Publications

  • Santulli, Gaetano, Valeria Visco, Michele Ciccarelli, Mario Nicola Vittorio Ferrante, Piero De Masi, Antonella Pansini, Nicola Virtuoso, et al. (2024) 2024. “Frail Hypertensive Older Adults With Prediabetes and Chronic Kidney Disease: Insights on Organ Damage and Cognitive Performance - Preliminary Results from the CARYATID Study”. Cardiovascular Diabetology 23 (1): 125. https://doi.org/10.1186/s12933-024-02218-x.

    BACKGROUND: Hypertension and chronic kidney disease (CKD) pose significant public health challenges, sharing intertwined pathophysiological mechanisms. Prediabetes is recognized as a precursor to diabetes and is often accompanied by cardiovascular comorbidities such as hypertension, elevating the risk of pre-frailty and frailty. Albuminuria is a hallmark of organ damage in hypertension amplifying the risk of pre-frailty, frailty, and cognitive decline in older adults. We explored the association between albuminuria and cognitive impairment in frail older adults with prediabetes and CKD, assessing cognitive levels based on estimated glomerular filtration rate (eGFR).

    METHODS: We conducted a study involving consecutive frail older patients with hypertension recruited from March 2021 to March 2023 at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, followed up after three months. Inclusion criteria comprised age over 65 years, prior diagnosis of hypertension without secondary causes, prediabetes, frailty status, Montreal Cognitive Assessment (MoCA) score < 26, and CKD with eGFR > 15 ml/min.

    RESULTS: 237 patients completed the study. We examined the association between albuminuria and MoCA Score, revealing a significant inverse correlation (r: 0.8846; p < 0.0001). Subsequently, we compared MoCA Score based on eGFR, observing a significant difference (p < 0.0001). These findings were further supported by a multivariable regression analysis, with albuminuria as the dependent variable.

    CONCLUSIONS: Our study represents the pioneering effort to establish a significant correlation between albuminuria and eGFR with cognitive function in frail hypertensive older adults afflicted with prediabetes and CKD.

  • Trimarco, Valentina, Raffaele Izzo, Daniela Pacella, Ugo Trama, Maria Virginia Manzi, Angela Lombardi, Roberto Piccinocchi, et al. (2024) 2024. “Incidence of New-Onset Hypertension Before, During, and After the COVID-19 Pandemic: A 7-Year Longitudinal Cohort Study in a Large Population”. BMC Medicine 22 (1): 127. https://doi.org/10.1186/s12916-024-03328-9.

    BACKGROUND: While the augmented incidence of diabetes after COVID-19 has been widely confirmed, controversial results are available on the risk of developing hypertension during the COVID-19 pandemic.

    METHODS: We designed a longitudinal cohort study to analyze a closed cohort followed up over a 7-year period, i.e., 3 years before and 3 years during the COVID-19 pandemic, and during 2023, when the pandemic was declared to be over. We analyzed medical records of more than 200,000 adults obtained from a cooperative of primary physicians from January 1, 2017, to December 31, 2023. The main outcome was the new diagnosis of hypertension.

    RESULTS: We evaluated 202,163 individuals in the pre-pandemic years and 190,743 in the pandemic years, totaling 206,857 when including 2023 data. The incidence rate of new hypertension was 2.11 (95% C.I. 2.08-2.15) per 100 person-years in the years 2017-2019, increasing to 5.20 (95% C.I. 5.14-5.26) in the period 2020-2022 (RR = 2.46), and to 6.76 (95% C.I. 6.64-6.88) in 2023. The marked difference in trends between the first and the two successive observation periods was substantiated by the fitted regression lines of two Poisson models conducted on the monthly log-incidence of hypertension.

    CONCLUSIONS: We detected a significant increase in new-onset hypertension during the COVID-19 pandemic, which at the end of the observation period affected   20% of the studied cohort, a percentage higher than the diagnosis of COVID-19 infection within the same time frame. This observation suggests that increased attention to hypertension screening should not be limited to individuals who are aware of having contracted the infection but should be extended to the entire population.

  • Forzano, Imma, and Gaetano Santulli. (2024) 2024. “Patent Foramen Ovale: The Unresolved Questions”. Top Italian Scientists Journal 1 (2). https://doi.org/10.62684/DMFZ6956.

    Patent Foramen Ovale (PFO) is a remnant of fetal circulation that could be observed in the 25% of the population worldwide. PFO is associated to numerous clinical conditions as migraines, coronary embolization, transient ischemic attacks, and stroke. The main PFO concerns are related to its correlation to stroke, in particular in young adults. Despite the impact on morbidity that PFO could have, to date there is not clear evidence about its management and treatment. In this narrative review our aim is to summarize the more recent evidence in the literature dealing with PFO, in order to provide an updated overview on this topic.

  • Mone, Pasquale, Stanislovas S Jankauskas, Maria Virginia Manzi, Jessica Gambardella, Antonietta Coppola, Urna Kansakar, Raffaele Izzo, et al. (2024) 2024. “Endothelial Extracellular Vesicles Enriched in MicroRNA-34a Predict New-Onset Diabetes in COVID-19 Patients: Novel Insights for Long-COVID Metabolic Sequelae”. The Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1124/jpet.122.001253.

    Emerging evidence indicates that the relationship between COVID-19 and diabetes is twofold: 1) it is known that the presence of diabetes and other metabolic alterations poses a considerably high risk to develop a severe COVID-19; 2) patients who survived a SARS-CoV-2 infection have an increased risk of developing new-onset diabetes. However the mechanisms underlying this association are mostly unknown and there are no reliable biomarkers to predict the development of new-onset diabetes. In the present study, we demonstrate that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells reliably predicts the risk of developing new-onset diabetes in COVID-19. This association was independent of age, sex, BMI, hypertension, dyslipidemia, smoking status, and D-dimer. Significance Statement We demonstrate for the first time that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells is able to reliably predict the risk of developing new-onset diabetes mellitus after having contracted COVID-19. Strikingly, this association was independent of age, sex, BMI, hypertension, dyslipidemia, smoking status, and D-dimer. Our findings are also relevant when considering the emerging importance of post-acute sequelae of COVID-19, with systemic manifestations observed even months after viral negativization (Long-COVID).

  • Trimarco, Valentina, Raffaele Izzo, Paola Gallo, Maria Virginia Manzi, Imma Forzano, Daniela Pacella, Gaetano Santulli, and Bruno Trimarco. (2024) 2024. “Long-Lasting Control of LDL Cholesterol Induces a 40% Reduction in the Incidence of Cardiovascular Events: New Insights from a 7-Year Study”. The Journal of Pharmacology and Experimental Therapeutics 388 (3): 742-47. https://doi.org/10.1124/jpet.123.001878.

    Recent studies have yielded controversial results on the long-term effects of statins on the risk of cardiovascular (CV) events. To fill this knowledge gap, we assessed the relationship between low-density lipoprotein cholesterol (LDL-C) levels and CV events in hypertensive patients without previous CV events and naïve to antidyslipidemic treatment within the "Campania Salute Network" in Southern Italy. We studied 725 hypertensive patients with a mean follow-up of 85.4 ± 25.7 months. We stratified our cohort into three groups based on LDL cholesterol (LDL-C) levels in mg/dl: group 1) patients showing during the follow-up a mean LDL-C value ≤100 mg/dl in absence of statin therapy; group 2) statin-treated patients with LDL ≤100 mg/dl; and group 3) patients with LDL-C >100 mg/dl. No significant difference among the groups was observed in terms of demographic and clinical characteristics and medications. The incidence of first CV events was 5.7% in group 1, 6.0% in group 2, and 11.9% in group 3 (P < 0.05 vs. group 1 and group 2). A stable long-term satisfactory control of LDL-C plasma concentration (≤100 mg/dl) reduced the incidence of major CV events from one event every 58.6 patients per year to one event every 115.9 patients per year. These findings were confirmed in a Cox regression analysis, adjusting for potential confounding factors. Collectively, our data demonstrate that a 7-year stable control of LDL-C reduces the incidence of CV events by 40%. SIGNIFICANCE STATEMENT: There are several discrepancies between Mendelian studies and other investigations concerning the actual effects of reduction of plasma concentration of low-density lipoprotein (LDL) cholesterol on the incidence of major cardiovascular events. Taken together, our data in nondiabetic subjects show that a 7-year stable control of LDL cholesterol induces a ∼40% reduction of the incidence of cardiovascular events.

  • Mone, Pasquale, Valentina Trimarco, Urna Kansakar, Raffaele Izzo, Gaetano Santulli, and Bruno Trimarco. (2024) 2024. “Combining Choline Bitartrate and Vitamin B12 Ameliorates Cognitive Impairment in Hypertensive Elders With Cognitive Frailty”. Pharmacological Research, 107103. https://doi.org/10.1016/j.phrs.2024.107103.
  • Mone, Pasquale, Germano Guerra, Angela Lombardi, Maddalena Illario, Antonella Pansini, Anna Marro, Salvatore Frullone, et al. (2024) 2024. “Effects of SGLT2 Inhibition via Empagliflozin on Cognitive and Physical Impairment in Frail Diabetic Elders With Chronic Kidney Disease”. Pharmacological Research 200: 107055. https://doi.org/10.1016/j.phrs.2023.107055.
  • Mone, Pasquale, Antonio De Luca, Urna Kansakar, and Gaetano Santulli. (2024) 2024. “Leukocytes and Endothelial Cells Participate in the Pathogenesis of Alzheimer’s Disease: Identifying New Biomarkers Mirroring Metabolic Alterations”. Journal of Alzheimer’s Disease : JAD 97 (4): 1685-87. https://doi.org/10.3233/JAD-231464.

    Alzheimer's disease (AD) is a neurodegenerative disorder marked by amyloid-β accumulation, tau dysfunction, and neuroinflammation, involving endothelial cells and leukocytes. The breakdown of the blood-brain barrier allows immune cell infiltration, intensifying inflammation. A decreased ratio of Connexin-37 (Cx37, also known as GJA4: Gap Junction Protein Alpha 4) and Prolyl Hydroxylase Domain-Containing Protein 3 (PHD3, also known as EGLN3: Egl-9 Family Hypoxia Inducible Factor 3), Cx37/PHD3, consistently observed in different AD-related models, may represent a novel potential biomarker of AD, albeit the exact mechanisms underlying this phenomenon, most likely based on gap junction-mediated cellular interaction that modulate the cellular metabolite status, remain to be fully elucidated.

  • Mone, Pasquale, Germano Guerra, Sofia Verderosa, Gaetano Santulli, and Klara Komici. (2024) 2024. “Effects of Moderate Caffeine Intake in Athletes”. European Journal of Internal Medicine 119: 139-40. https://doi.org/10.1016/j.ejim.2023.09.018.
  • Mone, Pasquale, Germano Guerra, Angela Lombardi, Maddalena Illario, Antonella Pansini, Anna Marro, Salvatore Frullone, et al. (2024) 2024. “Effects of SGLT2 Inhibition via Empagliflozin on Cognitive and Physical Impairment in Frail Diabetic Elders With Chronic Kidney Disease”. Pharmacological Research, 107055. https://doi.org/10.1016/j.phrs.2023.107055.
  • Santulli, Gaetano, Jessica Gambardella, Antonella Fiordelisi, Federica Andrea Cerasuolo, Xujun Wang, Nella Prevete, Eduardo Sommella, et al. (2023) 2023. “Infiltrating Macrophages Amplify Doxorubicin-Induced Cardiac Damage: Role of Catecholamines”. Cellular and Molecular Life Sciences : CMLS 80 (11): 323. https://doi.org/10.1007/s00018-023-04922-5.

    BACKGROUND: The functional contribution of non-myocyte cardiac cells, such as inflammatory cells, in the setup of heart failure in response to doxorubicin (Dox) is recently becoming of growing interest.

    OBJECTIVES: The study aims to evaluate the role of macrophages in cardiac damage elicited by Dox treatment.

    METHODS: C57BL/6 mice were treated with one intraperitoneal injection of Dox (20 mg/kg) and followed up for 5 days by cardiac ultrasounds (CUS), histological, and flow cytometry evaluations. We also tested the impact of Dox in macrophage-depleted mice. Rat cardiomyoblasts were directly treated with Dox (D-Dox) or with a conditioned medium from cultured murine macrophages treated with Dox (M-Dox).

    RESULTS: In response to Dox, macrophage infiltration preceded cardiac damage. Macrophage depletion prevents Dox-induced damage, suggesting a key role of these cells in promoting cardiotoxicity. To evaluate the crosstalk between macrophages and cardiac cells in response to DOX, we compared the effects of D-Dox and M-Dox in vitro. Cell vitality was lower in cardiomyoblasts and apoptosis was higher in response to M-Dox compared with D-Dox. These events were linked to p53-induced mitochondria morphology, function, and autophagy alterations. We identify a mechanistic role of catecholamines released by Dox-activated macrophages that lead to mitochondrial apoptosis of cardiac cells through β-AR stimulation.

    CONCLUSIONS: Our data indicate that crosstalk between macrophages and cardiac cells participates in cardiac damage in response to Dox.

  • Santulli, Gaetano, Valentina Trimarco, Raffaele Izzo, Paola Gallo, Maria Virginia Manzi, Imma Forzano, Daniela Pacella, and Bruno Trimarco. (2023) 2023. “Long-Lasting Control of LDL-Cholesterol Induces a Forty Percent Reduction in the Incidence of Cardiovascular Events: New Insights from a 7-Year Study”. The Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1124/jpet.123.001878.

    Recent studies have yielded controversial results on the long-term effects of statin treatment on the risk of cardiovascular (CV) events. In order to fill this knowledge gap, we analyzed the relationship between LDL-C levels and CV events in hypertensive patients without previous CV events and naïve to antidyslipidemic treatment, within the "Campania Salute Network" in Southern Italy. We studied 725 hypertensive patients with a mean follow-up of 85.4{plus minus}25.7 months. We stratified our population into 3 groups based on LDL-Cholesterol (LDL-C) levels in mg/dL: Group 1) patients showing during the follow-up a mean LDL-C value {less than or equal to}100 mg/dL in absence of statin therapy; Group 2) statin-treated patients with LDL {less than or equal to}100 mg/dL; Group 3) patients with LDL-C >100 mg/dL, with or without statins. No significant difference among the groups was observed in terms of demographic and clinical characteristics and medications. The incidence of first CV events was 6.0% in Group 1, 5.7% in Group 2 (n.s. vs Group 1), and 11.9% in Group 3 (p<0.05 vs Group 1 and Group 2). A stable long-term satisfactory control of LDL-C plasma concentration ({less than or equal to}100 mg/dL) reduced the incidence of major CV events from 1 event every 58,6 patient/years to 1 event every 115,9 patient/years. These findings were confirmed in a Cox regression analysis, adjusting for potential confounding factors. Taken together, our data demonstrate that a 7-year stable control of LDL-C induces a forty percent reduction in the incidence of CV events. Significance Statement There are several discrepancies between Mendelian studies and other investigations on the actual effects of reduction of plasma concentration of LDL cholesterol on the incidence of major cardiovascular events. Taken together, our data in non-diabetic subjects show that a 7-year stable control of LDL cholesterol induces a  40% reduction in the incidence of cardiovascular events.

  • Santulli, Gaetano. (2023) 2023. “Cardiac Sarcoidosis: Updated Insights on Epidemiology and Diagnostic Criteria”. The American Journal of Cardiology 204: 425-27. https://doi.org/10.1016/j.amjcard.2023.07.123.
  • Mone, Pasquale, Antonio De Luca, and Gaetano Santulli. (2023) 2023. “Editorial: Frailty and Oxidative Stress”. Frontiers in Aging 4: 1345486. https://doi.org/10.3389/fragi.2023.1345486.