Publications by authors named "Tomasz J Guzik"

160 Publications

Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.

Nat Genet 2021 May 6. Epub 2021 May 6.

Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
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http://dx.doi.org/10.1038/s41588-021-00835-wDOI Listing
May 2021

Echocardiography Predictors of Survival in Hypertensive Patients With Left Ventricular Hypertrophy.

Am J Hypertens 2021 May 5. Epub 2021 May 5.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Left ventricular hypertrophy (LVH) is a well-known target organ damage. Concentric hypertrophy is the strongest predictor of increased risk of cardiovascular events, but the predictive value of individual echocardiographic parameters remains unclear.The aim of this study was to search for echocardiographic and hemodynamic variables associated with concentric and eccentric remodeling and their association with long-term cardiovascular outcomes.

Methods: Patients with echocardiography performed within 1 year prior to the initial clinic visit were included into the study. Logistic regression and multivariable Cox-proportional hazards were calculated according to several risk factors and variables. Additionally, cubic spline interpolation was used.

Results: We observed 690 patients for 10 years. There was a total of 177 major adverse cardiac and cerebrovascular events (MACCE) and 90 deaths over a 10-year period. Left ventricular concentric hypertrophy is associated with worse outcomes than eccentric hypertrophy in hypertensive subjects. Interestingly, different echocardiographic parameters contributed to risk depending on type of hypertrophy. In concentric hypertrophy, relative wall thickness provides linear prediction of risk for all-cause mortality (ACM) and composite endpoint. Systolic blood pressure is a significant predictor of MACCE. Blood pressure variability also showed significant predictive value for MACCE and ACM.

Conclusions: These data indicate risk stratification based on LVH need to consider different measures based on the type of remodeling.
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http://dx.doi.org/10.1093/ajh/hpaa194DOI Listing
May 2021

A Call to Action for New Global Approaches to Cardiovascular Disease Drug Solutions.

Circulation 2021 Apr 20:CIR0000000000000981. Epub 2021 Apr 20.

Universite´ de Lorraine, INSERM CIC 1493, INI CRCT, CHRU, Nancy, France (F.Z.).

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
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http://dx.doi.org/10.1161/CIR.0000000000000981DOI Listing
April 2021

A call to action for new global approaches to cardiovascular disease drug solutions.

Eur Heart J 2021 Apr;42(15):1464-1475

Université de Lorraine, INSERM CIC 1493, INI CRCT, CHRU Nancy, France.

Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic 'buckets'. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased 'omic' approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
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http://dx.doi.org/10.1093/eurheartj/ehab068DOI Listing
April 2021

Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis.

Pharmacol Res 2021 Apr 19;166:105511. Epub 2021 Feb 19.

Oral Sciences Research Group, Glasgow Dental Hospital and School, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; Department of Experimental Dentistry and Dental Prophylaxis, Jagiellonian University, Krakow, Poland. Electronic address:

Aim: Quantitative comparison of the effects of intensive (IPT) or conventional (CPT) periodontal treatment on arterial blood pressure, endothelial function and inflammatory/metabolic biomarkers.

Materials And Methods: A systematic search was conducted to identify randomized controlled trials (RCT) of IPT (supra and subgingival instrumentation). Eight RCTs were included in the meta-analysis. Difference in change of systolic blood pressure (SBP) and diastolic blood pressure (DBP) before and after IPT or CPT were the primary outcomes. The secondary outcomes included: endothelial function and selected inflammatory/anti-inflammatory (CRP, IL-6, IL-10, IFN-γ) and metabolic biomarkers (HDL, LDL, TGs).

Results: The overall effect estimates (pooled Weighted Mean Difference (WMD)) of the primary outcome for SBP and DBP was -4.3 mmHg [95%CI: -9.10-0.48], p = 0.08 and -3.16 mmHg [95%CI: -6.51-0.19], p = 0.06 respectively. These studies were characterized by high heterogeneity. Therefore, random effects model for meta-analysis was performed. Sub-group analyses confirmed statistically significant reduction in SBP [WMD = -11.41 mmHg (95%CI: -13.66, -9.15) P < 0.00001] and DBP [WMD = -8.43 mmHg (95%CI: -10.96,-5.91)P < 0.00001] after IPT vs CPT among prehypertensive/hypertensive patients, while this was not observed in normotensive individuals. The meta-analyses showed significant reductions in CRP and improvement of endothelial function following IPT at all analysed timepoints.

Conclusions: IPT leads to improvement of the cardiovascular health in hypertensive and prehypertensive individuals.
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http://dx.doi.org/10.1016/j.phrs.2021.105511DOI Listing
April 2021

Leaders in Cardiovascular Research: Joseph Hill.

Cardiovasc Res 2021 Feb;117(3):e35-e38

University of Texas Southwestern Medical Center, Dallas, TX, USA.

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http://dx.doi.org/10.1093/cvr/cvab029DOI Listing
February 2021

Rivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial.

J Am Coll Cardiol 2021 Feb;77(5):511-525

Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: Direct oral anticoagulants are administered in fixed doses irrespective of body weight, but guidelines recommend against their use in patients with extremes of body weight.

Objectives: This study determined the effects of dual-pathway inhibition antithrombotic regimen (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/day) compared with aspirin Halone across a range of patient body mass indexes (BMIs) and body weights.

Methods: This was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial, which included patients with chronic coronary artery disease or peripheral artery disease. Efficacy and safety outcomes were studied in relation to BMI: (normal 18.5 ≤BMI <25 kg/m, overweight 25 ≤BMI <30 kg/m, obese ≥30 kg/m) and body weight (≤70 kg, 70 < weight ≤90 kg, and >90 kg; as well as ≤120 kg vs. >120 kg).

Results: Among 27,395 randomized patients, 6,459 (24%) had normal BMI, 12,047 (44%) were overweight, and 8,701 (32%) were obese. The combination of rivaroxaban and aspirin compared with aspirin produced a consistent reduction in the primary outcome of cardiovascular death, stroke, or myocardial infarction, irrespective of BMI or body weight. For 18.5 ≤BMI <25 kg/m: 3.5% vs. 5.0%; hazard ratio (HR): 0.73 (95% credible interval [CrI]: 0.58 to 0.90); 25 ≤ BMI <30 kg/m: 4.3% vs. 5.1%; HR: 0.80 (95% CrI: 0.66 to 0.96); BMI ≥30 kg/m: 4.2% vs. 6.1%; HR: 0.71 (95% CrI: 0.57 to 0.86). For body weight ≤70 kg: 4.1% vs. 5.3%; HR: 0.75 (95% CrI: 0.62 to 0.91); 70 < weight ≤90 kg: 4.1% vs. 5.3%; HR: 0.76 (95% CrI: 0.65 to 0.89); >90 kg: 4.2% vs. 5.7%; HR: 0.74 (95% CrI: 0.61 to 0.90). Effects on bleeding, mortality, and net clinical benefit were consistent irrespective of BMI or bodyweight.

Conclusions: The effects of dual-pathway antithrombotic therapy are consistent irrespective of BMI or body weight, suggesting no need for dose adjustments in the ranges of weights and BMI of patients enrolled in the COMPASS trial. Further studies need to address this problem in relation to greater extremes of body weight. (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease [COMPASS]; NCT01776424).
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http://dx.doi.org/10.1016/j.jacc.2020.11.061DOI Listing
February 2021

Reply.

J Hypertens 2021 Feb;39(2):383

Department of Life, Health and Environmental Sciences, San Salvatore Hospital, University of L'Aquila - Dental Clinic - Unit of Oral Diseases, Prevention and Translational Research - Oral DISeases and SYstemic interactions study group (ODISSY group), L'Aquila, Italy.

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http://dx.doi.org/10.1097/HJH.0000000000002720DOI Listing
February 2021

Role of inflammatory chemokines in hypertension.

Pharmacol Ther 2020 Dec 24;223:107799. Epub 2020 Dec 24.

Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland; BHF Centre for Excellence Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. Electronic address:

Hypertension is associated with immune cells activation and their migration into the kidney, vasculature, heart and brain. These inflammatory mechanisms are critical for blood pressure regulation and mediate target organ damage, creating unique novel targets for pharmacological modulation. In response to angiotensin II and other pro-hypertensive stimuli, the expression of several inflammatory chemokines and their receptors is increased in the target organs, mediating homing of immune cells. In this review, we summarize the contribution of key inflammatory chemokines and their receptors to increased accumulation of immune cells in target organs and effects on vascular dysfunction, remodeling, oxidative stress and fibrosis, all of which contribute to blood pressure elevation. In particular, the role of CCL2, CCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL16, CXCL1, CX3CL1, XCL1 and their receptors in the context of hypertension is discussed. Recent studies have tested the efficacy of pharmacological or genetic targeting of chemokines and their receptors on the development of hypertension. Promising results indicate that some of these pathways may serve as future therapeutic targets to improve blood pressure control and prevent target organ consequences including kidney failure, heart failure, atherosclerosis or cognitive impairment.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107799DOI Listing
December 2020

Leaders in Cardiovascular Research: Stefanie Dimmeler.

Cardiovasc Res 2020 Dec;116(14):e202-e204

Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.

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http://dx.doi.org/10.1093/cvr/cvaa317DOI Listing
December 2020

Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney.

Eur Heart J 2020 12;41(48):4580-4588

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Aims: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported.

Methods And Results: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis.

Conclusion: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.
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http://dx.doi.org/10.1093/eurheartj/ehaa794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665509PMC
December 2020

Response by Siedlinski et al to Letters Regarding Article, "White Blood Cells and Blood Pressure: A Mendelian Randomization Study".

Circulation 2020 Sep 28;142(13):e191-e192. Epub 2020 Sep 28.

Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland (M.S., T.J.G.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049870DOI Listing
September 2020

Picking up the pace: another record high impact factor for Cardiovascular Research.

Cardiovasc Res 2020 Oct;116(12):e165-e168

BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, 126 University Place, University of Glasgow, Glasgow, UK.

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http://dx.doi.org/10.1093/cvr/cvaa262DOI Listing
October 2020

Pleiotropic actions of factor Xa inhibition in cardiovascular prevention - mechanistic insights and implications for anti-thrombotic treatment.

Cardiovasc Res 2020 Sep 15. Epub 2020 Sep 15.

Thrombosis Expertise Center, Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

Atherosclerosis is a chronic inflammatory disease in which atherothrombotic complications lead to cardiovascular morbidity and mortality. At advanced stages, myocardial infarction, ischemic stroke and peripheral artery disease (PAD), including major adverse limb events (MALE), are caused either by acute occlusive atherothrombosis, or by thromboembolism. Endothelial dysfunction, vascular smooth muscle cell activation and vascular inflammation are essential in the development of acute cardiovascular events. Effects of the coagulation system on vascular biology extend beyond thrombosis. Under physiological conditions, coagulation proteases in blood are pivotal in maintaining hemostasis and vascular integrity. Under pathological conditions, including atherosclerosis, the same coagulation proteases (including factor Xa, factor VIIa and thrombin) become drivers of atherothrombosis, working in concert with platelets and vessel wall components. While initially atherothrombosis was attributed primarily to platelets, recent advances indicate the critical role of fibrin clot and plasma coagulation factors. Mechanisms of atherothrombosis and hypercoagulability vary depending on plaque erosion or plaque rupture. In addition to contributing to thrombus formation, factor Xa and thrombin can affect endothelial dysfunction, oxidative stress, vascular smooth muscle cell function as well as immune cell activation and vascular inflammation. By these mechanisms they promote atherosclerosis and contribute to plaque instability. In this review, we first discuss the postulated vasoprotective mechanisms of protease activated receptor (PARs) signaling induced by coagulation enzymes under physiological conditions. Next, we discuss preclinical studies linking coagulation with endothelial cell dysfunction, thromboinflammation and atherogenesis. Understanding these mechanisms is pivotal for the introduction of novel strategies in cardiovascular prevention and therapy. We therefore translate these findings to clinical studies of direct oral anticoagulant (DOAC) drugs and discuss the potential relevance of dual pathway inhibition for atherothrombosis prevention and vascular protection.
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http://dx.doi.org/10.1093/cvr/cvaa263DOI Listing
September 2020

Why do some asthma patients respond poorly to glucocorticoid therapy?

Pharmacol Res 2020 10 8;160:105189. Epub 2020 Sep 8.

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Department of Pharmacy, University of Naples Federico II, Naples, Italy; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Glucocorticosteroids are the first-line therapy for controlling airway inflammation in asthma. They bind intracellular glucocorticoid receptors to trigger increased expression of anti-inflammatory genes and suppression of pro-inflammatory gene activation in asthmatic airways. In the majority of asthma patients, inhaled glucocorticoids are clinically efficacious, improving lung function and preventing exacerbations. However, 5-10 % of the asthmatic population respond poorly to high dose inhaled and then systemic glucocorticoids. These patients form a category of severe asthma associated with poor quality of life, increased morbidity and mortality, and constitutes a major societal and health care burden. Inadequate therapeutic responses to glucocorticoid treatment is also reported in other inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease; however, asthma represents the most studied steroid-refractory disease. Several cellular and molecular events underlying glucocorticoid resistance in asthma have been identified involving abnormalities of glucocorticoid receptor signaling pathways. These events have been strongly related to immunological dysregulation, genetic, and environmental factors such as cigarette smoking or respiratory infections. A better understanding of the multiple mechanisms associated with glucocorticoid insensitivity in asthma phenotypes could improve quality of life for people with asthma but would also provide transferrable knowledge for other inflammatory diseases. In this review, we provide an update on the molecular mechanisms behind steroid-refractory asthma. Additionally, we discuss some therapeutic options for treating those asthmatic patients who respond poorly to glucocorticoid therapy.
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http://dx.doi.org/10.1016/j.phrs.2020.105189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672256PMC
October 2020

Active gingival inflammation is linked to hypertension.

J Hypertens 2020 10;38(10):2018-2027

Department of Life, Health and Environmental Sciences, San Salvatore Hospital, University of L'Aquila - Unit of Internal Medicine and Nephrology, Center for Hypertension and Cardiovascular Prevention - Oral DISeases and SYstemic interactions study group (ODISSY group), L'Aquila, Italy.

Background: Cardiovascular diseases (CVD) including hypertension, are characterized by underlying systemic inflammation. Periodontitis, which can impact the systemic inflammatory burden has recently been linked to high blood pressure (BP). However, the relationship of gingival bleeding, as an easily accessible marker of periodontal disorder, with hypertension, remains unclear.

Methods: Survey-based propensity score matching (PSM) incorporating major confounders shared between hypertension and periodontal diseases was applied to cross-sectional NHANES III data from 5396 adults at least 30 years old who underwent BP measurement and periodontal examination, identifying two matched groups with and without gingival bleeding. The association of bleeding gums with SBP (mmHg) and high/uncontrolled BP was then assessed with generalized additive models incorporating inflammatory markers. Stratification by periodontal status (healthy; gingivitis; stable periodontitis; unstable periodontitis) was performed. Variables importance was estimated using machine learning.

Results: Gingival bleeding (gingivitis; unstable periodontitis) was independently associated with +2.6 mmHg (P < 0.001) SBP compared with no bleeding (healthy periodontium; stable periodontitis), and with greater odds (OR = 1.42; 95% CI = 1.19-1.68; P < 0.001) of high/uncontrolled BP. Participants with unstable periodontitis had higher SBP than those with stable periodontitis (+2.1 mmHg; P < 0.001) or gingivitis (+5.3 mmHg; P < 0.001). Unstable periodontitis and gingivitis were consistently associated with increased risk of high/uncontrolled BP (OR = 1.65, 95% CI = 2.14-1.82; OR = 1.49, 95% CI = 1.22-1.82, respectively). Inflammatory markers allowed a maximum of 12% gain in the models' predictive power.

Conclusion: Gingival bleeding contributes to shaping the relationship between periodontal diseases and BP, but the burden represented by periodontitis is also crucial. Periodontal evaluation might be of importance in difficult to control hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000002514DOI Listing
October 2020

Leaders in Cardiovascular Research: Filippo Crea.

Cardiovasc Res 2020 Oct;116(12):e159-e161

Dipartimento Universitario di Scienze Cardiovascolari e Pneumologiche Università Cattolica del Sacro Cuore Fondazione Policlinico Universitario A. Gemelli IRCCS L.go Vito 1, 00168 Roma, Italy.

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http://dx.doi.org/10.1093/cvr/cvaa231DOI Listing
October 2020

Leaders in Cardiovascular Research: Stephan Achenbach.

Cardiovasc Res 2020 Sep;116(11):e143-e145

Department of Cardiology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

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http://dx.doi.org/10.1093/cvr/cvaa223DOI Listing
September 2020

Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science.

Cardiovasc Res 2020 12;116(14):2177-2184

Center for Molecular Medicine and Department of Cardiology, Karolinska University Hospital, Solna, Stockholm, Sweden and INSERM U1116, Université de Lorraine, Centre Hospitalier Régional Universitaire de Nancy, Vandoeuvre les Nancy, France.

The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.
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http://dx.doi.org/10.1093/cvr/cvaa230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454368PMC
December 2020

The swan song of dying cells.

Cardiovasc Res 2020 07;116(8):e90-e92

Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, Glasgow G12 8TA, UK.

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http://dx.doi.org/10.1093/cvr/cvaa152DOI Listing
July 2020

Periodontitis and Hypertension: Is the Association Causal?

High Blood Press Cardiovasc Prev 2020 Aug 4;27(4):281-289. Epub 2020 Jun 4.

Oral DISeases and SYstemic Interactions Study Group (ODISSY Group), Division of Internal Medicine and Nephrology, Department of Life, Health and Environmental Sciences, Center for Hypertension and Cardiovascular Prevention, San Salvatore Hospital, University of L'Aquila, Delta 6 Building, Coppito, 67100, L'Aquila, Italy.

High blood pressure (BP) and periodontitis are two highly prevalent conditions worldwide with a significant impact on cardiovascular disease (CVD) complications. Poor periodontal health is associated with increased prevalence of hypertension and may have an influence on BP control. Risk factors such as older age, male gender, non-Caucasian ethnicity, smoking, overweight/obesity, diabetes, low socioeconomic status, and poor education have been considered the common denominators underpinning this relationship. However, recent evidence indicates that the association between periodontitis and hypertension is independent of common risk factors and may in fact be causal in nature. Low-grade systemic inflammation and redox imbalance, in particular, represent the major underlying mechanisms in this relationship. Neutrophil dysfunction, imbalance in T cell subtypes, oral-gut dysbiosis, hyperexpression of proinflammatory genes, and increased sympathetic outflow are some of the pathogenetic events involved. In addition, novel findings indicate that common genetic bases might shape the immune profile towards this clinical phenotype, offering a rationale for potential therapeutic and prevention strategies of public health interest. This review summarizes recent advances, knowledge gaps and possible future directions in the field.
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http://dx.doi.org/10.1007/s40292-020-00392-zDOI Listing
August 2020

Cardiovascular Research at the frontier of biomedical science.

Cardiovasc Res 2020 06;116(7):e83-e86

Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, Glasgow G12 8TA, UK.

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http://dx.doi.org/10.1093/cvr/cvaa119DOI Listing
June 2020

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.

Cardiovasc Res 2020 08;116(10):1666-1687

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.
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http://dx.doi.org/10.1093/cvr/cvaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197627PMC
August 2020

Leaders in Cardiovascular Research: Valentin Fuster.

Cardiovasc Res 2020 05;116(6):e62-e63

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

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http://dx.doi.org/10.1093/cvr/cvaa056DOI Listing
May 2020

Binding of SARS-CoV-2 and angiotensin-converting enzyme 2: clinical implications.

Cardiovasc Res 2020 06;116(7):e87-e89

Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, Glasgow G12 8TA, UK.

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http://dx.doi.org/10.1093/cvr/cvaa096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184453PMC
June 2020

Efficacy and safety of rivaroxaban plus aspirin in women and men with chronic coronary or peripheral artery disease.

Cardiovasc Res 2021 Feb;117(3):942-949

Department of Medicine, Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Aims: The COMPASS trial demonstrated that the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced major adverse cardiovascular events (MACE) in patients with chronic coronary artery disease or peripheral artery disease by 24% during a mean follow-up of 23 months. We explored whether this effect varies by sex.

Methods And Results: The effects were examined in women and men using log-rank tests and Kaplan-Meier curve. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were obtained from stratified Cox proportional hazards models to explore subgroup effects including subgroup of women and men according to baseline modified REACH risk score. Of 27 395 patients randomized, 18 278 were allocated to receive rivaroxaban plus aspirin (n = 9152) or aspirin alone (n = 9126), and of these, 22.1% were women. Women compared with men had similar incidence rates for MACE and major bleeding but borderline lower rates for myocardial infarction (1.7% vs. 2.2%, P = 0.05). The effect of combination therapy compared with aspirin in women and men was consistent for MACE (women: 3.8% vs. 5.2%, HR 0.72, 95% CI 0.54-0.97; men: 4.2% vs. 5.5%, HR 0.76, 95% CI 0.66-0.89; P interaction 0.75) and major bleeding (women: 3.1% vs. 1.4%, HR 2.22, 95% CI 1.42-3.46; men: 3.2% vs. 2.0%, HR 1.60, 95% CI 1.29-1.97; P interaction 0.19). There was no significant interaction between randomized treatment and baseline modified REACH score above or below the median for MACE or major bleeding.

Conclusion: In patients with stable coronary artery disease or peripheral artery disease, the combination of rivaroxaban (2.5 mg twice daily) and aspirin compared with aspirin alone appears to produce consistent benefits in women and men, independent of baseline cardiovascular risk.
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http://dx.doi.org/10.1093/cvr/cvaa100DOI Listing
February 2021

Oleacein and Foam Cell Formation in Human Monocyte-Derived Macrophages: A Potential Strategy Against Early and Advanced Atherosclerotic Lesions.

Pharmaceuticals (Basel) 2020 Apr 9;13(4). Epub 2020 Apr 9.

Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.

Background: Oleacein is a secoiridoid group polyphenol found mostly in Olea europea L. and Ligustrum vulgare L. (Oleaceae). The aim of the present study was to investigate a potential role of oleacein in prevention of the foam cell formation.

Materials And Methods: Oleacein was isolated from Ligustrum vulgare leaves. Human monocyte-derived macrophages were obtained from monocytes cultured with Granulocyte-macrophage colony-stimulating factor (GM-CSF)Then, cells were incubated with 20 M or 50 M of oleacein and with oxidized low-density lipoprotein (oxLDL) (50 g/mL). Visualization of lipid deposition within macrophages was carried out using Oil-Red-O. Expression of CD36, Scavenger receptor A1 (SRA1) and Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) was determined by Reverse transcription polymerase chain reaction (RT-PCR) and by flow cytometry. Apoptosis was determined by flow cytometry using Annexin V assay. STAT3 and Acyl-coenzyme A:cholesterol acyltransferase type 1 (ACAT1)levels were determined by ELISA. P-STAT3, P-JAK1, P-JAK2 expressions were determined by Western blot (WB).

Results: Oleacein in dose-dependent manner significantly reduced lipid deposits in macrophages as well as their expression of selected scavenger receptors. The highest decrease of expression was found for CD36 and SRA1 receptors, from above 20% to more than 75% compared to oxLDL and the lowest for LOX-1 receptor, from approx. 8% to approx. 25% compared to oxLDL-stimulated macrophages. Oleacein significantly reduced (2.5-fold) early apoptosis of oxLDL-stimulated macrophages. Moreover, oleacein significantly increased the protein expression of JAK/STAT3 pathway and had no effect on ACAT1 level.

Conclusions: Our study demonstrates, for the first time, that oleacein inhibits foam cell formation in human monocyte-derived macrophages and thus can be a valuable tool in the prevention of early and advanced atherosclerotic lesions.
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http://dx.doi.org/10.3390/ph13040064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243116PMC
April 2020

Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis.

Cardiovasc Res 2021 Jan;117(1):29-42

Department of Infection, Immunity and Cardiovascular Disease, Bateson Centre & INSIGNEO Institute, University of Sheffield, Sheffield S10 2RX, UK.

Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.
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http://dx.doi.org/10.1093/cvr/cvaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797212PMC
January 2021

Inside the heart of COVID-19.

Cardiovasc Res 2020 05;116(6):e59-e61

Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, Glasgow G12 8TA, UK.

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http://dx.doi.org/10.1093/cvr/cvaa086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184380PMC
May 2020