The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis

BACKGROUND: The aim of this study was to systematically synthesise the global evidence on the prevalence of persistent symptoms in a general post COVID-19 population. METHODS: A systematic literature search was conducted using multiple electronic databases (MEDLINE and The Cochrane Library, Scopus, CINAHL, and medRxiv) until January 2022. Studies with at least 100 people with confirmed or self-reported COVID-19 symptoms at ≥28 days following infection onset were included. Patient-reported outcome measures and clinical investigations were both assessed. Results were analysed descriptively, and meta-analyses were conducted to derive prevalence estimates. This study was pre-registered (PROSPERO-ID: CRD42021238247). FINDINGS: 194 studies totalling 735,006 participants were included, with five studies conducted in those <18 years of age. Most studies were conducted in Europe (n = 106) or Asia (n = 49), and the time to follow-up ranged from ≥28 days to 387 days. 122 studies reported data on hospitalised patients, 18 on non-hospitalised, and 54 on hospitalised and non-hospitalised combined (mixed). On average, at least 45% of COVID-19 survivors, regardless of hospitalisation status, went on to experience at least one unresolved symptom (mean follow-up 126 days). Fatigue was frequently reported across hospitalised (28.4%; 95% CI 24.7%-32.5%), non-hospitalised (34.8%; 95% CI 17.6%-57.2%), and mixed (25.2%; 95% CI 17.7%-34.6%) cohorts. Amongst the hospitalised cohort, abnormal CT patterns/x-rays were frequently reported (45.3%; 95% CI 35.3%-55.7%), alongside ground glass opacification (41.1%; 95% CI 25.7%-58.5%), and impaired diffusion capacity for carbon monoxide (31.7%; 95% CI 25.8%-3.2%). INTERPRETATION: Our work shows that 45% of COVID-19 survivors, regardless of hospitalisation status, were experiencing a range of unresolved symptoms at ∼ 4 months. Current understanding is limited by heterogeneous study design, follow-up durations, and measurement methods. Definition of subtypes of Long Covid is unclear, subsequently hampering effective treatment/management strategies. FUNDING: No funding

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Impact of acute choline loading on circulating trimethylamine N-oxide levels.

Despite recent efforts to reduce cardiovascular disease risk by dietary intervention,1few markers are useful to assess the efficiency and progress of this. Circulating levels of trimethylamine N-oxide (TMAO) are associated with poor outcomes of cardiovascular disease.2–6TMAO is generated via hepatic flavin monooxygenase 3 (FMO3) mediated oxidation of trimethylamine (TMA),7derived largely from carnitine and choline through gut microbial metabolism. These substrates are found in red meat and eggs, which are representative of a Western diet. Therefore, TMAO levels could be used to monitor the effect of dietary intervention, particularly for the consumption of a Western diet. In this study, we examined the effect of acute choline loading on TMAO levels in healthy adult volunteers

Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: The T.O.S.CA. Registry

Aims Recent evidence supports the occurrence of multiple hormonal and metabolic deficiency syndrome (MHDS) in chronic heart failure (CHF). However, no large observational study has unequivocally demonstrated its impact on CHF progression and outcome. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Treatment in Heart Failure) Registry has been specifically designed to test the hypothesis that MHDS affects morbidity and mortality in CHF patients. Methods The T.O.S.CA. Registry is a prospective, multicentre, observational study involving 19 Italian centres. Thyroid and Results hormones, insulin-like growth factor-1, total testosterone, dehydropianoandrosterone sulfate, insulin resistance, and the presence of diabetes were evaluated. A MHDS was defined as the presence of &gt;_2 hormone deficiencies (HDs). Primary endpoint was a composite of all-cause mortality and cardiovascular hospitalizations. Four hundred and eighty heart failure patients with ejection fraction &lt;_45% were enrolled. MHDS or diabetes was diagnosed in 372 patients (77.5%). A total of 271 events (97 deaths and 174 cardiovascular hospitalizations) were recorded, 41% in NO-MHDS and 62% in MHDS (P &lt; 0.001). Median follow-up was of 36 months. MHDS was independently associated with the occurrence of the primary endpoint [hazard ratio 95% (confidence interval), 1.93 (1.37-2.73), P &lt; 0.001] and identified a group of patients with a higher mortality [2.2 (1.28-3.83), P = 0.01], with a graded relation between HDs and cumulative events (P &lt; 0.01). Conclusion MHDS is common in CHF and independently associated with increased all-cause mortality and cardiovascular hospitalization, representing a promising therapeutic target

Progressive right ventricular dysfunction and exercise impairment in patients with heart failure and diabetes mellitus: insights from the T.O.S.CA. Registry.

Background: Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance-IR or diabetes mellitus-T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. Methods: Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. Results: Compared with EU and IR, T2D was associated with increased filling pressures (E/e'ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p &lt; 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p &lt; 0.05). Likewise, impairment in peak oxygen consumption (peak VO2) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p &lt; 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO2 in the T2D group (+ 13% increase in RV dimension, - 21% decline in TAPSE/PAPS ratio and - 20% decrease in peak VO2). Conclusion: The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis

Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: the T.O.S.CA. Registry.

none131siAims Recent evidence supports the occurrence of multiple hormonal and metabolic deficiency syndrome (MHDS) in chronic heart failure (CHF). However, no large observational study has unequivocally demonstrated its impact on CHF progression and outcome. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Treatment in Heart Failure) Registry has been specifically designed to test the hypothesis that MHDS affects morbidity and mortality in CHF patients. Methods and Results The T.O.S.CA. Registry is a prospective, multicentre, observational study involving 19 Italian centres. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydropianoandrosterone sulfate, insulin resistance, and the presence of diabetes were evaluated. A MHDS was defined as the presence of ≥2 hormone deficiencies (HDs). Primary endpoint was a composite of all-cause mortality and cardiovascular hospitalizations. Four hundred and eighty heart failure patients with ejection fraction ≤45% were enrolled. MHDS or diabetes was diagnosed in 372 patients (77.5%). A total of 271 events (97 deaths and 174 cardiovascular hospitalizations) were recorded, 41% in NO-MHDS and 62% in MHDS (P &lt; 0.001). Median follow-up was of 36 months. MHDS was independently associated with the occurrence of the primary endpoint [hazard ratio 95% (confidence interval), 1.93 (1.37–2.73), P &lt; 0.001] and identified a group of patients with a higher mortality [2.2 (1.28–3.83), P = 0.01], with a graded relation between HDs and cumulative events (P &lt; 0.01). Conclusion MHDS is common in CHF and independently associated with increased all-cause mortality and cardiovascular hospitalization, representing a promising therapeutic target.openCittadini A, Salzano A, Iacoviello M, Triggiani V, Rengo G, Cacciatore F, Maiello C, Limongelli G, Masarone D, Perticone F, Cimellaro A, Perrone Filardi P, Paolillo S, Mancini A, Volterrani M, Vriz O, Castello R, Passantino A, Campo M, Modesti PA, De Giorgi A, Monte IP, Puzzo A, Ballotta A, D'Assante R, Arcopinto M, Gargiulo P, Sciacqua A, Bruzzese D, Colao A, Napoli R, Suzuki T, Eagle KA, Ventura HO, Marra AM, Bossone E. Saccà L, Monti MG, Matarazzo M, Stagnaro FM, Piccioli L, Lombardi A, Panicara V, Flora M, Golia L, Faga V, Ruocco A, Della Polla D, Franco R, Schiavo A, Gigante A, Spina E, Sicuranza M, Monaco F, Apicella M, Miele C, Campanino AG, Mazza L, Abete R, Farro A, Luciano F, Polizzi R, Ferrillo G, De Luca M, Crisci G, Giardino F, Barbato M, Ranieri B, Ferrara F, Russo V, Malinconico M, Citro R, Guastalamacchia E, Iacoviello M, Leone M, Triggiani V, Giagulli VA, Maiello C, Amarelli C, Mattucci I, Limongelli G, Calabrò P, Calabrò R, D’Andrea A, Maddaloni V, Pacileo G, Scarafile R, Perticone F, Belfiore A, Sciacqua A, Casaretti L, Paolillo S, Gargiulo P, Mancini A, Favuzzi AMR, Di Segni C, Bruno C, Vergani E, Volterrani M, Massaro R, Vriz O, F. Grimaldi F, Castello R, Frigo A, Campo MR, Sorrentino MR, Modesti PA, Malandrino D, Manfredini R, De Giorgi A, Fabbian F, Ragusa L, Caliendo L, Carbone L, Frigiola A, Generali T, Giacomazzi F, De Vincentiis C, Garofalo P, Malizia G, Milano S, Misiano G, Suzuki T, Israr MZ, Bernieh D, Cassambai S, Yazaki Y, Heaney LM, Eagle KA, Ventura HO, Colao A, Bruzzese D.Cittadini, A; Salzano, A; Iacoviello, M; Triggiani, V; Rengo, G; Cacciatore, F; Maiello, C; Limongelli, G; Masarone, D; Perticone, F; Cimellaro, A; Perrone Filardi, P; Paolillo, S; Mancini, A; Volterrani, M; Vriz, O; Castello, R; Passantino, A; Campo, M; Modesti, Pa; De Giorgi, A; Monte, Ip; Puzzo, A; Ballotta, A; D'Assante, R; Arcopinto, M; Gargiulo, P; Sciacqua, A; Bruzzese, D; Colao, A; Napoli, R; Suzuki, T; Eagle, Ka; Ventura, Ho; Marra, Am; Bossone E., Saccà L; Monti, Mg; Matarazzo, M; Stagnaro, Fm; Piccioli, L; Lombardi, A; Panicara, V; Flora, M; Golia, L; Faga, V; Ruocco, A; Della Polla, D; Franco, R; Schiavo, A; Gigante, A; Spina, E; Sicuranza, M; Monaco, F; Apicella, M; Miele, C; Campanino, Ag; Mazza, L; Abete, R; Farro, A; Luciano, F; Polizzi, R; Ferrillo, G; De Luca, M; Crisci, G; Giardino, F; Barbato, M; Ranieri, B; Ferrara, F; Russo, V; Malinconico, M; Citro, R; Guastalamacchia, E; Iacoviello, M; Leone, M; Triggiani, V; Giagulli, Va; Maiello, C; Amarelli, C; Mattucci, I; Limongelli, G; Calabrò, P; Calabrò, R; D’Andrea, A; Maddaloni, V; Pacileo, G; Scarafile, R; Perticone, F; Belfiore, A; Sciacqua, A; Casaretti, L; Paolillo, S; Gargiulo, P; Mancini, A; Favuzzi, Amr; Di Segni, C; Bruno, C; Vergani, E; Volterrani, M; Massaro, R; Vriz, O; F., Grimaldi F; Castello, R; Frigo, A; Campo, Mr; Sorrentino, Mr; Modesti, Pa; Malandrino, D; Manfredini, R; De Giorgi, A; Fabbian, F; Ragusa, L; Caliendo, L; Carbone, L; Frigiola, A; Generali, T; Giacomazzi, F; De Vincentiis, C; Garofalo, P; Malizia, G; Milano, S; Misiano, G; Suzuki, T; Israr, Mz; Bernieh, D; Cassambai, S; Yazaki, Y; Heaney, Lm; Eagle, Ka; Ventura, Ho; Colao, A; Bruzzese, D