Serum uric acid levels and the risk of recurrent venous thromboembolism
(J Thromb Haemost. 2021 Jen).
De Lucchi L, Nardin C, Sponchiado A, Raggi D, Faggin E, Martini E, Pagliara V, Callegari E, Caberlotto L, Plebani M, Pauletto P, Cinetto F, Agostini C, Villalta S, Rattazzi M.
Elevati livelli di acido urico si associano ad un aumentato rischio di andare incontro ad una recidiva di evento tromboembolico venoso, indipendentemente dalla presenza di fattori di rischio tradizionali.
Background. The link between serum uric acid (SUA) and the risk of cardiovascular disease is well established. However, the impact of SUA levels on the risk of venous thromboembolism (VTE) recurrence is unknown. Objectives. To investigate the association between SUA and the risk of VTE recurrence.
Patients and Methods. We performed a monocenter, prospective study on 280 patients with a previous episode of VTE that completed the oral anticoagulant period. SUA levels at enrollment were correlated with the risk of VTE recurrence (mean follow-up 71.1 ± 29.2 months).
Results. Patients were stratified according to SUA tertiles distribution at baseline (tertiles cut-off: I ≤ 4.37 mg/dL, II 4.38–5.54 mg/dL, III ≥ 5.55 mg/dL). Fifty episodes of VTE recurrence occurred during the follow-up and Kaplan-Meier survival analysis showed that subjects in the lower tertile of SUA distribution had significantly lower risk of future VTE recurrence (P = .003). No differences were seen among patients belonging to the second and the third tertile of SUA distribution. A multivariate Cox regression analysis showed that higher tertiles of SUA distribution had about three-fold increase in the risk of VTE recurrence as compared to subjects with SUA ≤ 4.37, independently from potential confounders (hazard ratio [HR] 3.04, 95% confidence interval [CI] 1.15–8.05 P = .025). Moreover, we observed that the adjusted hazard of VTE recurrence increased by 30% for each additional unit of SUA (mg/dL; HR 1.30, 95% CI 1.01–1.22, P = .040). Conclusion. Elevated SUA levels are associated with increased risk of future VTE recurrence independently from traditional risk factors.
Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives
(Am J Hypertens. 2020 Jun)
Felice C, Nardin C, Di Tanna GL, Grossi U, Bernardi E, Scaldaferri L, Romagnoli M, Tonon L, Cavasin P, Novello S, Scarpa R, Farnia A, De Menis E, Rigoli R, Cinetto F, Pauletto P, Agostini C, Rattazzi M.
Il trattamento con farmaci inibitori del sistema Renina-Angiotensina-Aldosterone (ACE inibitori e sartani) non interferisce negativamente con l’andamento clinico dell’infezione da COVID-19 nei pazienti ipertesi. Tale terapia dovrebbe essere pertanto proseguita in corso di infezione da Sars-Cov-2.
Background: The effect of chronic use of renin-angiotensin-aldosterone system (RAAS) inhibitors on the severity of COVID-19 infection is still unclear in patients with hypertension. We aimed to investigate the association between chronic use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and COVID-19-related outcomes in hypertensive patients.
Methods: A single-center study was conducted on 133 consecutive hypertensive subjects presenting to the emergency department with acute respiratory symptoms and/or fever who were diagnosed with COVID-19 infection between 9 and 31 March 2020.
Results: All patients were grouped according to their chronic antihypertensive medications (ACEIs, N = 40; ARBs, N = 42; not on RAAS inhibitors, N = 51). There was no statistical difference between ACEIs and ARBs groups in terms of hospital admission rate, oxygen therapy, and need for noninvasive ventilation. Patients chronically treated with RAAS inhibitors showed a significantly lower rate of admission to semi-intensive/intensive care units, when compared with the non-RAAS population (odds ratio (OR) 0.25, confidence interval (CI) 95% 0.09-0.66, P = 0.006). Similarly, the risk of mortality was lower in the former group, although not reaching statistical significance (OR 0.56, CI 95% 0.17-1.83, P = 0.341).
Conclusions: Our data suggest that chronic use of RAAS inhibitors does not negatively affect clinical course of COVID-19 in hypertensive patients. Further studies are needed to confirm this finding and determine whether RAAS inhibitors may have a protective effect on COVID-19-related morbidity and mortality.
l-Arginine prevents inflammatory and pro-calcific differentiation of interstitial aortic valve cells
(Atherosclerosis. 2020 Apr)
Rattazzi M, Donato M, Bertacco E, Millioni R, Franchin C, Mortarino C, Faggin E, Nardin C, Scarpa R, Cinetto F, Agostini C, Ferri N, Pauletto P, Arrigoni G.
L-Arginina, il principale precursore dell’ossido nitrico, previene la differenziazione osteogenica delle cellule interstiziali della valvola aortica e riduce la calcificazione della matrice extracellulare, processi coinvolti nella patogenesi della stenosi aortica calcifica.
Background and aims: Reduced bioavailability of nitric oxide (NO) has been implicated in the pathogenesis of calcific aortic stenosis. Herein, we investigated the effects of l-Arginine, the main precursor of NO, on the osteogenic differentiation of aortic interstitial valve cells (VICs). Methods: We isolated a clonal population of bovine VICs that expresses osteogenic markers and induces calcification of collagen matrix after stimulation with endotoxin (LPS 500 ng/mL). VICs were treated in vitro with different combinations of LPS ± l-Arginine (50 or 100 mM) and cell extracts were collected to perform proteomic (iTRAQ) and gene expression (RT-PCR) analysis. Results: l-Arginine prevents the over-expression of alkaline phosphatase (ALP, p < 0.001) and reduces matrix calcification (p < 0.05) in VICs treated with LPS. l-Arginine also reduces the over-expression of inflammatory molecules induced by LPS (TNF-alpha, IL-6 and IL-1beta, p < 0.001). The proteomic analysis allowed to identify 49 proteins with an altered expression profile after stimulation with LPS and significantly modified by l-Arginine. These include proteins involved in the redox homeostasis of the cells (i.e. Xanthine Oxidase, Catalase, Aldehyde Oxidase), remodeling of the extracellular matrix (i.e. ADAMTSL4, Basigin, COL3A1) and cellular signaling (i.e. Fibrillin-1, Legumain, S100A13). The RT-PCR analysis confirmed the modifications of Fibrillin-1, ADAMTSL4, Basigin and Xanthine Oxidase, whose expression levels increase after stimulation with LPS and are reduced by l-Arginine (p < 0.05). Conclusions: l-Arginine prevents osteogenic differentiation of VICs and reduces matrix calcification. This effect is achieved through the modulation of proteins involved in the cellular redox system, remodeling of extracellular matrix and inflammatory activation of VIC.
Cardiovascular Phenotype of Elevated Blood Pressure Differs Markedly Between Young Males and Females: The Enigma Study
(Hypertension 2018 Dec)
Nardin C, Maki-Petaja KM, Miles KL, Yasmin, McDonnell BJ, Cockcroft JR, Wilkinson IB, McEniery CM, Enigma Study Investigators Collaborators
Un fenotipo emodinamico di tipo cardiogeno, caratterizzato da elevata gittata cardiaca, gittata sistolica e frequenza cardiaca potrebbe essere dominante nello sviluppo dell’ipertensione sostenuta nei giovani maschi, mentre un fenotipo emodinamico di tipo vascolare, caratterizzato da un incremento delle resistenze vascolari periferiche e della rigidità arteriosa, potrebbe rappresentare il meccanismo prevalente nella genesi dell’ipertensione sostenuta nelle giovani donne.
Blood pressure (BP) in young adults predicts BP in later life. We aimed to identify metabolic, hemodynamic, and autonomic characteristics associated with raised BP in young adults and whether these differ between males and females. Three thousand one hundred forty-five healthy subjects, aged 18 to 40 years, were grouped according to sex and BP category following the recent reclassification of BP as part of American Heart Association/American College of Cardiology 2017 guidelines. All individuals undertook a lifestyle and medical history questionnaire and detailed metabolic, hemodynamic, and autonomic assessments. Stage 1 hypertension and normal BP were the most common BP phenotypes in males (29%) and females (68%), respectively. In both sexes, cardiac output was positively associated with increasing BP category (P<0.001 for both). Similar positive trends were observed for heart rate and stroke volume in males (P<0.001 for both) and heart rate in females (P<0.001). Unlike in males, peripheral vascular resistance, aortic pulse wave velocity, and augmentation index were significantly increased in hypertensive females (P<0.001 for all) compared with the other BP categories. Most heart rate variability indices decreased across the BP categories, particularly in males. In young adults, metabolic and hemodynamic abnormalities associated with hypertension are already present at the elevated BP stage and the overall phenotype differed markedly between sexes. Whereas a cardiac phenotype was associated with elevated BP and hypertension in males, a vascular phenotype, characterized by elevated peripheral vascular resistance, aortic pulse wave velocity, and augmentation index, was dominant in females.
Warfarin, but not rivaroxaban, promotes the calcification of the aortic valve in ApoE-/- mice
Cardiovasc Ther. 2018 Aug
Rattazzi M, Faggin E, Bertacco E, Nardin C, Pagliani L, Plebani M, Cinetto F, Guidolin D, Puato M, Pauletto P.
Il warfarin, ma non il rivaroxaban, potrebbe indurre degenerazione calcifica della valvola aortica nel modello animale di aterosclerosi, pur non interferendo con la progressione della stessa. Il rivaroxaban sembra quindi avere un profilo più sicuro rispetto al warfarin sul rischio di progressione di malattia cardiovascolare.
Introduction: Vitamin K antagonists, such as warfarin, are known to promote arterial calcification through blockade of gamma-carboxylation of Matrix-Gla-Protein. It is currently unknown whether other oral anticoagulants such as direct inhibitors of Factor Xa can have protective effects on the progression of aortic valve calcification. Aims: To compare the effect of warfarin and rivaroxaban on the progression of aortic valve calcification in atherosclerotic mice. Results: 42 ApoE-/- mice fed with Western-type Diet (WTD) were randomized to treatment with warfarin (n = 14), rivaroxaban (n = 14) or control (n = 14) for 8 weeks. Histological analyses were performed to quantify the calcification of aortic valve leaflets and the development of atherosclerosis. The analyses showed a significant increase in valve calcification in mice treated with warfarin as compared to WTD alone (P = .025) or rivaroxaban (P = .005), whereas no significant differences were found between rivaroxaban and WTD (P = .35). Quantification of atherosclerosis and intimal calcification was performed on the innominate artery of the mice and no differences were found between the 3 treatments as far as atherogenesis and calcium deposition is concerned. In vitro experiments performed using bovine interstitial valve cells (VIC) showed that treatment with rivaroxaban did not prevent the osteogenic conversion of the cells but reduce the over-expression of COX-2 induced by inflammatory mediators. Conclusion: We showed that warfarin, but not rivaroxaban, could induce calcific valve degeneration in a mouse model of atherosclerosis. Both the treatments did not significantly affect the progression of atherosclerosis. Overall, these data suggest a safer profile of rivaroxaban on the risk of cardiovascular disease progression.