Publications by authors named "Francesco Violi"

370 Publications

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways.

Int J Mol Sci 2021 Jul 3;22(13). Epub 2021 Jul 3.

I Clinica Medica, Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy.

Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. In a multicenter before-after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 ( < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.
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http://dx.doi.org/10.3390/ijms22137193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267646PMC
July 2021

Impaired Clinical Efficacy of Aspirin in Hypoalbuminemic Patients With Diabetes Mellitus.

Front Pharmacol 2021 22;12:695961. Epub 2021 Jun 22.

Department of Clinical, Internal, Anaesthesiological, and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

To investigate the impact of albumin levels on the aspirin efficacy, since aspirin inhibits platelet aggregation (PA) by cyclooxygenase one irreversible acetylation that is less effective in patients with type 2 diabetes mellitus (T2DM). A total of 612 aspirin (100 mg/day)-treated T2DM patients were followed-up for 54.4 ± 7.3 months. The primary endpoint, a composite of cardiovascular events (CVEs) including CV death, myocardial infarction, ischemic stroke and coronary revascularization, was analysed according to baseline values of serum albumin (≥ or < 3.5 g/dL). Serum thromboxane (Tx)B was also measured. 250 (40.8%) patients had serum albumin < 3.5 g/dL; these patients were overweight and had higher values of fibrinogen ( = 0.009), high sensitivity C-reactive protein ( = 0.001) and fasting plasma glucose ( < 0.0001) compared to those with albumin ≥ 3.5 g/dL. During follow-up, 86 CVEs were recorded, 49 and 37 in patients with serum albumin < or ≥3.5 g/dL, respectively ( = 0.001). At multivariable Cox regression analysis, serum albumin < 3.5 g/dL (hazard ratio [HR] 1.887, 95% confidence interval [CI] 1.136-3.135, = 0.014), age (HR 1.552 for every 10 years, 95%CI 1.157-2.081, = 0.003), fasting plasma glucose (HR 1.063, 95%CI 1.022-1.105, = 0.002) and beta-blocker use (HR 0.440, 95%CI 0.270-0.717, = 0.001) were associated to CVEs. Serum TxB levels ( = 377) were 0.32 ± 0.12 and 0.24 ± 0.12 ng/ml in patients with albumin < or ≥ 3.5 g/dL, respectively ( < 0.001). In T2DM patients, the efficacy of aspirin varies according to albumin levels. Hypoalbuminemia associated with impaired TxB inhibition and an increased risk of long-term CVEs.
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http://dx.doi.org/10.3389/fphar.2021.695961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258313PMC
June 2021

Arterial and venous thrombosis in coronavirus 2019 disease (Covid-19): relationship with mortality.

Intern Emerg Med 2021 08 4;16(5):1231-1237. Epub 2021 Jul 4.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.

Background: Patients with coronavirus disease 2019 (Covid-19) may experience venous thrombosis while data regarding arterial thrombosis are sparse.

Methods: Prospective multicenter study in 5 hospitals including 373 patients with Covid-19-related pneumonia. Demographic data, laboratory findings including coagulation tests and comorbidities were reported. During the follow-up any arterial or venous thrombotic events and death were registered.

Results: Among 373 patients, 75 (20%) had a thrombotic event and 75 (20%) died. Thrombotic events included 41 venous thromboembolism and 34 arterial thrombosis. Age, cardiovascular disease, intensive care unit treatment, white blood cells, D-dimer, albumin and troponin blood levels were associated with thrombotic events. In a multivariable regression logistic model, intensive care unit treatment (Odds Ratio [OR]: 6.0; 95% Confidence Interval [CI] 2.8-12.6; p < 0.001); coronary artery disease (OR: 2.4; 95% CI 1.4-5.0; p = 0.022); and albumin levels (OR: 0.49; 95% CI 0.28-0.87; p = 0.014) were associated with ischemic events. Age, sex, chronic obstructive pulmonary disease, diabetes, heart failure, coronary heart disease, intensive care unit treatment, in-hospital thrombotic events, D-dimer, C-reactive protein, troponin, and albumin levels were associated with mortality. A multivariable Cox regression analysis showed that in-hospital thrombotic events (hazard ratio [HR]: 2.72; 95% CI 1.59-4.65; p < 0.001), age (HR: 1.035; 95% CI 1.014-1.057; p = 0.001), and albumin (HR: 0.447; 95% CI 0.277-0.723; p = 0.001) predicted morality.

Conclusions: Covid-19 patients experience an equipollent rate of venous and arterial thrombotic events, that are associated with poor survival. Early identification and appropriate treatment of Covid-19 patients at risk of thrombosis may improve prognosis.
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http://dx.doi.org/10.1007/s11739-020-02621-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255055PMC
August 2021

Impact of chronic use of heat-not-burn cigarettes on oxidative stress, endothelial dysfunction and platelet activation: the SUR-VAPES Chronic Study.

Thorax 2021 06 19;76(6):618-620. Epub 2021 Apr 19.

IRCCS NeuroMed, Pozzilli, Italy.

Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215900DOI Listing
June 2021

An observed association between conjunctivitis and severity of COVID-19.

J Infect 2021 Jun 9. Epub 2021 Jun 9.

Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy.

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http://dx.doi.org/10.1016/j.jinf.2021.06.006DOI Listing
June 2021

Thrombosis in Covid-19 and non-Covid-19 pneumonia: role of platelets.

Platelets 2021 Jun 7:1-9. Epub 2021 Jun 7.

I Clinica Medica, Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Platelets may be a target of bacteria and viruses, which can directly or indirectly activate them so promoting thrombosis. In accordance with this, community-acquired pneumonia (CAP) is complicated by ischemia-related vascular disease (myocardial infarction and stroke) in roughly 10% of patients while the incidence of venous thrombosis is uncertain. In CAP platelet biosynthesis of TxA2 is augmented and associated with myocardial infarction; however, a cause-effect relationship is still unclear as unclear is if platelet activation promotes thrombosis or functional changes of coronary tree such vasospasm. Retrospective studies suggested a potential role of aspirin in reducing mortality but the impact on vascular disease is still unknown. Coronavirus disease 2019 (Covid-19) is complicated by thrombosis in roughly 20% of patients with an almost equivalent localization in arterial and venous circulation. Platelet activation seems to have a pivot role in the thrombotic process in Covid-19 as consistently evidenced by its involvement in promoting Tissue Factor up-regulation via leucocyte interaction. Until now, antiplatelet treatment has been scarcely considered for the treatment of Covid-19; interventional trials, however, are in progress to explore this issue. The aim of this review is 1) to compare the type of vascular diseases complicating CAP and Covid-19 2) to assess the different role of platelets in both diseases and 3) to discuss if antiplatelet treatment is potentially useful to improve clinical outcomes.
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http://dx.doi.org/10.1080/09537104.2021.1936478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204311PMC
June 2021

Low-Grade Endotoxemia and Thrombosis in COVID-19.

Clin Transl Gastroenterol 2021 06 4;12(6):e00348. Epub 2021 Jun 4.

Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Introduction: Patients with community-acquired pneumonia display enhanced levels of lipopolysaccharides (LPS) compared with controls, suggesting that low-grade endotoxemia may be implicated in vascular disturbances. It is unknown whether this occurs in patients with coronavirus 2019 (COVID-19) and its impact on thrombotic complications.

Methods: We measured serum levels of zonulin, a marker of gut permeability, LPS, and D-dimer in 81 patients with COVID-19 and 81 healthy subjects; the occurrence of thrombotic events in COVID-19 during the intrahospital stay was registered.

Results: Serum LPS and zonulin were higher in patients with COVID-19 than in control subjects and, in COVID-19, significantly correlated (R = 0.513; P < 0.001). Among the 81 patients with COVID-19, 11 (14%) experienced thrombotic events in the arterial (n = 5) and venous circulation (n = 6) during a median follow-up of 18 days (interquartile range 11-27 days). A logistic regression analysis showed that LPS (P = 0.024) and D-dimer (P = 0.041) independently predicted thrombotic events.

Discussion: The study reports that low-grade endotoxemia is detectable in patients with COVID-19 and is associated with thrombotic events. The coexistence of low-grade endotoxemia with enhanced levels of zonulin may suggest enhanced gut permeability as an underlying mechanism.
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http://dx.doi.org/10.14309/ctg.0000000000000348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183715PMC
June 2021

Corticosteroid use, myocardial injury and in-hospital cardiovascular events in patients with community-acquired pneumonia.

Br J Clin Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

Mediterranea Cardiocentro, Naples, Italy.

Background And Purpose: Corticosteroids are often prescribed to community-acquired pneumonia (CAP) patients, but the relationship with major cardiovascular events (MACEs) is unclear.

Experimental Approach: 541 CAP patients were recruited (334 males, mean age 71.9 ± 16.2 years). High-sensitivity troponin T (hs-cTnT) was measured at admission, during the hospital stay and at discharge. MACE occurrence was registered during a long-term follow-up.

Key Results: Overall, 318 patients (59%) showed hs-cTnT elevation >99th percentile (>0.014 μg/L). Age, heart failure and the increasing quintiles of hs-cTnT (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.82-2.58, P < .001) predicted MACEs. Among patients with hs-cTnT >0.014 μg/L at admission, 102 patients (31%) were on corticosteroids and showed lower hs-cTnT increase (P = .021), (NADPH) oxidase-2 (Nox2) activation (P = .005) and incidence of MACEs than untreated ones (HR 0.64, 95% CI 0.41-0.97, P = .038); no effect of corticosteroids on MACEs was observed in CAP patients with normal troponin. In vitro study showed that glucocorticoids have an antioxidant effect via downregulation of Nox2 activity.

Conclusion And Implications: The study provides evidence that corticosteroid use is associated with lower increase of hs-cTnT and incidence of MACEs in CAP patients.
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http://dx.doi.org/10.1111/bcp.14936DOI Listing
June 2021

Cancer and atrial fibrillation: Epidemiology, mechanisms, and anticoagulation treatment.

Prog Cardiovasc Dis 2021 May-Jun;66:28-36. Epub 2021 Apr 26.

Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy. Electronic address:

Cancer patients are at an increased risk of developing atrial fibrillation (AF) and thrombosis. However, the management of anticoagulation in patients with both diseases may be challenging, and data on these patients are lacking. We summarize the current evidence on the incidence and prevalence of cancer in AF and vice versa and provide some practical considerations on the management of oral anticoagulation in specific clinical situations. Low-molecular weight heparins are not approved for thromboprophylaxis in AF, and management of warfarin can be difficult. The use of direct oral anticoagulants may be particularly attractive for their rapid onset/offset action and lower bleeding risk.
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http://dx.doi.org/10.1016/j.pcad.2021.04.004DOI Listing
April 2021

Nox2 up-regulation and hypoalbuminemia in patients with type 2 diabetes mellitus.

Free Radic Biol Med 2021 05 26;168:1-5. Epub 2021 Mar 26.

Mediterranea Cardiocentro, Napoli, Italy; Department of Clinical, Internal, Anaesthesiologic, and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy. Electronic address:

Type 2 diabetes mellitus (T2DM) is associated with oxidative stress but the underlying mechanisms promoting oxidative stress as well as its relationship with cardiovascular events is still unclear. In 375 T2DM patients who were followed-up for approximately 5 years we measured the serum levels of soluble NOX2-derived peptide (sNOX2-dp), a marker of Nox2 activation, and albumin, a powerful antioxidant protein. In the entire cohort soluble Nox2 and serum albumin were significantly correlated (r = -0.348, P < 0.0001). During the follow-up 49 cardiovascular events (CVE) were registered, of which 45 were non-fatal myocardial infarction (MI); patients with non-fatal MI had significantly higher soluble NOX2/albumin ratio compared to cardiovascular events-free patients. Cox regression analysis showed a significant association between sNox2-dp/serum albumin ratio and the incidental risk of non-fatal MI (HR 1.106, CI95% 1.020-1.198, P = 0.014). The study suggests that redox status imbalance negatively influences vascular outcomes in T2DM.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.03.026DOI Listing
May 2021

Non-alcoholic fatty liver disease (NAFLD), metabolic syndrome and cardiovascular events in atrial fibrillation. A prospective multicenter cohort study.

Intern Emerg Med 2021 Mar 13. Epub 2021 Mar 13.

I Clinica Medica, Atherothrombosis Centre, Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.

Whether non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular events (CVEs) independently from metabolic syndrome (MetS) is still matter of debate. Aim of the study was to investigate the risk of CVEs in a high-risk population of patients with non-valvular atrial fibrillation (AF) according to the presence of MetS and NAFLD. Prospective observational multicenter study including 1,735 patients with non-valvular AF treated with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). NAFLD was defined by a fatty liver index ≥ 60. We categorized patients in 4 groups: 0 = neither MetS or NAFLD (38.6%), 1 = NAFLD alone (12.4%), 2 = MetS alone (19.3%), 3 = both MetS and NAFLD (29.7%). Primary endpoint was a composite of CVEs. Mean age was 75.4 ± 9.4 years, and 41.4% of patients were women. During a mean follow-up of 34.1 ± 22.8 months (4,926.8 patient-years), 155 CVEs were recorded (incidence rate of 3.1%/year): 55 occurred in Group 0 (2.92%/year), 12 in Group 1 (2.17%/year), 45 in Group 2 (4.58%/year) and 43 in Group 3 (2.85%/year). Multivariable Cox regression analysis showed that use of DOACs, and female sex were inversely associated with CVEs, whilst age, heart failure, previous cardiac and cerebrovascular events, and group 2 (Group 2, Hazard Ratio 1.517, 95% Confidence Interval, 1.010-2.280) were directly associated with CVEs. In patients with AF, MetS increases the risk of CVEs. Patients with NAFLD alone have lower cardiovascular risk but may experience higher liver-related complications.
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http://dx.doi.org/10.1007/s11739-021-02682-3DOI Listing
March 2021

[Clinical management of older, frail patients with atrial fibrillation. Operative strategies from a multidisciplinary expert group].

G Ital Cardiol (Rome) 2021 02;22(2 Suppl 1):e3-e27

Direzione Sanitaria, Azienda USL di Bologna.

Atrial fibrillation (AF) is the most common arrhythmia in elderly people. Older patients with AF have several comorbidities and should be treated with complex therapeutic schemes. Arrhythmia complications are also common at an advanced age. Accordingly, AF can be considered a marker of frailty. Few indications can be found concerning the management of frail older subjects in current guidelines. The Frailty in Atrial Fibrillation Survey Study (FAST) was designed to overcome the gap of knowledge about this extremely vulnerable subset of patients. A multidisciplinary team composed by cardiologists, geriatricians and internists participated in the project. In a first phase, a survey was conducted aiming at clarifying specialty-related differences in definition and oral anticoagulant therapy (OAT) management of frail individuals. In the second phase, specific chapters were prepared about AF and frailty epidemiology, the network for the management of the arrhythmia, the diagnostic strategies for AF (including a minimum data set of tools derived from the geriatric multidimensional assessment), OAT and the choice between a rate or a rhythm control strategy. For each chapter, up-to-date evidence and current guideline recommendations were presented and discussed among the 47 Italian centers participating in the project. In the last phase of FAST, the results of the survey and the final draft of the chapters were merged into the present document. A lack of homogeneity in frailty definition existed. The integration among cardiologists, geriatricians and internists can represent the most effective tool to get through these differences improving the management of frail older patients.
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http://dx.doi.org/10.1714/3547.35222DOI Listing
February 2021

Hypoalbuminemia and clinical adverse events in children with COVID-19.

J Med Virol 2021 May 15;93(5):2611-2613. Epub 2021 Feb 15.

Department of Clinical, Internal Medicine, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1002/jmv.26856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013663PMC
May 2021

Procedure-related bleeding risk in patients with cirrhosis and severe thrombocytopenia.

Eur J Clin Invest 2021 Jun 26;51(6):e13508. Epub 2021 Feb 26.

I Clinica Medica, Sapienza University of Rome, Rome, Italy.

Background: Gaps of knowledge still exist about the potential association between severe thrombocytopenia and increased risk of procedure-associated bleeding in patients with liver disease.

Methods: In this narrative review, we aimed at examining the association between procedure-related bleeding risk and platelet count in patients with cirrhosis and severe thrombocytopenia in various settings. We updated to 2020 a previously conducted literature search using MEDLINE/PubMed and EMBASE. The search string included clinical studies, adult patients with chronic liver disease and thrombocytopenia undergoing invasive procedures, any interventions and comparators, and haemorrhagic events of any severity as outcome.

Results: The literature search identified 1276 unique publications, and 15 studies met the inclusion criteria and were analysed together with those identified by the previous search. Most of the new studies included in our analysis did not assess the association between post-procedural bleeding risk and platelet count alone in patients with chronic liver disease. Furthermore, some results could have been biased by prophylactic platelet transfusions. A few studies found that severe thrombocytopenia may be predictive of bleeding following percutaneous liver biopsy, dental extractions, percutaneous ablation of liver tumours and endoscopic polypectomy.

Conclusions: Currently available literature cannot support definitive conclusions about the appropriate target platelet counts to improve the risk of bleeding in cirrhotic patients who underwent invasive procedures; moreover, it showed enormous variability in the use of prophylactic platelet transfusions.
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http://dx.doi.org/10.1111/eci.13508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244048PMC
June 2021

Sex-based difference in anticoagulated patients with mechanical prosthetic heart valves and long-term mortality risk.

Int J Clin Pract 2021 May 11;75(5):e14064. Epub 2021 Feb 11.

I Clinica Medica, Atherothrombosis Centre, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Background: Vitamin K antagonists (VKAs) reduce thromboembolism in patients with mechanical prosthetic heart valves (MPHV). It is unclear whether a sex-based difference in MPHV patients regarding valve site, anticoagulation quality, and mortality risk does exist.

Methods: We analysed 2111 MPHV patients from the nationwide PLECTRUM study promoted by the Italian Federation of Anticoagulation Clinics (FCSA). We analysed the site of MPHV, anticoagulation quality, as assessed by the time in therapeutic range (TiTR), and mortality risk in women and men.

Results: The mean age of the patients was 56.8 ± 12.3 years. Women were older with a lower prevalence of ischemic heart disease and smoking habit and a higher prevalence of atrial fibrillation at baseline. Aortic MPHV was more frequent in men (74.7% vs 43.3%, P < .001), whereas mitral (41.1% vs 17.6%, P < .001) and mitro-aortic (15.6% vs 7.7%, P < .001) MPVH in women. The association between female sex and mitral/mitro-aortic site remained at multivariable logistic regression analysis (Odds Ratio 3.623, 95% Confidence Interval [CI] 2.947-4.455, P < .001). Regarding anticoagulation quality, women showed lower mean TiTR (63.0 ± 19.4 vs 57.5 ± 19.2, P < .001), and a higher proportion of TiTR < 60% (54.9% vs 43.3%, P < .001). During a mean follow-up of 123 months (21 665 pt-years), 152 deaths occurred (0.7%/year); 83 in the aortic (0.63%/year) and 69 in the mitral/mitro-aortic (0.81%/year) group. At multivariable Cox proportional hazard regression analysis, female sex was not associated with mortality (HR 0.953, 95%CI 0.678 1.340, P = .783).

Conclusions: Female sex is independently associated with mitral/mitro-aortic MPHV. Despite a lower TiTR in women, mortality risk did not differ between the two groups.
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http://dx.doi.org/10.1111/ijcp.14064DOI Listing
May 2021

Beneficial effects of a combination of natural product activators of autophagy on endothelial cells and platelets.

Br J Pharmacol 2021 05 24;178(10):2146-2159. Epub 2021 Apr 24.

Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy.

Background And Purpose: Oxidative stress and insufficient autophagy activity are associated with inflammatory processes and are common features of many cardiovascular diseases (CVDs). We investigated if a combination of natural activators of autophagy could modulate oxidative stress, platelet aggregation and endothelial cell survival and function in response to stress.

Experimental Approach: Ex vivo platelet aggregation and activation, H O production and autophagy were measured in platelets of subjects at high cardiovascular risk, including smokers, patients with metabolic syndrome (MetS) and patients with atrial fibrillation (AF). In vitro, the effects of a mixture of natural pro-autophagy molecules and antioxidants on platelets and human umbilical vein endothelial cells (HUVECs) were evaluated.

Key Result: Autophagy appeared to be inhibited, whereas aggregation was increased in platelets from AF and MetS patients and in smokers, as compared with healthy subjects. Treatment of platelets isolated from these patients with a mixture composed of trehalose, spermidine, catechin and epicatechin (Mix1) or with a mixture composed of trehalose, spermidine and nicotinamide (Mix2), significantly reduced platelet activation and oxidative stress, and increased autophagy, compared with the effect of each compound alone. Similarly, treatment of HUVECs with a combination of these compounds exhibited beneficial effects and increased endothelial cell survival, nitric oxide bioavailability and angiogenesis in response to stress in a potentiated manner.

Conclusion And Implications: A combination of natural activators of autophagy could inhibit platelet activity and oxidative stress and improve endothelial cell survival and function in a potentiated manner representing a useful strategy to reduce the effect of risk factors on CVD occurrence.

Linked Articles: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.
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http://dx.doi.org/10.1111/bph.15399DOI Listing
May 2021

Real-world safety and efficacy of direct oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of 605 771 patients.

Eur Heart J Cardiovasc Pharmacother 2021 Apr;7(FI1):f11-f19

Department of Clinical, Internal, Anesthesiological, and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy.

Aims: To analyse the safety and efficacy of direct oral anticoagulants (DOACs) in real-world studies including atrial fibrillation (AF) patients.

Methods And Results: Systematic review and meta-analysis of observational studies including AF patients on DOACs. Primary endpoints: any, major, gastrointestinal (GI), intracranial haemorrhage (ICH), and haemorrhagic stroke (HS). Secondary endpoints: ischaemic stroke (IS), systemic embolism (SE), myocardial infarction (MI), and all-cause of death. A set of pair-wise meta-analyses using a random effect model and a random effect network meta-analysis under a Bayesian framework were performed. Prospero registration number: CRD42019137111. We included 21 studies with 605 771 AF patients. Apixaban was associated with lower major and GI bleeding compared with Rivaroxaban [hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.6-2.5] and Dabigatran (HR 1.6, 95% CI 1.3-2.1). The latter drug performed better than Rivaroxaban (HR 1.2, 95% CI 1.0-1.5). Dabigatran and Apixaban had a similar association with HS, but Apixaban performed better than Rivaroxaban (HR 1.8, 95% CI 1.1-3.0). Apixaban had a similar association with Rivaroxaban and Dabigatran for ICH, the latter drug performing better than Rivaroxaban (HR 1.3, 95% CI 1.0-1.7). Rankograms showed that Apixaban was likely to be the first-choice treatment in relation to any (65%) major (100%) and GI bleeding (100%) followed by Dabigatran (46%, 100%, 99%, respectively). Dabigatran and Apixaban had similar rank as first choice for ICH (44% and 55%) and HS (52% and 48%). DOACs showed similar association with IS/SE, MI, all-cause of death.

Conclusions: Analysis of real-world studies shows significant differences for safety among DOACs.
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http://dx.doi.org/10.1093/ehjcvp/pvab002DOI Listing
April 2021

Waves of SARS-CoV-2 Infection and Blood Coagulation-A Link and Beyond.

Thromb Haemost 2021 01 21;121(1):4-6. Epub 2021 Jan 21.

DOASENSE GmbH, Heidelberg, Germany.

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http://dx.doi.org/10.1055/s-0040-1721778DOI Listing
January 2021

Statin use and mortality in atrial fibrillation: A systematic review and meta-analysis of 100,287 patients.

Pharmacol Res 2021 03 13;165:105418. Epub 2021 Jan 13.

Liverpool Centre for Cardiovascular Science University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom.

Statins are effective for reducing cardiovascular disease in patients at risk or with cardiovascular disease. The benefit of statin therapy on adverse cardiovascular outcomes in patients with non-valvular atrial fibrillation (AF) is not clear. We performed a systematic review and meta-analysis of studies retrieved from MEDLINE via PubMed and Cochrane (CENTRAL) database of studies investigating the efficacy of statins in AF patients. The principal endpoint was all-cause mortality. Other endpoints were cardiovascular mortality, ischemic stroke, composite endpoints and any bleeding. We included 14 studies (2 post-hoc analysis of randomized clinical trials, 8 prospective and 4 retrospective) with 100,287 AF patients, of whom 23,228 were on statins. The pooled hazard ratio (HR) for all-cause mortality was 0.59 (95 % Confidence Interval [CI] 0.54-0.65). This association was consistent by aging, sex and prevalent cardiovascular or cerebrovascular disease. and the beneficial effect was evident already after 12 months of therapy. The absolute risk reduction for all-cause mortality in patients treated with statins was 10 % (95 % CI 9-10). The pooled HR for statins against cardiovascular mortality was 0.75 (95 % CI 0.58-0.96). No association was found with other secondary endpoints. Regarding bleeding events, the pooled HR for statin use was 0.60 (95 % CI 0.48-0.76). Our meta-analysis shows that in AF patients, statin therapy was associated with a reduction in all-cause and cardiovascular mortality are reduced by 41 % and 25 %, respectively. Randomized clinical trials in AF patients are necessary, as well as clarity on AF-specific LDL cholesterol targets.
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http://dx.doi.org/10.1016/j.phrs.2021.105418DOI Listing
March 2021

Lipopolysaccharide induces platelet activation in HIV patients: the role of different viral load patterns.

HIV Med 2021 Jul 10;22(6):434-444. Epub 2021 Jan 10.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

Objectives: This study aimed to assess whether gut-derived lipopolysaccharide (LPS) could affect platelet function in HIV-1 patients with residual viral load.

Methods: In 23 HIV-1 patients on effective antiretroviral treatment, 10 treatment-naïve HIV-1 subjects and 20 healthy subjects (HS), LPS, zonulin, markers of platelet activation and oxidative stress were evaluated. In vitro, platelets from HS were exposed to plasma from HIV-1-infected treated and untreated patients.

Results: Compared with HS, LPS was higher in treated and treatment-naïve subjects with HIV-1 (7.7 ± 2.9, 80.9 ± 13.7 and 75.3 ± 22.6 pg/mL, P < 0.001 vs. HS) as well as serum zonulin (1.3 ± 0.5, 6.1 ± 1.5 and 5.3 ± 1.7 ng/mL, P < 0.001 vs. HS). LPS and zonulin were correlated in HIV patients (Spearman correlation coefficient (rS) = 0.73, P < 0.0001). Levels of soluble CD40 ligand (sCD40L), soluble P-selectin (sP-selectin) and thromboxane B (TxB ) were higher in HIV-1-treated and treatment-naïve subjects compared with HS as well as NADPH oxidase 2 (NOX2) activation and hydrogen peroxide (H O ) production. In vitro, sCD40L, sP-selectin and TxB production, NOX2 activation and p47 phosphorylation were higher in platelets exposed to plasma from HIV-1 patients with different viral load compared with the exposure to plasma from HS. This effect was blunted in platelets pre-treated with TLR4 or TLR7 inhibitors.

Conclusions: Low-grade endotoxaemia and persistent viraemia increase platelet function with a mechanism mediated by NOX2 in patients with HIV-1 infection.
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http://dx.doi.org/10.1111/hiv.13059DOI Listing
July 2021

The Atrial fibrillation Better Care (ABC) pathway and cardiac complications in atrial fibrillation: a potential sex-based difference. The ATHERO-AF study.

Eur J Intern Med 2021 Mar 6;85:80-85. Epub 2021 Jan 6.

Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, United Kingdom; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark.

Background: An integrated care approach is recommended to optimize management of patients with atrial fibrillation (AF). The impact of the Atrial fibrillation Better Care (ABC) pathway on major adverse cardiac events (MACE), which are the main causes of death in AF, has not been explored.

Material And Methods: We investigated the association between ABC compliance and MACE incidence in 1157 (2690 patient-years) nonvalvular AF patients from the ATHERO-AF study. A subgroup analysis by sex and high cardiovascular risk patients as defined by a 2MACE score ≥3 was performed.

Results: Overall, 428 (37%) patients composed the ABC-compliant group. During a median follow up of 23 (IQR 12-37) months, 64 MACE occurred (2.38%/year). Kaplan Meier curve analysis showed a higher rate of MACE in ABC non-compliant group compared to the ABC-compliant (log-rank test p=0.006). The risk of MACE increased by the number of non-fulfilled ABC criteria. On multivariable Cox proportional hazard regression analysis, the ABC non-compliance was associated with an increased risk of MACE (Hazard ratio (HR) 2.244, 95% Confidence Interval (95%CI) 1.129-4.462). Men were more likely to have suboptimal anticoagulation control (group A), while uncontrolled symptoms were more frequent in women. The association between non-ABC and MACE was more evident in men than women (HR 3.647, 95%CI 1.294-10.277) and in patients with 2MACE score ≥3 (HR 1.728, 95%CI 1.209-2.472).

Conclusion: An integrated care ABC approach is associated with a reduced risk of MACE in the AF population, especially in men and in patients at high risk of MACE.
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http://dx.doi.org/10.1016/j.ejim.2020.12.011DOI Listing
March 2021

Long-Term Risk of Major Adverse Cardiac Events in Atrial Fibrillation Patients on Direct Oral Anticoagulants.

Mayo Clin Proc 2021 03 9;96(3):658-665. Epub 2020 Dec 9.

I Clinica Medica, Atherothrombosis Center, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy; Mediterranea Cardiocentro, Naples, Italy.

Objective: To determine the association between direct oral anticoagulant (DOAC) use and risk of major adverse cardiac events (MACEs) in patients with atrial fibrillation (AF).

Patients And Methods: This study is a single-center prospective observational cohort study including 2366 outpatients with non-valvular AF on treatment with DOACs or vitamin K antagonists (VKAs) from February 2008 for patients on VKA and September 2013 for patients on novel oral anticoagulants. The primary endpoint was the incidence of MACE including fatal and non-fatal myocardial infarction (MI), cardiac revascularization, and cardiovascular death.

Results: The mean age was 75.1±9.0 years; 44.7% were women. During a mean follow-up of 33.3±21.9 months (6567 patients/years) 133 MACEs occurred (2.03%/year): 79 MI/cardiac revascularization and 54 cardiovascular deaths. Of these, 101 were on VKAs (2.42%/year) and 32 on DOACs (1.34%/year; log-rank test P=.040). This difference was evident also considering MI alone (1.53%/year and 0.63%/year in the VKA and DOAC group, respectively, log-rank test P=.009). At multivariable Cox proportional hazard regression analysis, use of DOACs was associated with a lower risk of MACE (hazard ratio, 0.636; 95% CI, 0.417 to 0.970; P=.036) and MI (hazard ratio, 0.497; 95% CI, 0.276 to 0.896; p=.020). Sensitivity analysis showed that this association was consistent in younger patients (<75 years), in patients with anemia, and in those without chronic obstructive pulmonary disease and heart failure. We also found that both dabigatran and apixaban/rivaroxaban were associated with a lower rate of MACE, with similar efficacy between full and low doses.

Conclusion: DOACs are associated with a lower risk of MACE in patients with AF independently from dosage.
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http://dx.doi.org/10.1016/j.mayocp.2020.06.057DOI Listing
March 2021

Relation of Atrial Fibrillation to Angiographic Characteristics and Coronary Artery Disease Severity in Patients Undergoing Percutaneous Coronary Intervention.

Am J Cardiol 2021 02 18;141:1-6. Epub 2020 Nov 18.

Department of Clinical Internal, Anesthesiologic, and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Patients with atrial fibrillation (AF) have an increased risk of coronary artery disease (CAD) compared to patients without. Angiographic characteristics, clinical presentation and severity of CAD according to the presence of AF have been poorly described. We performed a retrospective study of 303 consecutive patients (mean age 69.6 ± 10.8 years; 23.1% women) with and without AF undergoing percutaneous coronary intervention. Data on (1) type of CAD presentation, (2) coronary involvement, and (3) number of diseased coronary vessels (≥70%/luminal narrowing) were collected. CHADS-VASc and 2 major adverse cardiac event (MACE) scores were calculated. Presentation of CAD was ST-segment elevation myocardial infarction (STEMI) in 37.6% of patients, non-STEMI- unstable angina in 55.1%, and other in 7.3%. Non-STEMI-unstable angina was more common in AF (69.6% vs 46.6%, p <0.001), while STEMI was more in the non-AF (22.3% vs 46.6%, p <0.001) group. Left anterior descending artery (LAD) was the most common diseased vessel (70.6%) followed by right coronary artery (RCA, 56.4%) and obtuse marginal artery (36.6%). Patients with AF had a significantly lower RCA involvement (47.3% vs 61.8%, p = 0.016), with a trend for LAD (64.3% vs 74.3%, p = 0.069). At multivariable logistic regression analysis, AF remained inversely associated with RCA involvement (odds ratio [OR] 0.541, 95% confidence interval [CI] 0.335 to 0.874, p = 0.012) and with ≥3 vessel CAD (OR 0.470, 95% CI 0.272 to 0.810, p = 0.007). The 2MACE score was associated with diseased LAD (OR 1.301, 95% CI 1.103 to 1.535, p = 0.002) and with ≥3 vessel CAD (OR 1.330, 95% CI 1.330 to 1.140, p <0.001). In conclusion, patients with AF show lower RCA involvement and generally less severe CAD compared to non-AF ones. The 2MACE score was higher in LAD obstruction and identified patients with severe CAD.
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http://dx.doi.org/10.1016/j.amjcard.2020.11.006DOI Listing
February 2021

Atrial fibrillation pattern, left atrial diameter and risk of cardiovascular events and mortality. A prospective multicenter cohort study.

Int J Clin Pract 2021 Mar 9;75(3):e13771. Epub 2020 Nov 9.

I Clinica Medica, Atherothrombosis Centre, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Background: There are conflicting evidence on the association between atrial fibrillation (AF) pattern, such as persistent/permanent (Pers/Perm) and paroxysmal (PAF) AF and risk of ischemic events. We investigated if left atrial diameter (LAd) may affect the risk of cardiovascular outcomes according to AF pattern.

Methods: Prospective multicenter observational including 1,252 non-valvular AF patients (533 PAF and 719 Pers/Perm AF). Study endpoints were cardiovascular events (CVEs), major adverse cardiac events (MACE) and CV death. LA anteroposterior diameter (LAd) was obtained by transthoracic echocardiography.

Results: Pers/Perm AF patients had a higher proportion of LAd above median than PAF (≥44 mm, 59.5% vs 37.5% respectively, P < .001). In a mean follow-up of 42.2 ± 31.0 months (4,315 patients/year) 179 CVEs (incidence rate [IR] 4.2%/year), 133 MACE (IR 3.1%/year), and 97 CV deaths (IR 2.2%/year) occurred. Compared to patients with LAd below median, those with LAd above the median had a higher rate of CVEs (log-rank test, P < .001), MACE (log-rank test P < .001), and CV death (log-rank test P < .001). Multivariable Cox regression analysis showed that LAd above the median was associated with CVEs, (HR 1.569, 95% CI 1.129-2.180, P = .007) MACE (HR 1.858, 95% CI 1.257-2.745, P = .002) and CV death (HR 2.106, 95% CI 1.308-3.390, P = .002). The association between LAd and outcomes was evident both in PAF and Pers/Perm AF patients. No association between AF pattern and outcomes was found.

Conclusion: LAd is a simple parameter that can be obtained in virtually all AF patients and can provide prognostic information on the risk of CVEs, MACE and CV death regardless of AF pattern.
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http://dx.doi.org/10.1111/ijcp.13771DOI Listing
March 2021

Anticoagulation in patients with advanced liver disease: an open issue.

Intern Emerg Med 2021 Jan 18;16(1):61-71. Epub 2020 Oct 18.

Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, I Clinica Medica, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.

Liver disease has been long considered as a risk factor for bleeding for the presence of prolongation of global tests of clotting activation and low platelet count. For this reason, the use of anticoagulants in patients with liver disease and an indication to anticoagulation, such as atrial fibrillation of venous thrombosis, has been poorly considered. Furthermore, recent studies underscored the fact that patients with chronic liver disease may experience thrombosis in portal as well as systemic circulation and treatment with anticoagulants should be considered. The introduction of direct oral anticoagulants has increased therapeutic options for thromboprophylaxis; however, evidence on their safety and efficacy in specific populations, such as patients with liver disease, is still scarce and needs further investigation. Thus, atrial fibrillation patients with coexistent liver disease have been excluded from clinical trials with direct oral anticoagulants. Here, we provide an overview on mechanisms of thrombosis in patients with advanced chronic liver disease and a summary of evidence on the use of oral anticoagulants in patients with liver disease and portal vein thrombosis or atrial fibrillation.
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http://dx.doi.org/10.1007/s11739-020-02526-6DOI Listing
January 2021

T2238C atrial natriuretic peptide gene variant and cardiovascular events in patients with atrial fibrillation: A substudy from the ATHERO-AF cohort.

Int J Cardiol 2021 01 28;322:245-249. Epub 2020 Aug 28.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, Latina 40100, Italy; IRCCS Neuromed, Località Camerelle, Pozzilli, (IS), 86077, Italy; This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Background: The T2238C variant of the atrial natriuretic peptide (ANP) gene has emerged as a novel risk factor for the incidence of cardiovascular events. However, the impact of this variant on cardiovascular outcome in patients with atrial fibrillation (AF) is unknown.

Methods: We included 557 anticoagulated patients with non-valvular AF randomly selected from the prospective ATHERO-AF cohort. Patients underwent genetic analysis for the T2238C/ANP variant and were grouped as wild type or heterozygous or homozygous for C2238 variant allele. Primary endpoint was a composite of cardiovascular events (CVEs) including cardiovascular death, fatal/non-fatal ischemic stroke and myocardial infarction. Overall, 429 patients carried the TT wild type genotype, 110 patients (19.7%) were heterozygous (T/C) and 18 patients (3.2%) were homozygous (CC).

Results: Incidence of CVEs was higher in homozygous patients for C2238 allele at unadjusted analysis (log-rank test, p = 0.042 for additive model, p = 0.043 for recessive model). The multivariable Cox proportional hazards regression analysis confirmed that C2238 ANP allele was associated with CVEs in the additive (p = 0.008) and recessive models (p = 0.005).

Conclusions: Carrier status for the C2238/ANP variant allele is associated with an increased risk of CVEs in anticoagulated AF patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.077DOI Listing
January 2021

Increased intestinal barrier permeability in patients with moderate to severe plaque-type psoriasis.

J Dermatol 2020 Oct 12;47(10):e366-e368. Epub 2020 Aug 12.

Department of Internal Medicine and Medical Specialties, Unit of Dermatology, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1111/1346-8138.15361DOI Listing
October 2020

Nox2 activation in Covid-19.

Redox Biol 2020 09 25;36:101655. Epub 2020 Jul 25.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.

Nox2 is responsible for artery dysfunction via production of reactive oxidant species. RNA viruses may activate Nox2, but it is unknown if this occurs in coronavirus 2019(Covid-19). Nox2 activation by soluble Nox2-derived peptide(sNox2-dp) was measured in patients hospitalized for Covid-19 (n = 182) and controls (n = 91). sNox2-dp values were higher in Covid-19 patients versus controls and in severe versus non severe Covid-19. Patients with thrombotic events(n = 35,19%) had higher sNox2-dp than thrombotic event-free ones. A logistic regression analysis showed that sNox2 and coronary heart disease predicted thrombotic events. Oxidative stress by Nox2 activation is associated severe disease and thrombotic events in Covid-19 patients.
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http://dx.doi.org/10.1016/j.redox.2020.101655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381406PMC
September 2020

Family History of Atrial Fibrillation and Risk of Cardiovascular Events: A Multicenter Prospective Cohort Study.

Circ Arrhythm Electrophysiol 2020 09 27;13(9):e008477. Epub 2020 Jul 27.

I Clinica Medica, Atherothrombosis Center, Department of Clinical, Internal Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy (D.P., D.M., F.V., P.P.).

Background: To investigate the association between family history of atrial fibrillation (AF) with cardiovascular events (CVEs), major adverse cardiac events (MACE), and cardiovascular mortality.

Methods: Multicenter prospective observational cohort study including 1722 nonvalvular AF patients from February 2008 to August 2019 in Italy. Family history of AF was defined as the presence of AF in a first-degree relative: mother, father, sibling, or children. Primary outcome was a composite of CVEs including fatal/nonfatal ischemic stroke and myocardial infarction, and cardiovascular death. Second, we analyzed the association with major adverse cardiac event.

Results: Mean age was 74.6±9.4 years; 44% of women. Family history of AF was detected in 368 (21.4%) patients, and 3.5% had ≥2 relatives affected by AF. Age of AF onset progressively decreased from patients without family history of AF, compared with those with single and multiple first-degree affected relatives (<0.001). During a mean follow-up of 23.7 months (4606 patients/y) 145 CVEs (3.15%/y), 98 major adverse cardiac event (2.13%/y), and 57 cardiovascular deaths (0.97%/y) occurred. After adjustment for cardiovascular risk factors, family history of AF was associated with a higher risk of CVEs (hazard ratio, 1.524 [95% CI, 1.021-2.274], =0.039), major adverse cardiac event (hazard ratio, 1.917 [95% CI, 1.207-3.045], =0.006), and cardiovascular mortality (hazard ratio, 2.008 [95% CI, 1.047-3.851], =0.036). Subgroup analysis showed that this association was modified by age, sex, and prior ischemic heart disease.

Conclusions: In a cohort of elderly patients with a high atherosclerotic burden, family history of AF is evident in >20% of patients and was associated with an increased risk for CVEs and mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01882114.
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http://dx.doi.org/10.1161/CIRCEP.120.008477DOI Listing
September 2020
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