Publications by authors named "Gianpaolo Reboldi"

199 Publications

Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension.

Cardiol Ther 2021 Jul 12. Epub 2021 Jul 12.

Department of Medicine and Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia, Perugia, Italy.

Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed. Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.
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http://dx.doi.org/10.1007/s40119-021-00233-7DOI Listing
July 2021

SARS-CoV-2 infection and ACE2 inhibition.

J Hypertens 2021 08;39(8):1555-1558

Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy.

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http://dx.doi.org/10.1097/HJH.0000000000002859DOI Listing
August 2021

[Nephrology: where we stand and where we should go].

G Ital Nefrol 2021 Jun 24;38(3). Epub 2021 Jun 24.

SC di Nefrologia e Dialisi, Ospedale di Trento, Trento, Italy.

In the last year, the Italian National Health Service as a whole and the Nephrology community have been severely challenged by the pandemic. It has been a dramatic stress test for the entire healthcare system, not only in Italy but worldwide. The general organization of our Nephrology units and our models of care were put under extreme pressure, and we had to quickly adopt unprecedented clinical practice recommendations and organizational models to overcome the impasse caused by the pandemic. The time has come to evaluate these new experiences, ask how we could have been better prepared and look for change. In this editorial, we outline a few proposals and suggestions for the future, weighing the information gathered in the 2018 Nephrology Census against the new organizational requirements imposed by the COVID-19 pandemic.
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June 2021

Ageing, ACE2 deficiency and bad outcome in COVID-19.

Clin Chem Lab Med 2021 Jun 14. Epub 2021 Jun 14.

Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy.

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http://dx.doi.org/10.1515/cclm-2021-0658DOI Listing
June 2021

Worldwide Early Impact of COVID-19 on Dialysis Patients and Staff and Lessons Learned: A DOPPS Roundtable Discussion.

Kidney Med 2021 May 14. Epub 2021 May 14.

Arbor Research Collaborative for Health, Ann Arbor, USA.

As the worst global pandemic of the past century, COVID-19 has had a disproportionate effect on maintenance dialysis patients and their health care providers. At a virtual roundtable on 12 June 2020, DOPPS investigators from fifteen countries in Asia, Europe, and the Americas described and compared the effects of COVID-19 on dialysis care, with recent updates added. Most striking is the huge difference in risk to dialysis patients and staff across the world. Per-population cases and deaths among dialysis patients vary over 100-fold across participating countries, mirroring burden in the general population. International data indicate case fatality ratio remains at 10-30% among dialysis patients, confirming the gravity of infection, and that cases are much more common among in-center than home dialysis patients. This latter finding merits urgent study because in-center patients often have greater community exposure, and in-center transmission may be uncommon under optimal protocols. Greater telemedicine use is a welcome change here to stay, and our community needs to improve emergency planning and protect dialysis staff from the next pandemic. Finally, the pandemic's challenges have prompted widespread partnering and innovation in kidney care and research that must be sustained after this global health crisis.
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http://dx.doi.org/10.1016/j.xkme.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120787PMC
May 2021

SARS-CoV-2 vaccines: Lights and shadows.

Eur J Intern Med 2021 06 30;88:1-8. Epub 2021 Apr 30.

Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy.

Vaccines to prevent acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicit an immune neutralizing response. Some concerns have been raised regarding the safety of SARS-CoV-2 vaccines, largely based on case-reports of serious thromboembolic events after vaccination. Some mechanisms have been suggested which might explain the adverse cardiovascular reactions to SARS-CoV-2 vaccines. Different vaccine platforms are currently available which include live attenuated vaccines, inactivated vaccines, recombinant protein vaccines, vector vaccines, DNA vaccines and RNA vaccines. Vaccines increase the endogenous synthesis of SARS-CoV-2 Spike proteins from a variety of cells. Once synthetized, the Spike proteins assembled in the cytoplasma migrate to the cell surface and protrude with a native-like conformation. These proteins are recognized by the immune system which rapidly develops an immune response. Such response appears to be quite vigorous in the presence of DNA vaccines which encode viral vectors, as well as in subjects who are immunized because of previous exposure to SARS-CoV-2. The resulting pathological features may resemble those of active coronavirus disease. The free-floating Spike proteins synthetized by cells targeted by vaccine and destroyed by the immune response circulate in the blood and systematically interact with angiotensin converting enzyme 2 (ACE2) receptors expressed by a variety of cells including platelets, thereby promoting ACE2 internalization and degradation. These reactions may ultimately lead to platelet aggregation, thrombosis and inflammation mediated by several mechanisms including platelet ACE2 receptors. Whereas Phase III vaccine trials generally excluded participants with previous immunization, vaccination of huge populations in the real life will inevitably include individuals with preexisting immunity. This might lead to excessively enhanced inflammatory and thrombotic reactions in occasional subjects. Further research is urgently needed in this area.
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http://dx.doi.org/10.1016/j.ejim.2021.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084611PMC
June 2021

High heart rate amplifies the risk of cardiovascular mortality associated with elevated uric acid.

Eur J Prev Cardiol 2021 Feb 14. Epub 2021 Feb 14.

Hypertension Unit, Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University of Rome Sapienza, Sant'Andrea Hospital, Rome, Italy.

Aims : Whether the association between uric acid (UA) and cardiovascular disease is influenced by some facilitating factors is unclear. The aim of this study was to investigate whether the risk of cardiovascular mortality (CVM) associated with elevated UA was modulated by the level of resting heart rate (HR).

Methods And Results : Multivariable Cox analyses were made in 19 128 participants from the multicentre Uric acid Right for heArt Health study. During a median follow-up of 11.2 years, there were 1381 cases of CVM. In multivariable Cox models both UA and HR, either considered as continuous or categorical variables were independent predictors of CVM both improving risk discrimination (P ≤ 0.003) and reclassification (P < 0.0001) over a multivariable model. However, the risk of CVM related to high UA (≥5.5 mg/dL, top tertile) was much lower in the subjects with HR
Conclusion : This data suggest that the contribution of UA to determining CVM is modulated by the level of HR supporting the hypothesis that activation of the sympathetic nervous system facilitates the action of UA as a cardiovascular risk factor.
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http://dx.doi.org/10.1093/eurjpc/zwab023DOI Listing
February 2021

The Link between Inflammation and Hypertension: Unmasking Mediators.

Am J Hypertens 2021 Feb 11. Epub 2021 Feb 11.

Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia - Italy.

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http://dx.doi.org/10.1093/ajh/hpab034DOI Listing
February 2021

Lessons Learnt during the COVID-19 Pandemic: For Patients with End-Stage Renal Disease, We Should Prioritize Home-Based Treatment and Telemedicine.

Kidney Blood Press Res 2021 29;46(1):11-16. Epub 2021 Jan 29.

Nephrology and Dialysis Unit, Fondazione "Casa Sollievo Della Sofferenza," IRCCS, San Giovanni Rotondo, Italy.

Backgrounds: The recent coronavirus disease 2019 (CO-VID-19) pandemic has placed worldwide health systems and hospitals under pressure, and so are the renal care models. This may be a unique opportunity to promote and expand alternative models of health-care delivery in patients undergoing renal replacement therapies.

Summary: Despite the high risk of acquiring communicable diseases when undergoing in-centre treatments, only a small proportion of patients are currently being treated with home therapies. Recent data provided by the Italian Society of Nephrology (SIN), the REIN French Registry and the Wuhan Hemodialysis Quality Control Center clearly show that patients receiving hospital-based treatment have a 3- to 4-fold greater risk of infection, and a subsequent fatality proportion between 21 and 34%. On the other hand, home-based therapy can be managed remotely, there is little or no need for transport to and from the hospital, and it is less expensive. Besides, the digital revolution in health care with the development of virtual care systems can make home dialysis with telehealth a cost-effective solution for both patients and health-care providers. Such a transition would require specific training for physicians and health-care professionals and a functional re-organization of dialysis centres to improve the skills and expertise in caring for patients at home.

Conclusion: The need for more widespread home treatment is the main lesson learnt by nephrologists by the COVID-19 pandemic.
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http://dx.doi.org/10.1159/000512629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900471PMC
March 2021

Masked Nocturnal Hypertension: A Complex Phenomenon to Detect in Clinical Practice.

Am J Hypertens 2021 06;34(6):578-580

Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy.

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http://dx.doi.org/10.1093/ajh/hpab007DOI Listing
June 2021

Risk factors and action thresholds for the novel coronavirus pandemic. Insights from the Italian Society of Nephrology COVID-19 Survey.

J Nephrol 2021 04 2;34(2):325-335. Epub 2021 Jan 2.

Italian Society of Nephrology, Viale dell'Università, 11, 00185, Rome, RM, Italy.

Background And Aim: Over 80% (365/454) of the nation's centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, 2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment.

Methods: We investigated fixed factors and contextual effects by multilevel modeling. Classification and Regression Tree (CART) analysis was used to develop decision rules.

Results: Increased positivity among hemodialysis patients was predicted by center location [incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 1.20-1.51], positive healthcare workers (IRR 1.09, 95% CI 1.02-1.17), test-all policy (IRR 5.94, 95% CI 3.36-10.45), and infected proportion in the general population (IRR 1.002, 95% CI 1.001-1.003) (all p < 0.01). Conversely, lockdown duration exerted a protective effect (IRR 0.95, 95% CI 0.94-0.98) (p < 0.01). The province-contextual effects accounted for 10% of the total variability. Predictive factors for peritoneal dialysis and transplant cases were center location and infected proportion in the general population. Using recursive partitioning, we identified decision thresholds at general population incidence ≥ 229 per 100,000 and at ≥ 3 positive healthcare workers.

Conclusions: Beyond fixed risk factors, shared with the general population, the increased and heterogeneous proportion of positive patients is related to the center's testing policy, the number of positive patients and healthcare workers, and to contextual effects at the province level. Nephrology centers may adopt simple decision rules to strengthen containment measures timely.
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http://dx.doi.org/10.1007/s40620-020-00946-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776284PMC
April 2021

Indications for renal biopsy in patients with diabetes. Joint position statement of the Italian Society of Nephrology and the Italian Diabetes Society.

Nutr Metab Cardiovasc Dis 2020 11 19;30(12):2123-2132. Epub 2020 Sep 19.

Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy; Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.

Aims: This joint document of the Italian Society of Nephrology and the Italian Diabetes Society reviews the main indications to perform a renal biopsy in diabetic patients, according to the recommendations of a panel of experts based on all available scientific evidence.

Data Synthesis: Renal biopsy has a pivotal role in assessing the nature and severity of renal injury in patients with diabetic kidney disease (DKD). The procedure is mandatory in the presence of one of more of the following features: rapid onset or progression of albuminuria or sudden onset of nephrotic syndrome, rapid GFR decline with or without albuminuria, hematuria, active urine sediment, clinical and/or laboratory suspicion of other systemic diseases, and, in patients with type 1 diabetes, short diabetes duration and absence of retinopathy. Indeed, ~40% of diabetic individuals with kidney injury undergoing renal biopsy are affected by a non-diabetic renal disease (NDRD). Furthermore, the histological evaluation of patients with suspected classical diabetic nephropathy allows to define the extent of glomerular, tubulo-interstitial and vascular lesions, thus providing important prognostic (and potentially therapeutic) data. In the future, the indications for renal biopsy might be extended to the definition of the histological lesions underlying the "nonalbuminuric" DKD phenotypes, as well as to the evaluation of the response to treatment with the new anti-hyperglycemic drugs that provide cardiorenal protection.

Conclusions: In view of the heterogeneous clinical presentation and course of DKD and of the related heterogeneous histopathological patterns, a more extensive use of renal biopsy may be crucial to provide valuable information with important pathogenic, diagnostic, prognostic, and therapeutic implications.
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http://dx.doi.org/10.1016/j.numecd.2020.09.013DOI Listing
November 2020

RAAS Inhibitors and Risk of Covid-19.

N Engl J Med 2020 Nov 27;383(20):1990-1991. Epub 2020 Oct 27.

University of Perugia, Perugia, Italy.

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http://dx.doi.org/10.1056/NEJMc2030446DOI Listing
November 2020

The 2020 International Society of Hypertension global hypertension practice guidelines - key messages and clinical considerations.

Eur J Intern Med 2020 12 22;82:1-6. Epub 2020 Sep 22.

Department of Medicine and Surgery, University of Insubria, Varese and Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, Varese, Italy.

The International Society of Hypertension (ISH) has recently developed practice guidelines for the management of hypertension in adults aged ≥18 years. Conceptually, the 2020 ISH Guidelines are closer to the 2018 ESC/ESH Guidelines rather than to the 2017 ACC/AHA Guidelines. The ISH Guidelines have two distinctive features when compared with the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines and the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines. First, they are written in a concise and easy-to-read style; second, they focuses on practical issues related to the management of hypertension in 'high-income' as well as in 'low-income' countries, where there is limited access to resources for the diagnosis and treatment of hypertension. In our opinion, the 2020 ISH Guidelines share with the 2018 ESC/ESH Guidelines an important limitation which may impair the retention of these key aspects of Guidelines by physicians, with consequent difficult adoption in clinical practice. It consists in the definition of several blood pressure targets in relation to age, target organ damage and concomitant disease. We believe that results of randomized clinical trials and meta-analysis do not support the recommendation of differential BP targets, as well as of rigid 'safety boundaries'. This review critically examines similarities and differences across the three major Hypertension Guidelines, which include the definition of hypertension, drug treatment, and blood pressure targets, with emphasis on key messages relevant for clinical practice.
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http://dx.doi.org/10.1016/j.ejim.2020.09.001DOI Listing
December 2020

Performance of creatinine- and cystatin C-based formulas to estimate glomerular filtration rate.

Eur J Intern Med 2020 10 13;80:16-17. Epub 2020 Aug 13.

Department of Medicine, University of Perugia, Perugia, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2020.08.011DOI Listing
October 2020

Exposure to novel coronavirus in patients on renal replacement therapy during the exponential phase of COVID-19 pandemic: survey of the Italian Society of Nephrology.

J Nephrol 2020 08 3;33(4):725-736. Epub 2020 Jul 3.

Italian Society of Nephrology, Viale dell'Università, 11, 00185, Roma, RM, Italy.

Background: Between February and April 2020, Italy experienced an overwhelming growth of the COVID-19 pandemic. Little is known, at the country level, where and how patients on renal replacement therapy (RRT) have been mostly affected.

Methods: Survey of the network of Nephrology centers using a simplified 17 items electronic questionnaire designed by Italian Society of Nephrology COVID-19 Research Group. We used spatial epidemiology and geographical information systems to map SARS-CoV-2 spread among RRT patients in Italy.

Results: On April 9th 2020, all nephrology centers (n = 454) listed in the DialMap database were invited to complete the electronic questionnaire. Within 11 days on average, 365 centers responded (80.4% response rate; 2.3% margin of error) totaling 60,441 RRT patients. The surveyed RRT population included 30,821 hemodialysis (HD), 4139 peritoneal dialysis (PD), and 25,481 transplanted (Tx) patients respectively. The proportion of SARS-CoV-2 positive RRT patients in Italy was 2.26% (95% CI 2.14-2.39) with significant differences according to treatment modality (p < 0.001). The proportion of patients positive for SARS-CoV-2 was significantly higher in HD (3.55% [95% CI 3.34-3.76]) than PD (1.38% [95% CI 1.04-1.78] and Tx (0.86% [95% CI 0.75-0.98]) (p < 0.001), with substantial heterogeneity across regions and along the latitude gradient (p < 0.001). In RRT patients the highest rate was in the north-west (4.39% [95% CI 4.11-4.68], followed by the north-east (IR 2.06% [1.79-2.36]), the center (0.91% [0.75-1.09]), the main islands (0.67% [0.47-0.93]), and the south (0.59% [0.45-0.75]. During the COVID-19 pandemic, among SARS-Cov-2 positive RRT patients the fatality rate was 32.8%, as compared to 13.3% observed in the Italian population as of April 23rd.

Conclusions: A substantial proportion of the 60,441 surveyed RRT patients in Italy were SARS-Cov-2 positive and subsequently died during the exponential phase of COVID-19 pandemic. Infection risk and rates seems to differ substantially across regions, along geographical latitude, and by treatment modality.
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http://dx.doi.org/10.1007/s40620-020-00794-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333370PMC
August 2020

Electrocardiographic features of patients with COVID-19 pneumonia.

Eur J Intern Med 2020 08 20;78:101-106. Epub 2020 Jun 20.

Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia - Italy.

Background: . The electrocardiographic (ECG) changes which may occur during hospitalization for COVID-19 have not yet been comprehensively assessed.

Patients And Methods: . We examined 50 patients admitted to hospital with proven COVID-19 pneumonia. At entry, all patients underwent a detailed clinical examination, 12-lead ECG, laboratory tests and arterial blood gas test. ECG was also recorded at discharge and in case of worsening clinical conditions.

Results: . Mean age of patients was 64 years and 72% were men. At baseline, 30% of patients had ST-T abnormalities, and 33% had left ventricular hypertrophy. During hospitalization, 26% of patients developed new ECG abnormalities which included atrial fibrillation, ST-T changes, tachy-brady syndrome, and changes consistent with acute pericarditis. One patient was transferred to intensive care unit for massive pulmonary embolism with right bundle branch block, and another for non-ST segment elevation myocardial infarction. Patients free of ECG changes during hospitalization were more likely to be treated with antiretrovirals (68% vs 15%, p = 0.001) and hydroxychloroquine (89% vs 62%, p = 0.026) versus those who developed ECG abnormalities after admission. Most measurable ECG features at discharge did not show significant changes from baseline (all p>0.05) except for a slightly decrease in Cornell voltages (13±6 vs 11±5 mm; p = 0.0001) and a modest increase in the PR interval. The majority (54%) of patients with ECG abnormalities had 2 prior consecutive negative nasopharyngeal swabs. ECG abnormalities were first detected after an average of about 30 days from symptoms' onset (range 12-51 days).

Conclusions: . ECG abnormalities during hospitalization for COVID-19 pneumonia reflect a wide spectrum of cardiovascular complications, exhibit a late onset, do not progress in parallel with pulmonary abnormalities and may occur after negative nasopharyngeal swabs.
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http://dx.doi.org/10.1016/j.ejim.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305928PMC
August 2020

Treatment strategies for isolated systolic hypertension in elderly patients.

Expert Opin Pharmacother 2020 Oct 25;21(14):1713-1723. Epub 2020 Jun 25.

Department of Medicine, University of Perugia , Perugia, Italy.

Introduction: Hypertension is a major and modifiable risk factor for cardiovascular disease. Its prevalence is rising as the result of population aging. Isolated systolic hypertension mostly occurs in older patients accounting for up to 80% of cases.

Areas Covered: The authors systematically review published studies to appraise the scientific and clinical evidence supporting the role of blood pressure control in elderly patients with isolated systolic hypertension, and to assess the influence of different drug treatment regimens on outcomes.

Expert Opinion: Antihypertensive treatment of isolated systolic hypertension significantly reduces the risk of morbidity and mortality in elderly patients. Thiazide diuretics and dihydropyridine calcium-channel blockers are the primary compounds used in randomized clinical trials. These drugs can be considered as first-line agents for the management of isolated systolic hypertension. Free or fixed combination therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and calcium-channel blockers or thiazide-like diuretics should also be considered, particularly when compelling indications such as coronary artery disease, chronic kidney disease, diabetes, and congestive heart failure coexist. There is also hot scientific debate on the optimal blood pressure target to be achieved in elderly patients with isolated systolic hypertension, but current recommendations are scarcely supported by evidence.
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http://dx.doi.org/10.1080/14656566.2020.1781092DOI Listing
October 2020

The revolution of the anti-diabetic drugs in cardiology.

Eur Heart J Suppl 2020 Jun 29;22(Suppl E):E162-E166. Epub 2020 Mar 29.

Dipartimento di Medicina, Università di Perugia, Perugia, Italy.

Beginning in December 2008, under the auspices of Food and Drug Administration, numerous controlled clinical trial were planned, and in part completed, concerning the cardiovascular (CV) effects of hypoglycaemic drug in patients with Type 2 diabetes mellitus. At least 9 studies have been concluded, 13 are still open, and 4 have been initiated and closed ahead of time. Of the nine completed studies, three concerned inhibitor of the dipeptidyl peptidase 4 (inhibitors of DPP-4), four the glucagon-like peptide 1 agonist (GLP-1 agonist), and two the inhibitor of sodium-glucose co-transporter-2 (inhibitors of SGLT-2). Only four studies demonstrated the superiority, and not the mere 'non-inferiority', of the anti-diabetic drugs compared to placebo, in addition to standard treatment, in terms of reduction of the primary endpoint (CV death, non-fatal myocardial infarction, and non-fatal stroke). Two of the four studies regarded GLP-1 analogues (liraglutide and semaglutide), and two inhibitors of SGLT-2 (empaglifozin and canaglifozin). As a whole, these studies provided solid data supporting major beneficial CV effects of anti-diabetic drugs. During the next 3-4 years, an equal number of studies will be completed and published, so we will soon have the 'final word' on this issue. In the meantime, the clinical cardiologist should become familiar with these drugs, selecting the patients able to gain the best clinical advantage from this treatment, also by establishing a close relationship with the diabetologist.
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http://dx.doi.org/10.1093/eurheartj/suaa084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270967PMC
June 2020

Management of hypertension in the very old: an intensive reduction of blood pressure should be achieved in most patients.

J Hum Hypertens 2020 09 12;34(8):551-556. Epub 2020 May 12.

Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy.

There is large evidence that treatment of hypertension significantly reduces the risk of morbidity and mortality in the elderly. Although it is generally accepted that the benefit of antihypertensive treatment is largely explained by the reduction in systolic blood pressure, the optimal blood pressure target in elderly patients is still a topic of debate. Unfortunately, the clinical trials which demonstrated the benefit of antihypertensive treatment in old and very old patients with hypertension included relatively fit patients since frail patients were generally excluded. Available data suggest that when treating older adults, and especially frail older hypertensive adults, extra caution is appropriate in the setting of significant adverse events. Nonetheless, recent observations demonstrated a similar benefit from a more intensive compared with a less intensive blood pressure lowering in both fit and frail older adults. Of note, the rate of serious adverse events appears not dissimilar in the two treatment strategies, and not associated to frailty. Taken together, these findings support the concept that an intensive therapeutic strategy appears reasonable even in elderly hypertensive patients, particularly when the treatment is well tolerated.
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http://dx.doi.org/10.1038/s41371-020-0345-1DOI Listing
September 2020

Safety of catheter ablation of atrial fibrillation in cancer survivors.

J Interv Card Electrophysiol 2021 Apr 6;60(3):419-426. Epub 2020 May 6.

Arrhythmia and Electrophysiology Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.

Purpose: In patients with cancer, the safety of catheter ablation for non-valvular atrial fibrillation (AF) has not been evaluated, yet. The aim of this study was to assess the safety of AF ablation in cancer survivors.

Methods: Consecutively recruited patients undergoing catheter ablation of non-valvular AF at our center between March 2015 and March 2017 were evaluated. The primary outcome of the study was clinically relevant bleedings occurred within 30 ± 5 days after the procedure. Patients with cancer were propensity matched to patients without cancer in a 1:3 and 1:6 ratio after stratification by baseline clinical features.

Results: Overall, 184 patients were included in the study. Of them, 21 (11%) were cancer survivors. Cancer site was more frequently gastrointestinal (36%), breast (23%), and genitourinary (18%). At 30 ± 5 days, clinically relevant bleedings occurred in 14 patients. Crude odds ratio (OR) for clinically relevant bleedings was 3.60 (95% CI 1.02-12.7) higher in cancer than in non-cancer patients. This trend remained after propensity score-matched population (OR 3.48, 95% CI 0.76-15.90 for matched 1:3, OR 4.95, 95% CI 1.2-20.2 for matched 1:6). Type of anticoagulation was not associated with bleedings.

Conclusions: Preliminary results suggest that clinically relevant bleeding after catheter ablation for AF is more frequent in cancer survivors than in patients without cancer. Further studies are required to confirm the present data.
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http://dx.doi.org/10.1007/s10840-020-00745-7DOI Listing
April 2021

[ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus].

G Ital Cardiol (Rome) 2020 May;21(5):321-327

Dipartimento di Medicina e Chirurgia, Università degli Studi dell'Insubria, Varese; Dipartimento di Medicina e Riabilitazione Cardio-Respiratoria, Istituti Clinici Scientifici Maugeri, IRCCS, Tradate (VA).

Some Authors recently suggested that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be discontinued, even temporarily, given the current pandemic of SARS-CoV-2 virus. The suggestion is based on the hypothesis that ACE-inhibitors and ARBs may favor the entry and diffusion of SARS-CoV-2 virus into the human cells. ACE-inhibitors and ARBs may increase the expression of ACE2 receptors, which are the sites of viral entry into the human organism. ACE2 receptors are ubiquitous, although they are extremely abundant on the cell surface of type 2 pneumocytes. Type 2 pneumocytes are small cylindrical alveolar cells located in close vicinity to pulmonary capillaries and responsible for the synthesis of alveolar surfactant, which is known to facilitate gas exchanges. The increased expression of ACE2 for effect of ACE-inhibitors and ARBs can be detected by increased production of angiotensin1-7 and mRNA related to ACE2. There is the fear that the increased expression of ACE2 induced by ACE-inhibitors and ARBs may ultimately facilitate the entry and diffusion of the SARS-CoV-2 virus. However, there is no clinical evidence to support this hypothesis. Furthermore, available data are conflicting and some counter-intuitive findings suggest that ARBs may be beneficial, not harmful. Indeed, studies conducted in different laboratories demonstrated that ACE2 receptors show a down-regulation (i.e. the opposite of what would happen with ACE-inhibitors and ARBs) for effect of their interaction with the virus. In animal studies, down-regulation of ACE2 has been found as prevalent in the pulmonary areas infected by virus, but not in the surrounding areas. In these studies, virus-induced ACE2 down-regulation would lead to a reduced formation of angiotensin1-7 (because ACE2 degrades angiotensin II into angiotensin1-7) with consequent accumulation of angiotensin II. The excess angiotensin II would favor pulmonary edema and inflammation, a phenomenon directly associated with angiotensin II levels, along with worsening in pulmonary function. Such detrimental effects have been blocked by ARBs in experimental models. In the light of the above considerations, it is reasonable to conclude that the suggestion to discontinue ACE-inhibitors or ARBs in all patients with the aim of preventing or limiting the diffusion of SARS-CoV-2 virus is not based on clinical evidence. Conversely, experimental studies suggest that ARBs might be useful in these patients to limit pulmonary damage through the inhibition of type 1 angiotensin II receptors. Controlled clinical studies in this area are eagerly awaited. This review discusses facts and theories on the potential impact of ACE-inhibitors and ARBs in the setting of the SARS-CoV-2 pandemic.
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http://dx.doi.org/10.1714/3343.33127DOI Listing
May 2020

Optimal Use of the Non-Inferiority Trial Design.

Pharmaceut Med 2020 06;34(3):159-165

Department of Medicine, University of Perugia, 06156, Perugia, Italy.

Superiority trials are conducted to test the hypothesis that a treatment or strategy A is superior to (i.e., better than) treatment strategy B in reducing the impact of disease. However, A may be considerably safer, more convenient, or cheaper than B. These features may make A more attractive than B even if the burden of disease is reduced comparably by the two treatments, or even a bit worse by A over B. In this context, non-inferiority trials have become increasingly popular to test the hypothesis that a new treatment is not 'unacceptably worse' than an active comparator by more than a predefined non-inferiority margin. Non-inferiority trials have unique design features and methodology and require a different analysis than traditional superiority trials. The main aim of this overview is to analyze the role of non-inferiority trials in the development of new treatments, involving some scientific, statistical, and practical considerations. We elucidate some aspects of non-inferiority trials that contribute to the validity of the results. The unique design features and methodology of non-inferiority trials are summarized and key findings to consider when evaluating a non-inferiority trial are illustrated.
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http://dx.doi.org/10.1007/s40290-020-00334-zDOI Listing
June 2020

Blood pressure variability and risk of stroke in chronic kidney disease.

J Hypertens 2020 04;38(4):599-602

Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy.

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http://dx.doi.org/10.1097/HJH.0000000000002339DOI Listing
April 2020

Microalbuminuria assessment after thoracic surgery: Early identification of complication risks.

Clin Respir J 2020 Jun 25;14(6):564-570. Epub 2020 Feb 25.

Thoracic Surgery Unit, Department of Surgical Science, S. Maria della Misericordia Hospital, University of Perugia Medical School, Perugia, Italy.

Introduction: Microalbuminuria (MA) is considered a reflection of systemic capillary leak and an early marker of acute stress reaction to the surgical insult, proportional to the severity of the initiating condition and predictive of the individual response to surgical stress.

Objectives: We conducted a prospective study to assess for the variation of MA within 4 days after thoracic surgery. We correlated observed MA levels with both their respective PaO /FiO respiratory ratio and the onset of postoperative complications.

Methods: This single-centre study enrolled 255 consecutive patients having an American Society of Anaesthesiologists (ASA) score ≤ 3. The mean age was 62 years with 67% male. All patients were scheduled for elective pulmonary resection. MA was measured in urine samples as the albumin-to-creatinine ratio (A/C), prior to, at and after extubation up to 96 hours. PaO /FiO was measured at extubation and on the first postoperative day.

Results: Overall, preoperative A/C levels resulted normal, with a significant average increase at extubation which peaked 6 hours later (P < 0.001). Larger postoperative A/C increases were observed in patients who developed postoperative complications, compared to those without these complications (P < 0.019). Moreover, patients undergoing major open pulmonary resections had larger postoperative A/C increases, compared to those undergoing minor video-assisted thoracic surgery resections (P < 0.006). At the time of extubation, A/C was inversely related to the PaO /FiO ratio (r = -0.25; P = 0.038). Peak A/C > 61 mg/g (P = 0.0003) was associated with postoperative cardio-pulmonary complications (OR 3.85; P = 0.003).

Conclusion: Within 6 hours after extubation, MA assessment may be a rapid and relatively inexpensive method for better predicting perioperative risk in an ASA score ≤ 3 population.
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http://dx.doi.org/10.1111/crj.13169DOI Listing
June 2020

Use of Antibiotics and Mortality in Women: Does Duration of Exposure Matter?

Circ Res 2020 01 30;126(3):374-376. Epub 2020 Jan 30.

Department of Medicine, University of Perugia, Italy (G.R.).

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http://dx.doi.org/10.1161/CIRCRESAHA.119.316406DOI Listing
January 2020

Association of Extreme Nocturnal Dipping With Cardiovascular Events Strongly Depends on Age.

Hypertension 2020 02 23;75(2):324-330. Epub 2019 Dec 23.

University of Perugia, Italy (S.S., G.R.).

Whether extreme dipping is associated with cardiovascular events (CVE) is unclear. The present study was conducted to test the hypothesis that the prognostic role of extreme dipping varies as a function of age. The analysis was performed in 10 868 participants (53% men) aged 53±15 (mean±SD) years enrolled in 8 prospective studies. Using the ambulatory systolic blood pressure nocturnal decline, we identified 4 groups: dippers (>10%-20%), nondippers (>0%-10%), reverse dippers (≤0%), and extreme dippers (>20%). The association between dipping category and CVE was estimated as a function of age using Cox models adjusted for sex, average 24-hour systolic blood pressure, and traditional risk factors. During a median follow-up of 5.7 years, there were a total of 829 CVE (168 fatal). For extreme dippers, no increase in risk of CVE was observed among the participants <70 years (hazard ratio, 0.99 [95% CI, 0.73-1.34]; =0.93) compared with dippers. In contrast, among the participants ≥70 years, there was a significant increase in risk (hazard ratio, 1.88 [95% CI, 1.14-3.11]; =0.013). Among the octogenarians, the hazard ratio (95% CI) for CVE were 2.34 (1.12-4.93) for nondippers (=0.024), 3.91 (1.75-8.73) for reverse dippers (=0.001), and 4.12 (1.64-10.37) for extreme dippers (=0.003) compared with dippers. These data show that extreme dipping is not associated with poorer outcome in people younger than 70 years. A U-shaped relationship between nocturnal blood pressure dipping and adverse outcome is present in subjects older than 70 years. In the octogenarian extreme dippers, the risk of CVEs was 4× higher than in the dippers and similar to that in the reverse dippers.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14085DOI Listing
February 2020

Echocardiography in Low-Risk Hypertensive Patients.

J Am Heart Assoc 2019 12 16;8(24):e013497. Epub 2019 Dec 16.

Department of Medicine University of Perugia Italy.

Background It is debated whether echocardiography should be part of the diagnostic workup in all hypertensive patients. We identified some factors potentially associated with left ventricular hypertrophy (LVH) at echocardiography in untreated hypertensive patients. Methods and Results We studied 2150 patients without LVH at ECG. All patients underwent standard 12-lead ECG and echocardiography. Mean age was 48.7 years, and mean office blood pressure was 154/97 mm Hg. Prevalence of echocardiographic LVH (LV mass >47.0 g/m in women and >50.0 g/m in men) was 37.1%. We developed a nomogram based on 7 items (age, smoking, body mass index, office systolic and diastolic blood pressure, Cornell voltage, and chronic kidney disease) on the basis of a multivariable logistic regression analysis. We internally validated the model by bootstrap recalibration and obtained a calibration curve to assess agreement in the validation data set. Probability of LVH at echocardiography ranged from <10% (score, ≤100 points) to >90% (score, ≥180 points). Proportion of patients with LVH progressively increased with the total score (χ=444.8; <0.001). Prevalence of LVH was <2% and 90% at the lower 5th and upper 95th percentile of its distribution, respectively. Conclusions We developed and validated a novel score to assess the probability of LVH at echocardiography in hypertensive patients without LVH at ECG. The score may guide the appropriateness of echocardiographic study in low-risk hypertensive patients. Echocardiography appears most appropriate for score values >136 in men and >124 in women.
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http://dx.doi.org/10.1161/JAHA.119.013497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951057PMC
December 2019
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