternatively, infected macrophage migration from the lung.
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http://dx.doi.org/10.1002/ejhf.1828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262276PMC
May 2020

Renal and brain complications in GLA p.Phe113Leu Fabry disease. Comments on "Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: Natural history in males" by Oliveira et al. (Eur. J. Med. Genet. 2019).

Eur J Med Genet 2020 04 13;63(4):103847. Epub 2020 Jan 13.

Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ejmg.2020.103847DOI Listing
April 2020

Familial cardiomyopathy caused by a novel heterozygous mutation in the gene (c.1434dupG): a cardiac MRI-augmented segregation study.

Acta Myol 2019 Sep 1;38(3):159-162. Epub 2019 Sep 1.

Barts Heart Center, The Cardiovascular Magnetic Resonance Imaging Unit, St Bartholomew's Hospital, West Smithfield, London, UK.

In a five-generation family carrying a novel frameshift variant (c.1434dupG, p.Leu479AlafsX72), imaging-augmented segregation analysis supports its association with lamin heart disease. Affected members exhibit conduction abnormalities, supraventricular and ventricular arrythmias, dilated cardiomyopathy with non-infarct pattern midwall septal fibrosis, heart failure and thromboembolic complications.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859410PMC
September 2019

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants.

Orphanet J Rare Dis 2019 11 21;14(1):264. Epub 2019 Nov 21.

VASCERN HTAD European Reference Centre, Ghent, Belgium.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.
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http://dx.doi.org/10.1186/s13023-019-1186-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868850PMC
November 2019

Diagnostic Criteria of Left Ventricular Dysfunction in Patients With Myotonic Dystrophy Type 1.

J Card Fail 2020 10 8;26(10):857-859. Epub 2019 Oct 8.

Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.cardfail.2019.09.016DOI Listing
October 2020

Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome: the CLIMA study.

Eur Heart J 2020 01;41(3):383-391

Centre for Inherited Cardiovascular Diseases, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

Aims: The CLIMA study, on the relationship between coronary plaque morphology of the left anterior descending artery and twelve months clinical outcome, was designed to explore the predictive value of multiple high-risk plaque features in the same coronary lesion [minimum lumen area (MLA), fibrous cap thickness (FCT), lipid arc circumferential extension, and presence of optical coherence tomography (OCT)-defined macrophages] as detected by OCT. Composite of cardiac death and target segment myocardial infarction was the primary clinical endpoint.

Methods And Results: From January 2013 to December 2016, 1003 patients undergoing OCT evaluation of the untreated proximal left anterior descending coronary artery in the context of clinically indicated coronary angiogram were prospectively enrolled at 11 independent centres (clinicaltrial.gov identifier NCT02883088). At 1-year, the primary clinical endpoint was observed in 37 patients (3.7%). In a total of 1776 lipid plaques, presence of MLA <3.5 mm2 [hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.1-4.0], FCT <75 µm (HR 4.7, 95% CI 2.4-9.0), lipid arc circumferential extension >180° (HR 2.4, 95% CI 1.2-4.8), and OCT-defined macrophages (HR 2.7, 95% CI 1.2-6.1) were all associated with increased risk of the primary endpoint. The pre-specified combination of plaque features (simultaneous presence of the four OCT criteria in the same plaque) was observed in 18.9% of patients experiencing the primary endpoint and was an independent predictor of events (HR 7.54, 95% CI 3.1-18.6).

Conclusion: The simultaneous presence of four high-risk OCT plaque features was found to be associated with a higher risk of major coronary events.
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http://dx.doi.org/10.1093/eurheartj/ehz520DOI Listing
January 2020

Management of the axilla in patients with breast cancer and positive sentinel lymph node biopsy: An evidence-based update in a European breast center.

Eur J Surg Oncol 2020 01 13;46(1):15-23. Epub 2019 Aug 13.

Breast Center, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Pavia, Italy.

The surgical approach to the axilla in breast cancer has been a controversial issue for more than three decades. Data from recently published trials have provided practice-changing recommendations in this scenario. However, further controversies have been triggered in the surgical community, resulting in heterogeneous diffusion of these recommendations. The development of clinical guidelines for the management of the axilla in patients with breast cancer is a work in progress. A multidisciplinary team discussion was held at the research hospital Policlinico San Matteo from the Università degli Studi di Pavia with the aim to update recommendations for the management of the axilla in patients with breast cancer. An evidence-based approach is presented. Our multidisciplinary panel determined that axillary dissection after a positive sentinel lymph node biopsy may be avoided in cN0 patients with micro/macrometastasis to ≤2 sentinel nodes, with age ≥40y, lesions ≤3 cm, who have not received neoadjuvant chemotherapy and have planned breast conservation (BCS) with whole breast radiotherapy (WBRT). Cases with gross (>2 mm) ECE in SLNs are evaluated on individual basis for completion ALND, axillary radiotherapy or omission of both. Patients fulfilling the criteria listed above who undergo mastectomy, may also avoid axillary dissection after multidisciplinary discussion of individual cases for consideration of axillary irradiation. Women 70 years or older with hormone receptors positive invasive lesions ≤3 cm, clinically negative nodes, and serious or multiple comorbidities who undergo BCS with WBRT, may forgo axillary staging/surgery (if mastectomy or larger tumor, comorbidities and life expectancy are taken into account).
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http://dx.doi.org/10.1016/j.ejso.2019.08.013DOI Listing
January 2020

Age-specific reference values for carotid arterial stiffness estimated by ultrasonic wall tracking.

J Hum Hypertens 2020 03 21;34(3):214-222. Epub 2019 Aug 21.

Wales Heart Research Institute, School of Medicine, Cardiff University, Cardiff, UK.

Interaction between arterial stiffness and hypertension plays an important role in the development of cardiovascular disease. Accordingly, assessment of arterial stiffness may provide a tool for estimating cardiovascular risk and monitoring therapy in hypertensive patients. Radiofrequency-based vascular ultrasound allows accurate noninvasive assessment of local mechanical properties of large arteries, but for its use in clinical practice, reference values according to age and sex are mandatory for each vascular site. To provide reference values for common carotid artery stiffness as assessed by an echo-tracking imaging system Hitachi-Aloka, we pooled measurements collected in 1847 healthy subjects aged 3-74 years (1008 males and 839 females) recruited in 14 European centers in the E-tracking International Collaboration (ETIC). Statistical models were developed to describe relationships of different stiffness indices with age and to calculate median values and Z-scores corresponding to ± 1 and ± 2 standard deviations. In our apparently healthy population, age accounted for 53% of variability in the elastic modulus (epsilon), 39% in arterial compliance, 47% in stiffness index (β), and 56% in local pulse wave velocity; on average, blood pressure accounted for a further 7.5% of variability. Dependence on age was not linear; changes in mean values increased at older ages, especially for epsilon and β. There was an interaction between age and gender for arterial compliance, which was higher in males. We present nomograms and a software that can be used for the automated calculation of Z-scores for local carotid stiffness in individual patients. These tools can be used to establish prognostic indicators or surrogate targets for treatment monitoring.
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http://dx.doi.org/10.1038/s41371-019-0228-5DOI Listing
March 2020

Mid-regional proatrial natriuretic peptide for predicting prognosis in hypertrophic cardiomyopathy.

Heart 2020 02 26;106(3):196-202. Epub 2019 Jul 26.

Département de Cardiologie, Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), ACTION Study Group, INSERM UMRS 1166, Paris 75013, France.

Objectives: N-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM.

Methods: We prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion.

Results: Of 357 patients enrolled, the median age was 52 (IQR: 36-65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p<10) were strongly associated with the primary endpoint, and the areas under the receiver operating characteristic (ROC) curves for both peptides were not significantly different. However, in a multiple stepwise regression analysis, the best model for predicting outcome was NYHA 1-2 vs 3-4 (HR=0.35, 95% CI 0.16 to 0.77, p<0.01), LVEF (HR=0.96, 95% CI 0.94 to 0.98, p=0.0005) and MR-proANP (HR=3.77, 95% CI 2.01 to 7.08, p<0.0001).

Conclusions: MR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.
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http://dx.doi.org/10.1136/heartjnl-2019-314826DOI Listing
February 2020