Publications by authors named "Guido Iaccarino"

172 Publications

The Future Evolution of the Mortality Acceleration Due to the COVID-19: The Charlson Comorbidity Index in Stochastic Setting.

Front Cardiovasc Med 2022 14;9:938086. Epub 2022 Jul 14.

Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.

The empirical evidence from different countries point out many of those who die from coronavirus would have died anyway in the relatively near future due to their existing frailties or co-morbidities. The of the mortality conceives the underlying insight according to deaths are "accelerated" ahead of schedule due to COVID-19. Starting from this idea, we forecast the future mortality acceleration, based on the deterioration due to the presence of the comorbidities at COVID-19 diagnosis. Accordingly, we explicitly determine the contribution of each comorbidity on the acceleration forecasting, showing the future trend of the excess of deaths due to the COVID-19. To this aim, our proposal consists in developing a revised Charlson Comorbidity Index in a stochastic environment. Based on a post-stratification scheme, we obtain an unbiased comorbidity index that varies by age, centered on the reference population.
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http://dx.doi.org/10.3389/fcvm.2022.938086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330029PMC
July 2022

Editorial: Highlights in Hypertension: 2021.

Authors:
Guido Iaccarino

Front Cardiovasc Med 2022 15;9:926949. Epub 2022 Jun 15.

Center for Research on Hypertension and Related Conditions, Federico II University of Naples, Naples, Italy.

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http://dx.doi.org/10.3389/fcvm.2022.926949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241515PMC
June 2022

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J Pharmacol Exp Ther 2022 Jul 2. Epub 2022 Jul 2.

Department of Medicine, Surgery and Dentistry, University of Salerno, Italy

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to be a global challenge due to resulting morbidity and mortality. Cardiovascular (CV) involvement is a crucial complication in COVID-19, and no strategies are available to prevent or specifically address CV events in COVID patients. The identification of molecular partners contributing to CV manifestations in COVID-19 patients is crucial for providing early biomarkers, prognostic predictors and new therapeutic targets. The current report will focus on the role of miRNAs in CV complications associated with COVID-19. Indeed, miRNAs have been proposed as valuable biomarkers and predictors of both cardiac and vascular damage occurring in SARS-CoV-2 infection. It is essential to identify the molecular mediators of COVID-19 cardiovascular (CV) complications. This report focused on the role of miRNAs in CV complications associated with COVID-19, discussing their potential use as biomarkers, prognostic predictors, and therapeutic targets.
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http://dx.doi.org/10.1124/jpet.122.001210DOI Listing
July 2022

Mitochondrial microRNAs are dysregulated in patients with Fabry Disease.

J Pharmacol Exp Ther 2022 Jun 28. Epub 2022 Jun 28.

Department of Advanced Biomedical Sciences, "Federico II" University, Italy

Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the gene for alpha- galactosidase A (GAL) inducing a progressive accumulation of globotriaosylceramide (Gb3) and its metabolites in different organs and tissues. GB3 deposition does not fully explain the clinical manifestations of FD, and other pathogenetic mechanisms have been proposed requiring the identification of new biomarkers for monitoring FD patients. Previous evidence suggests the involvement of mitochondrial alterations in FD. Here, we propose mitochondrial related microRNA (miRNAs, miRs) as potential biomarkers of mitochondrial involvement in FD. We observed that miRNAs regulating different aspects of mitochondrial homeostasis including expression and assembly of respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are consistently dysregulated in FD patients. Our data unveil a novel non-coding RNA signature of FD patients, indicating mitochondrial related miRNAs (mitomiRs) as new potential pathogenic players and biomarkers in FD. We demonstrate for the first time that a specific signature of circulating mitochondrial microRNAs (mitomiRs) are dysregulated in Fabry disease (FD). In our study, we observed that mitomiRs regulating fundamental aspects of mitochondrial homeostasis, including expression and assembly of the respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are significantly dysregulated in FD patients. Taken together, our new findings introduce mitomiRs as unprecedented biomarkers of FD and point at mitochondrial dysfunction as a novel potential mechanistic target for therapeutic approaches.
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http://dx.doi.org/10.1124/jpet.122.001250DOI Listing
June 2022

World Hypertension Day 2021 in Italy: Results of a Nationwide Survey.

High Blood Press Cardiovasc Prev 2022 Jul 13;29(4):353-359. Epub 2022 Apr 13.

Internal Medicine and Nephrology Unit, ESH Excellence Center for Hypertension and Cardiovascular Prevention, San Salvatore Hospital, University of L'Aquila, Department of Clinical Medicine, Public Health, Life and Environmental Sciences, G. Petrini str., 67100, L'Aquila, Italy.

Introduction: Hypertension is the biggest contributor to the global burden of cardiovascular diseases and related death, but the rates of hypertension awareness, treatment, and control remain largely perfectible.

Methods: During the XVII World Hypertension Day (May 17th, 2021), a nationwide cross-sectional opportunistic study endorsed by the Italian Society of Hypertension was conducted on volunteer adults ≥ 18 years to raise awareness of high blood pressure (BP). A questionnaire on major demographic/clinical features (sex, age, employment, education, BP status awareness, hypertension family/personal history, antihypertensive medications use) and BP measurement habits (≥1 BP measurement in the previous month/week) was administered. Due to the ongoing SARS-CoV-2 pandemic, BP was measured with standard procedures in a subset of participants (24.4%).

Results: A total of 1354 participants (mean age 56.3 ± 15.3 years; 57.3% women; mean BP: 131.2 ± 17.5/81.6 ± 10.5 mmHg; 42.3% self-declared hypertensive; 41.4% on antihypertensive medications) were enrolled; 73.6% declared being aware of their BP status. Among treated individuals with measured BP, 26.9% showed BP levels within the predefined therapeutic goals. Interestingly, BP status awareness rates were the highest among individuals with uncontrolled hypertension (85.1%) and the lowest among those with normal measured BP (54.4%).

Conclusions: This survey provides an updated insight into hypertension awareness and control in a setting of daily clinical practice, emphasizing the centricity of patients in the therapeutic alliance for a successful reduction of cardiovascular risk.
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http://dx.doi.org/10.1007/s40292-022-00519-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006201PMC
July 2022

Interactions Between EIP on AHA Reference Sites and Action Groups to Foster Digital Innovation of Health and Care in European Regions.

Clin Interv Aging 2022 2;17:343-358. Epub 2022 Apr 2.

Executive Board, EIP on AHA Reference Sites Collaborative Network, Brussels, Belgium.

The article describes some of the achievements of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA), after eight years in operation. These results were achieved thanks to the collaborative work of the action groups (AGs) and reference sites (RSs). RS regional ecosystems include key organisations committed to investing in innovation to foster active and healthy ageing. The AGs are groups of professionals committed to sharing their knowledge and skills in active and healthy ageing. This article reports on the approach used by the EIP on AHA to bring together experts and regions in identifying and addressing these challenges. Synergies between AGs offered substantial support to RSs, allowing regional health and care priorities and challenges to be identified and pursued through AG commitments. Building upon the experiences of the EIP on AHA, the Reference Sites Collaborative Network has set up a number of thematic action groups that bring together multidisciplinary experts from across Europe to address the main health and social care challenges at regional, national and European level.
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http://dx.doi.org/10.2147/CIA.S323723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985824PMC
April 2022

Serum uric acid levels threshold for mortality in diabetic individuals: The URic acid Right for heArt Health (URRAH) project.

Nutr Metab Cardiovasc Dis 2022 05 3;32(5):1245-1252. Epub 2022 Feb 3.

Department of Internal Medicine, University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Background And Aim: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes.

Methods And Results: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders.

Conclusions: SUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.
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http://dx.doi.org/10.1016/j.numecd.2022.01.028DOI Listing
May 2022

The association of uric acid with mortality modifies at old age: data from the uric acid right for heart health (URRAH) study.

J Hypertens 2022 04;40(4):704-711

Department of Internal Medicine, University of Genoa and Policlinico San Martino, Genoa.

Objectives: In older individuals, the role of serum uric acid (SUA) as risk factor for mortality is debated. This study investigated the association of SUA with all-cause and cardiovascular (CV) mortality in older adults participating in the large multicentre observational uric acid right for heart health (URRAH) study.

Methods: Eight thousand URRAH participants aged 65+ were included in the analysis. The predictive role of SUA was assessed using Cox regression models stratified according to the cut-off age of 75. SUA was tested as continuous and categorical variable (age-specific quartiles). The prognostic threshold of SUA for mortality was analysed using receiver operating characteristic curves.

Results: Among participants aged 65-74, multivariate Cox regression analysis adjusted for CV risk factors and comorbidities identified an independent association of SUA with both all-cause mortality (hazard ratio [HR] 1.169, 95% confidence interval [CI] 1.107-1.235) and CV mortality (HR 1.146, 95% CI 1.064-1.235). The cut-off value of 4.8 mg/dl discriminated mortality status. In participants aged 75+, we observed a J-shaped relationship of SUA with all-cause and CV mortality, with risk increasing at extreme SUA levels.

Conclusions: These results confirmed the predictive role of SUA for all-cause and CV mortality in older adults, while revealing considerable age-related differences. Mortality risk increased at higher SUA levels in participants aged 65-74, with a prognostic threshold of 4.8 mg/dl. The relationship between SUA and mortality was J-shaped in oldest participants. Large interventional studies are needed to clarify the benefits and possible risks of urate-lowering treatments in older adults.
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http://dx.doi.org/10.1097/HJH.0000000000003068DOI Listing
April 2022

Digitally Enabled Health Service for the Integrated Management of Hypertension: A Participatory User-Centred Design Process.

Int J Environ Res Public Health 2021 11 26;18(23). Epub 2021 Nov 26.

Dipartimento di Sanità Pubblica, Università Degli Studi di Napoli Federico II, Via S. Pansini 5, 80131 Naples, Italy.

This article describes a user-centred approach taken by a group of five procurers to set specifications for the procurement of value-based research and development services for IT-supported integrated hypertension management. The approach considered the unmet needs of patients and health systems of the involved regions. The procurers established a framework for requirements and a solution design consisting of nine building blocks, divided into three domains: service delivery, devices and integration, and health care organisation. The approach included the development of questionnaires, capturing patients' and professionals' views on possible system functionalities, and a template collecting information about the organisation of healthcare, professionals involved and existing IT systems at the procurers' premises. A total of 28 patients diagnosed with hypertension and 26 professionals were interviewed. The interviewees identified 98 functional requirements, grouped in the nine building blocks. A total of nine use cases and their corresponding process models were defined by the procurers' working group. As result, a digitally enabled integrated approach to hypertension has been designed to allow citizens to learn how to prevent the development of hypertension and lead a healthy lifestyle, and to receive comprehensive, individualised treatment in close collaboration with healthcare professionals.
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http://dx.doi.org/10.3390/ijerph182312442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656774PMC
November 2021

Heart Mitochondrial Metabolic Flexibility and Redox Status Are Improved by Donkey and Human Milk Intake.

Antioxidants (Basel) 2021 Nov 13;10(11). Epub 2021 Nov 13.

Department of Biology, University of Naples Federico II, 80126 Naples, Italy.

The biological mechanisms linking nutrition and antioxidants content of the diet with cardiovascular protection are subject of intense investigation. It has been demonstrated that dietary supplementation with cow, donkey or human milk, characterized by distinct nutritional properties, triggers significant differences in the metabolic and inflammatory status through the modulation of hepatic and skeletal muscle mitochondrial functions. Cardiac mitochondria play a key role for energy-demanding heart functions, and their disfunctions is leading to pathologies. Indeed, an altered heart mitochondrial function and the consequent increased reactive oxygen species (ROS) production and inflammatory state, is linked to several cardiac diseases such as hypertension and heart failure. In this work it was investigated the impact of the milk consumption on heart mitochondrial functions, inflammation and oxidative stress. In addition, it was underlined the crosstalk between mitochondrial metabolic flexibility, lipid storage and redox status as control mechanisms for the maintenance of cardiovascular health.
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http://dx.doi.org/10.3390/antiox10111807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614950PMC
November 2021

Serum Uric Acid and Kidney Disease Measures Independently Predict Cardiovascular and Total Mortality: The Uric Acid Right for Heart Health (URRAH) Project.

Front Cardiovasc Med 2021 27;8:713652. Epub 2021 Sep 27.

Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality. We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality. After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardiovascular mortality, stratified based on eGFR (>90, between 60 and 90 and <60 ml/min) was significantly higher in patients with hyperuricemia and albuminuria (3.8, 22.1 and 19.1, respectively) as compared to those with only one risk factor or none (0.4, 2.8 and 3.1, respectively). Serum uric acid and eGFR significantly interact in determining cardiovascular and all-cause mortality. For each SUA increase of 1 mg/dl the risk for mortality increased by 10% even after adjustment for potential confounding factors included eGFR and the presence of albuminuria. hyperuricemia is a risk factor for cardiovascular and all-cause mortality additively to eGFR strata and albuminuria, in patients at cardiovascular risk.
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http://dx.doi.org/10.3389/fcvm.2021.713652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502977PMC
September 2021

Identification of a plausible serum uric acid cut-off value as prognostic marker of stroke: the Uric Acid Right for Heart Health (URRAH) study.

J Hum Hypertens 2021 Sep 29. Epub 2021 Sep 29.

Department of Geriatric and Intensive Care Medicine, Careggi Hospital and University of Florence, Florence, Italy.

The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting combined (fatal and non-fatal) cerebrovascular (CBV) events in the whole database. The URic acid Right for heArt Health study is a nationwide, multicenter, observational cohort study involving data on subjects aged 18-95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 120.7 ± 61.8 months. A total of 14,588 subjects were included in the analysis. A prognostic cut-off value of SUA able to discriminate combined CBV events (>4.79 mg/dL or >284.91 µmol/L) was identified by means of receiver operating characteristic curve in the whole database. Multivariate Cox regression analysis adjusted for confounders (age, sex, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, body mass index, low-density lipoprotein cholesterol, and use of diuretics) identified an independent association between SUA and combined CBV events in the whole database (HR 1.249, 95% confidence interval, 1.041-1.497, p = 0.016). The results of the present study confirm that SUA is an independent risk marker for CBV events after adjusting for potential confounding variables, including arterial hypertension, and demonstrate that >4.79 mg/dL is a valid prognostic cut-off value.
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http://dx.doi.org/10.1038/s41371-021-00613-5DOI Listing
September 2021

Preexisting Oral Anticoagulant Therapy Ameliorates Prognosis in Hospitalized COVID-19 Patients.

Front Cardiovasc Med 2021 13;8:633878. Epub 2021 May 13.

Department of Clinical Medicine, Public Health, Life and Environment Sciences, University of L'Aquila, L'Aquila, Italy.

Altered coagulation parameters in COVID-19 patients is associated with a poor prognosis. We tested whether COVID-19 patients on chronic oral anticoagulants (cOACs) for thromboembolism prophylaxis could receive protection from developing more severe phenotypes of the disease. We searched the database of the SARS-RAS study (Clinicaltrials.gov: NCT04331574), a cross-sectional observational multicenter nationwide survey in Italy designed by the Italian Society of Hypertension. The database counts 2,377 charts of Italian COVID-19 patients in 26 hospitals. We calculated the Charlson comorbidity index (CCI), which is associated with death in COVID-19 patients. In our population ( = 2,377, age 68.2 ± 0.4 years, CCI: 3.04 ± 0.04), we confirm that CCI is associated with increased mortality [OR: 1.756 (1.628-1.894)], admission to intensive care units [ICU; OR: 1.074 (1.017-1.134)], and combined hard events [CHE; OR: 1.277 (1.215-1.342)]. One hundred twenty-five patients were on cOACs (age: 79.3 ± 0.9 years, CCI: 4.35 ± 0.13); despite the higher CCI, cOACs patients presented with a lower risk of admissions to the ICU [OR 0.469 (0.250-0.880)] but not of death [OR: 1.306 (0.78-2.188)] or CHE [OR: 0.843 (0.541-1.312)]. In multivariable logistic regression, cOACs confirmed their protective effect on ICU admission and CHE. The CCI remains the most important risk factor for ICU admission, death, and CHE. Our data support a mechanism for the continuation of cOAC therapy after hospital admission for those patients who are on chronic treatment. Our preliminary results suggest the prophylactic use of direct cOACs in patients with elevated CCI score at the time of the COVID-19 pandemic even in absence of other risks of thromboembolism.
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http://dx.doi.org/10.3389/fcvm.2021.633878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155285PMC
May 2021

"One Health" Approach for Health Innovation and Active Aging in Campania (Italy).

Front Public Health 2021 11;9:658959. Epub 2021 May 11.

Dipartimento di Sanità Pubblica, Università degli Studi di Napoli "Federico II, " Naples, Italy.

This article describes how innovations are exploited in Campania (Italy) to improve health outcomes, quality of life, and sustainability of social and healthcare services. Campania's strategy for digitalization of health and care and for healthy aging is based on a person-centered, life-course, "One Health" approach, where demographic change is considered capable of stimulating a growth dynamic linked to the opportunities of combining the "Silver Economy" with local assets and the specific health needs of the population. The end-users (citizens, patients, and professionals) contribute to the co-creation of products and services, being involved in the identification of unmet needs and test-bed activity. The Campania Reference Site of the European Innovation Partnership on Active and Healthy Aging is a flexible regional ecosystem to address the challenge of an aging population with a life-course approach. The good practices, developed in the context of research and innovation projects and innovative procurements by local stakeholders and collaborations with international networks, have been allowing the transfer of innovative solutions, knowledge, and skills to the stakeholders of such a multi-sectoral ecosystem for health.
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http://dx.doi.org/10.3389/fpubh.2021.658959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144456PMC
June 2021

Physical Exercise: A Novel Tool to Protect Mitochondrial Health.

Front Physiol 2021 27;12:660068. Epub 2021 Apr 27.

Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy.

Mitochondrial dysfunction is a crucial contributor to heart diseases. Alterations in energetic metabolism affect crucial homeostatic processes, such asATP production, the generation of reactive oxygen species, and the release of pro-apoptotic factors, associated with metabolic abnormalities. In response to energetic deficiency, the cardiomyocytes activate the Mitochondrial Quality Control (MQC), a critical process in maintaining mitochondrial health. This process is compromised in cardiovascular diseases depending on the pathology's severity and represents, therefore, a potential therapeutic target. Several potential targeting molecules within this process have been identified in the last years, and therapeutic strategies have been proposed to ameliorate mitochondria monitoring and function. In this context, physical exercise is considered a non-pharmacological strategy to protect mitochondrial health. Physical exercise regulates MQC allowing the repair/elimination of damaged mitochondria and synthesizing new ones, thus recovering the metabolic state. In this review, we will deal with the effect of physical exercise on cardiac mitochondrial function tracing its ability to modulate specific steps in MQC both in physiologic and pathologic conditions.
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http://dx.doi.org/10.3389/fphys.2021.660068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110831PMC
April 2021

Effects of Chronic Supplementation of L-Arginine on Physical Fitness in Water Polo Players.

Oxid Med Cell Longev 2021 15;2021:6684568. Epub 2021 Mar 15.

Department of Advanced Biomedical Sciences, Federico II University of Naples, Italy.

Background: Ergogenic nutritional supplementation is sought by professional athletes for improving physical performance; nevertheless, scientific evidence to support the chronic use of L-Arginine among water polo players is missing.

Methods: Seventeen male professional water polo players were randomly assigned to assume 5 grams per day of L-Arginine ( = 9) or placebo ( = 8) for 4 weeks. The players' fitness level was assessed in the maximal speed swimming test. Ear lobe blood samples taken before and after the effort for serum lactate content were analyzed. A speed-to-lactate ratio was generated at the baseline and after 4 weeks of treatment. We also tested the effects of L-Arginine , measuring NO production, mitochondrial respiration, and gene expression in human fibroblasts.

Results: L-Arginine did not modify BMI, muscle strength, and maximal speed at 200 meters after 4 weeks. However, L-Arginine ameliorated oxidative metabolism to exercise as suggested by the statistically significant lower lactate-to-speed ratio, which was not observed in placebo-treated controls. , L-Arginine induced the expression of a key regulator of mitochondrial biogenesis (PGC1) and genes encoding for complex I and increased the production of nitric oxide and the maximal oxygen consumption rate.

Conclusions: Chronic L-Arginine is safe and effective in ameliorating the oxidative metabolism of professional water polo players, through a mechanism of enhanced mitochondrial function.
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http://dx.doi.org/10.1155/2021/6684568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994081PMC
May 2021

Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development.

Pharmacol Res 2021 06 26;168:105581. Epub 2021 Mar 26.

Laboratory of Cellular and Molecular Cardiovascular Patho-Physiology, Department of Biology, E. and E.S., University of Calabria, Arcavacata di Rende, CS, Italy.

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches.
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http://dx.doi.org/10.1016/j.phrs.2021.105581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997688PMC
June 2021

Association of uric acid with kidney function and albuminuria: the Uric Acid Right for heArt Health (URRAH) Project.

J Nephrol 2022 Jan 23;35(1):211-221. Epub 2021 Mar 23.

Department of Medicine, University of Padua, Padua, Italy.

Background: Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). However, a better understanding of the relationship among uric acid (UA) values, glomerular filtration rate (GFR) and albuminuria may shed light on the mechanisms underlying the excess of cardiovascular mortality associated with both chronic kidney disease and hyperuricemia and lead to better risk stratification. Our main goal was to study the relationships between serum uric acid and kidney disease measures (namely estimated GFR [eGFR] and albuminuria) in a large cohort of individuals at cardiovascular risk from the URic acid Right for heArt Health (URRAH) Project database.

Methods: Clinical data of 26,971 individuals were analyzed. Factors associated with the presence of hyperuricemia defined on the basis of previously determined URRAH cutoffs for cardiovascular and all-cause mortality were evaluated through multivariate analysis. Chronic kidney disease was defined as eGFR < 60 ml/min per 1.73 m and/or abnormal urinary albumin excretion diagnosed as: (i) microalbuminuria if urinary albumin concentration was > 30 and ≤ 300 mg/L, or if urinary albumin-to-creatinine ratio (ACR) was > 3.4 mg/mmol and ≤ 34 mg/mmol; (ii) macroalbuminuria if urinary albumin concentration was > 300 mg/L, or if ACR was > 34 mg/mmol.

Results: Mean age was 58 ± 15 years (51% males, 62% with hypertension and 12% with diabetes), mean eGFR was 81 ml/min per 1.73m2with a prevalence of eGFR < 60 and micro- or macroalbuminuria of 16, 15 and 4%, respectively. Serum uric acid showed a trend towards higher values along with decreasing renal function. Both the prevalence of gout and the frequency of allopurinol use increased significantly with the reduction of eGFR and the increase in albuminuria. Hyperuricemia was independently related to male gender, eGFR strata, and signs of insulin resistance such as body mass index (BMI) and triglycerides.

Conclusions: The lower the eGFR the higher the prevalence of hyperuricemia and gout. In subjects with eGFR < 60 ml/min the occurrence of hyperuricemia is about 10 times higher than in those with eGFR > 90 ml/min. The percentage of individuals treated with allopurinol was below 2% when GFR was above 60 ml/min, it increased to 20% in the presence of CKD 3b and rose further to 35% in individuals with macroalbuminuria.
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http://dx.doi.org/10.1007/s40620-021-00985-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803667PMC
January 2022

The importance of including uric acid in the definition of metabolic syndrome when assessing the mortality risk.

Clin Res Cardiol 2021 Jul 18;110(7):1073-1082. Epub 2021 Feb 18.

Department of Cardiovascular, Neural and Metabolic Sciences, Istituto Auxologico Italiano, IRCCS S. Luca Hospital, Lucca, Italy.

Introduction: Serum uric acid (SUA) has been depicted as a contributory causal factor in metabolic syndrome (MS), which in turn, portends unfavourable prognosis.

Aim: We assessed the prognostic role of SUA in patients with and without MS.

Methods: We used data from the multicentre Uric Acid Right for Heart Health study and considered cardiovascular mortality (CVM) as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure.

Results: A total of 9589 subjects (median age 58.5 years, 45% males) were included in the analysis, and 5100 (53%) patients had a final diagnosis of MS. After a median follow-up of 142 months, we observed 558 events. Using a previously validated cardiovascular SUA cut-off to predict CVM (> 5.1 mg/dL in women and 5.6 mg/dL in men), elevated SUA levels were significantly associated to a worse outcome in patients with and without MS (all p < 0.0001) and provided a significant net reclassification improvement of 7.1% over the diagnosis of MS for CVM (p = 0.004). Cox regression analyses identified an independent association between SUA and CVM (Hazard Ratio: 1.79 [95% CI, 1.15-2.79]; p < 0.0001) after the adjustment for MS, its single components and renal function. Three specific combinations of the MS components were associated with higher CVM when increasing SUA levels were reported, and systemic hypertension was the only individual component ever-present (all p < 0.0001).

Conclusion: Increasing SUA levels are associated with a higher CVM risk irrespective of the presence of MS: a cardiovascular SUA threshold may improve risk stratification.
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http://dx.doi.org/10.1007/s00392-021-01815-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238697PMC
July 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 Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field.

Int J Mol Sci 2021 Jan 29;22(3). Epub 2021 Jan 29.

Department of Advanced Biomedical Sciences, Federico II University, Via Pansini 5, 80131 Naples, Italy.

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD's development and progression that could become useful targets for therapeutics. This review discusses FD's cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage.
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http://dx.doi.org/10.3390/ijms22031331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865937PMC
January 2021

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19.

Int Arch Allergy Immunol 2021 10;182(4):324-338. Epub 2021 Feb 10.

Division of Infection, Immunity & Respiratory Medicine, Royal Manchester Children's Hospital, University of Manchester, Manchester, United Kingdom.

In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.
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http://dx.doi.org/10.1159/000514204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018185PMC
April 2021

Clinical Characteristics and Outcomes of Patients with COVID-19 Infection: The Results of the SARS-RAS Study of the Italian Society of Hypertension.

High Blood Press Cardiovasc Prev 2021 Jan 20;28(1):5-11. Epub 2021 Jan 20.

Department of Advanced Biomedical Sciences, Federico II University of Naples, Via Panisini 5, 80138, Naples, Italy.

The COVID-19 infection has rapidly spread around the world and a second wave is sweeping in many countries. Different clinical and epidemiological aspects characterize the disease and their understanding is necessary to better face the management of the pandemic in progress. The Italian society of arterial hypertension with the SARS-RAS study has contributed significantly to the knowledge of the interaction between inhibition of the renin-angiotensin system and COVID-19 infection. Furthermore, the study results help to understand some of the main aspects related to mortality and morbidity deriving from the infection through a multicentre analysis throughout the national territory.
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http://dx.doi.org/10.1007/s40292-020-00429-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816058PMC
January 2021

The Metabolic Role of GRK2 in Insulin Resistance and Associated Conditions.

Cells 2021 01 15;10(1). Epub 2021 Jan 15.

Dipartimento di Scienze Biomediche Avanzate, Università Federico II di Napoli, 80131 Napoli, Italy.

Insulin resistance (IRES) is a pathophysiological condition characterized by the reduced response to insulin of several tissues, including myocardial and skeletal muscle. IRES is associated with obesity, glucose intolerance, dyslipidemia, and hypertension, evolves toward type 2 diabetes, and increases the risk of developing cardiovascular diseases. Several studies designed to explore the mechanisms involved in IRES allowed the identification of a multitude of potential molecular targets. Among the most promising, G Protein Coupled Receptor Kinase type 2 (GRK2) appears to be a suitable one given its functional implications in many cellular processes. In this review, we will discuss the metabolic role of GRK2 in those conditions that are characterized by insulin resistance (diabetes, hypertension, heart failure), and the potentiality of its inhibition as a therapeutic strategy to revert both insulin resistance and its associated phenotypes.
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http://dx.doi.org/10.3390/cells10010167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830135PMC
January 2021

Efficacy of broccoli and glucoraphanin in COVID-19: From hypothesis to proof-of-concept with three experimental clinical cases.

World Allergy Organ J 2021 Jan 9;14(1):100498. Epub 2020 Dec 9.

IMIM (Hospital del Mar Research Institute), Barcelona, Spain.

COVID-19 is described in a clinical case involving a patient who proposed the hypothesis that Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-interacting nutrients may help to prevent severe COVID-19 symptoms. Capsules of broccoli seeds containing glucoraphanin were being taken before the onset of SARS-CoV-2 infection and were continued daily for over a month after the first COVID-19 symptoms. They were found to reduce many of the symptoms rapidly and for a duration of 6-12 h by repeated dosing. When the patient was stable but still suffering from cough and nasal obstruction when not taking the broccoli capsules, a double-blind induced cough challenge confirmed the speed of onset of the capsules (less than 10 min). A second clinical case with lower broccoli doses carried out during the cytokine storm confirmed the clinical benefits already observed. A third clinical case showed similar effects at the onset of symptoms. In the first clinical trial, we used a dose of under 600 μmol per day of glucoraphanin. However, such a high dose may induce pharmacologic effects that require careful examination before the performance of any study. It is likely that the fast onset of action is mediated through the TRPA1 channel. These experimental clinical cases represent a proof-of-concept confirming the hypothesis that Nrf2-interacting nutrients are effective in COVID-19. However, this cannot be used in practice before the availability of further safety data, and confirmation is necessary through proper trials on efficacy and safety.
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http://dx.doi.org/10.1016/j.waojou.2020.100498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770975PMC
January 2021

Spices to Control COVID-19 Symptoms: Yes, but Not Only….

Int Arch Allergy Immunol 2021 22;182(6):489-495. Epub 2020 Dec 22.

Maladies Infectieuses et Tropicales, CHU, Montpellier, France.

There are large country variations in COVID-19 death rates that may be partly explained by diet. Many countries with low COVID-19 death rates have a common feature of eating large quantities of fermented vegetables such as cabbage and, in some continents, various spices. Fermented vegetables and spices are agonists of the antioxidant transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and spices are transient receptor potential ankyrin 1 and vanillin 1 (TRPA1/V1) agonists. These mechanisms may explain many COVID-19 symptoms and severity. It appears that there is a synergy between Nrf2 and TRPA1/V1 foods that may explain the role of diet in COVID-19. One of the mechanisms of COVID-19 appears to be an oxygen species (ROS)-mediated process in synergy with TRP channels, modulated by Nrf2 pathways. Spicy foods are likely to desensitize TRP channels and act in synergy with exogenous antioxidants that activate the Nrf2 pathway.
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http://dx.doi.org/10.1159/000513538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900475PMC
June 2021

Serum Uric Acid and Left Ventricular Mass in Essential Hypertension.

Front Cardiovasc Med 2020 26;7:570000. Epub 2020 Nov 26.

Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy.

Serum uric acid (sUA) has been associated with cardiovascular risk. Although the recent mechanistic hypothesis poses the basis for the association between sUA and left ventricular mass index (LVMi), the issue remains poorly investigated in a clinical setup. Through a retrospective analysis of the database of the departmental Hypertension Clinic of University Hospital of Salerno Medical School, we identified 177 essential hypertensives (age 60.3 ± 13.3 years; 85 men), free from uric acid-modulating medications and severe chronic kidney disease, and whose sUA values, anthropometric, clinical, and echocardiographic data were available. In the studied cohort, the average duration of hypertension was 8.4 ± 7.1 years. LVMi associated with classical determinants, such as age, blood pressure, and kidney function, although after multivariate correction, only age remained significant. Also, sUA correlated positively with LVMi, as well as body size, metabolism, and kidney function. In a multivariate analysis, sUA confirmed the independent association with LVMi. Also, levels of sUA >5.6 mg/dl are associated with larger cardiac size. We confirmed our data in a replicate analysis performed in a larger population (1,379 hypertensives) from an independent clinic. Our results demonstrate that sUA increases with LVMi, and a cutoff of 5.6 mg/dl predict larger LV sizes. Our data suggest that hyperuricemia might help to stratify the risk of larger cardiac size in hypertensives.
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http://dx.doi.org/10.3389/fcvm.2020.570000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725708PMC
November 2020
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