Gender Differences in the Pathogenesis and Risk Factors of Hepatocellular Carcinoma.

Several chronic liver diseases are characterized by a clear gender disparity. Among them, hepatocellular carcinoma (HCC) shows significantly higher incidence rates in men than in women. The different epidemiological distribution of risk factors for liver disease and HCC only partially accounts for these gender differences. In fact, the liver is an organ with recognized sexual dysmorphism and is extremely sensitive to the action of androgens and estrogens. Sex hormones act by modulating the risk of developing HCC and influencing its aggressiveness, response to treatments, and prognosis. Furthermore, androgens and estrogens are able to modulate the action of other factors and cofactors of liver damage (e.g., chronic HBV infection, obesity), significantly influencing their carcinogenic power. The purpose of this review is to examine the factors related to the different gender distribution in the incidence of HCC as well as the pathophysiological mechanisms involved, with particular reference to the central role played by sex hormones.

Neoadjuvant and Adjuvant Systemic Therapies in Loco-Regional Treatments for Hepatocellular Carcinoma: Are We at the Dawn of a New Era?

Despite maximizing techniques and patient selection, liver resection and ablation for HCC are still associated with high rates of recurrence. To date, HCC is the only cancer with no proven adjuvant or neoadjuvant therapy used in association to potentially curative treatment. Perioperative combination treatments are urgently needed to reduce recurrence rates and improve overall survival. Immunotherapy has demonstrated encouraging results in the setting of adjuvant and neoadjuvant treatments for non-hepatic malignancies. Conclusive data are not yet available in the context of liver neoplasms. However, growing evidence suggests that immunotherapy, and in particular immune checkpoint inhibitors, could represent the cornerstone of an epochal change in the treatment of HCC, improving recurrence rates and overall survival through combination treatments. Furthermore, the identification of predictive biomarkers of treatment response could drive the management of HCC into the era of a precision medicine. The purpose of this review is to analyze the state of the art in the setting of adjuvant and neoadjuvant therapies for HCC in association with loco-regional treatments in patients not eligible for liver transplantation and to hypothesize future scenarios.

The impact of UEFA Euro 2020 football championship on Takotsubo Syndrome: Results of a multicenter national registry.

Objectives: The UEFA 2020 European Football Championship held in multiple cities across Europe from June 11 to July 11, 2021, was won by Italy, providing an opportunity to examine the relationship between emotional stress and the incidence of acute cardiovascular events (ACE). Methods and results: Cardiovascular hospitalizations in the Cardiac Care Units of 49 hospital networks in Italy were assessed by emergency physicians during the UEFA Euro 2020 Football Championship. We compared the events that occurred during matches involving Italy with events that occurred during the remaining days of the championship as the control period. ACE was assessed in 1,235 patients. ACE during the UEFA Euro 2020 Football Championship semifinal and final, the most stressful matches ended with penalties and victory of the Italian team, were assessed. A significant increase in the incidence of Takotsubo Syndrome (TTS) by a factor of 11.41 (1.6-495.1, P < 0.003), as compared with the control period, was demonstrated during the semifinal and final, whereas no differences were found in the incidence of ACS [IRR 0.93(0.74-1.18), P = 0.57]. No differences in the incidence of ACS [IRR 0.98 (0.87-1.11; P = 0.80)] or TTS [IRR 1.66(0.80-3.4), P = 0.14] were found in the entire period including all matches of the UEFA Euro 2020 compared to the control period. Conclusions: The data of this national registry demonstrated an association between the semifinal and final of UEFA Euro 2020 and TTS suggesting that it can be triggered by also positive emotions such as the victory in the European Football Championship finals.

Cardiac Remodeling after Surgical Mitral Valvuloplasty for Barlow's Disease: Is it the Time to Look to the Load?

We present the case of a 48-year-old man referred for a reduced exercise tolerance in whom a bileaflet mitral prolapse (Barlow's disease), associated with flail motion of posterior mitral leaflet and ruptured chordae tendineae and complicated by eccentric severe regurgitation, was incidentally diagnosed. Albeit paucisymptomatic, at echocardiography he showed the signs of LV dysfunction and, accordingly, was underwent surgical mitral valvuloplasty with implantation of the Memo 3D ReChord Ring without complications. We analyzed the changes of echocardiographic parameters of cardiac remodeling from baseline to post operative setting, highlighting the utility of modern imaging tools (strain and myocardial work) in grade to gauge with more sensitivity LV deformation and function in different conditions of pre and afterload and to overcome the limits of ancient ejection fraction. In conclusion, especially LV myocardial work may be a promising and accurate non load dipendent tool to quantify subclinical LV dysfunction, to guide therapeutic decisions and in post-surgical follow up.

Cardiovascular Involvement in COVID-19: What Sequelae Should We Expect?

Several forms of cardiovascular involvement have been described in patients with Coronavirus disease 19 (COVID-19): myocardial injury, acute coronary syndrome, acute heart failure, myocarditis, pericardial diseases, arrhythmias, takotsubo syndrome, and arterial and venous atherothrombotic and thromboembolic events. Data on long-term outcome of these patients are still sparse, and the type and real incidence of cardiovascular sequelae are poorly known. It is plausible that myocardial injury may be the initiator of an inflammatory cascade, edema, and subsequent fibrosis, but also a consequence of systemic inflammation. The extent and distribution of ongoing inflammation may be the basis for ventricular dysfunction and malignant arrhythmias. Indeed, preliminary observational findings seem to emphasize the importance of close monitoring of COVID-19 patients with myocardial injury after discharge. Residual subclinical disease may be effectively investigated by using second-level imaging modalities such as cardiac magnetic resonance, which allows better characterization of the type and extension of myocardial damage, as well as of the ongoing inflammation after the acute phase. In patients with venous thromboembolism, a very common complication of COVID-19, the type and the duration of anticoagulation therapy after the acute phase should be tailored to the patient and based on the estimation of the individual thromboembolic and hemorrhagic risk. Large randomized clinical trials are ongoing to address this clinical question. Whether the severity of cardiovascular involvement, the type of treatments adopted during the acute phase, and the hemodynamic response, may influence the long-term outcome of patients recovered from COVID-19 is unknown. An etiological diagnosis of myocardial injury during the hospitalization is the first step for an appropriate follow-up in these patients. After discharge, the screening for residual left and right ventricular dysfunction, arrhythmias, residual thrombosis, and myocardial scar should be considered on a case-by-case basis, whereas an active clinical surveillance is mandatory in any patient.

Unusual liver-related heart injury.

A 72-year-old man with polycystic liver disease and unexplained shock was admitted to our Emergency Department. The presence of turgidity in the jugular veins and acute prerenal kidney failure led to a possible hypothesis of right ventricular heart failure. A massive hepatic cyst resulted in right atrial compression and, secondarily, a state of shock. Surgical decompression by drainage of the hepatic cyst resulted in rapid improvement in the patient's hemodynamics. We report the description of an extremely rare complication of polycystic liver disease.

Interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection.

The Toll-interleukin 1 receptor superfamily includes the genes interleukin 1 receptor-like 1 (IL1RL1), Toll like receptors (TLRs), myeloid differentiation primary-response 88 (MyD88), and MyD88 adaptor-like (TIRAP). This study describes the interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection. Cases and controls were genotyped at the polymorphic sites MyD88 rs6853, TIRAP rs8177374 and IL1RL1 rs11123923. The results show that specific combinations of IL1RL1-TIRAP (AA-CT; P: 2,8 × 10-17) and MyD88-TIRAP-IL1RL1 (AA-CT-AA; P: 1,4 × 10-8) - but not MyD88 alone-act synergistically against Helicobacter pylori. Nuclear magnetic resonance (NMR) clearly discriminates cases from controls by highlighting significantly different expression levels of several metabolites (tyrosine, tryptophan, phenylalanine, branched-chain amino acids, short chain fatty acids, glucose, sucrose, urea, etc.). NMR also identifies the following dysregulated metabolic pathways associated to Helicobacter pylori infection: phenylalanine and tyrosine metabolism, pterine biosynthesis, starch and sucrose metabolism, and galactose metabolism. Furthermore, NMR discriminates between the cases heterozygous at the IL1RL1 locus from those homozygous at the same locus. Heterozygous patients are characterized by high levels of lactate, and IL1RL1-both associated with anti-inflammatory activity-and low levels of the pro-inflammatory molecules IL-1ß, TNF-α, COX-2, and IL-6.

Epistatic interaction between MyD88 and TIRAP against Helicobacter pylori.

The genes MyD88 and TIRAP encode the adaptor proteins MyD88 and TIRAP. TIRAP plays the crucial role of activating the MyD88-dependent pathway, which in turn controls the immune response (innate and adaptive) to Helicobacter pylori. We looked for an association of MyD88 and TIRAP with H. pylori infection. Cases and controls were genotyped at the polymorphic sites MyD88 rs6853 and TIRAP rs8177374 by real-time PCR. When the genes were analyzed separately, only TIRAP was associated with infection. When the genes were analyzed concurrently, certain combinations of MyD88 and TIRAP protected the host against H. pylori colonization more efficiently than could be done by TIRAP alone.

Acute and Chronic Effects of Noninvasive Ventilation on Left and Right Myocardial Function in Patients with Obstructive Sleep Apnea Syndrome: A Speckle Tracking Echocardiographic Study.

BACKGROUND: In patients with obstructive sleep apnea syndrome (OSAS), repetitive hypoxia due to sleep-induced apnea adversely affects the interaction between myocardial oxygen demand and supply, resulting in the development of subclinical cardiac dysfunction. The purpose of the study was to analyze the different involvement of left and right heart myocardial function in patients with OSAS treated with noninvasive ventilation (NIV). METHODS: Conventional Doppler echocardiography, Doppler myocardial imaging (DMI), and two-dimensional speckle tracking echocardiography (2DSTE) of left (LV) and right ventricular (RV) longitudinal and right atrial (RA) deformation were performed in 55 patients with OSAS undergoing NIV (M/F 38/17; mean age 67.8 ± 11.2 years). LV and RV global longitudinal strain (GLS) was calculated by averaging local strain along the entire right and left ventricle, before and during NIV, and after 6 months of nocturnal NIV therapy. RESULTS: LV morphology was comparable before and during NIV, whereas LV ejection fraction and LV DMI early diastolic peak velocity were significantly improved in patients with OSAS during NIV, as was LV regional peak myocardial strain (P < 0.001). RV diameters were slightly increased in patients with OSAS during ventilation, whereas pulmonary artery systolic pressure (PASP), RV GLS, and regional peak myocardial RV strain were significantly reduced during ventilation (P < 0.0001). RA transverse diameters and RA area were also slightly increased during NIV, whereas RA lateral wall strain was reduced (P < 0.001). Acute RV myocardial impairment completely reversed at follow-up, with a decrease in PASP and subsequent increase in both RV and RA myocardial performance. CONCLUSIONS: Conventional 2DSTE is a useful tool for assessing left and right heart morphology and myocardial deformation in patients with OSAS and for monitoring both acute and chronic effects of NIV.

Peri-procedural tight glycemic control during early percutaneous coronary intervention up-regulates endothelial progenitor cell level and differentiation during acute ST-elevation myocardial infarction: effects on myocardial salvage.

BACKGROUND: We examined the effects of peri-procedural intensive glycemic control during early percutaneous coronary intervention (PCI) on the number and differentiation of endothelial progenitor cells (EPCs) and myocardial salvage (MS) in hyperglycemic patients with first ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We conducted a randomized, prospective, open label study on 194 patients with STEMI undergoing PCI: 88 normoglycemic patients (glucose < 140 mg/dl) served as the control group. Hyperglycemic patients (glucose ≥140 mg/dl) were randomized to intensive glycemic control (IGC) for almost 24 h after PCI (n = 54; 80-140 mg/dl) or conventional glycemic control (CGC, n = 52; 180-200 mg/dl). EPC number, differentiation, and SIRT1expression were assessed immediately before, 24 h, 7, 30 and 180 days after PCI. The primary end point of the study was salvage index, measured as the proportion of initial perfusion defect (acute technetium-99m sestamibi scintigraphy, performed 5 to 7 days after STEMI) and myocardium salvaged by therapy (6 months after STEMI). Hyperglycemic patients had lower EPC number and differentiation and lower SIRT1 levels than normoglycemic patients (P < 0.01). After the insulin infusion, mean plasma glucose during peri-procedural period was greater in CGC group than in IGC group (P < 0.001). The EPC number, their capability to differentiate, and SIRT1 levels were significantly higher in IGC group than in CGC, peaking after 24 h (P < 0.01). In the IGC group, the salvage index was greater than in patients treated with CGC (P < 0.001). CONCLUSIONS: Optimal peri-procedural glycemic control, by increasing EPC number and their capability to differentiate, may improve the myocardial salvage.

Global longitudinal speckle-tracking strain is predictive of left ventricular remodeling after coronary angioplasty in patients with recent non-ST elevation myocardial infarction.

AIMS: To test whether two-dimensional longitudinal strain (2DSE) performed after revascularization by percutaneous coronary intervention (PCI) could predict left ventricular (LV) remodeling in patients with recent non-ST elevation myocardial infarction (NSTEMI). METHODS: In 70 patients (62.7 ± 8.7 years) with recent NSTEMI (between 72 hours and 14 days), undergoing coronary angiography for recurrent angina, myocardial deformation parameters were measured by 2DSE before and 24 hours after reperfusion therapy. Strain in all LV segments was averaged to obtain a global value (Global longitudinal Strain--GLS). Infarct size was estimated by clinical parameters and cardiac markers. After 6 months from intervention, LV negative remodeling was defined as lack of improvement of LV function, with increase in LV end-diastolic volume of greater than or equal than 15%. RESULTS: At follow-up, patients were subdivided into remodeled (n=32) and non-remodeled (n = 38) groups. Patients with negative LV remodeling had significantly lower baseline LV ejection fraction (44.8±6.9 vs. 48.7 ± 5.5 %; p < 0.05), higher peak troponin I (p < 0.001) and reduced GLS (- 10.6±6.1 vs - 17.6 ± 6.7 % p < 0.001) than those without LV remodeling. GLS showed a close correlation with peak troponin I after PCI (r = 0.64, P < 0.0001) and LV WMSI (r = 0.42, p < 0.01). By multivariable analysis, diabetes mellitus (P < 0.005), peak of Troponin I after PCI (P < 0.0005), GLS at baseline (OR: 4.3; p < 0.0001), and lack of improvement of GLS soon after PCI (OR: 1.45, P < 0.01) were powerful independent predictors of negative LV remodelling at follow-up. In particular, a GLS ≤ 12 % showed a sensitivity and a specificity respectively of 84.8% and 87.8% to predict negative LV remodelling at follow-up. CONCLUSIONS: in patients with recent NSTEMI, longitudinal LV global and regional speckle-tracking strain measurements are powerful independent predictors of LV remodeling after reperfusion therapy.

[Early interventricular septum rupture after systemic thrombolysis in a patient with STEMI]. / Rottura precoce di setto interventricolare dopo trombolisi sistemica nell'infarto miocardico acuto con ST elevation.

Intraventricular septal rupture (ISR) is one of the most dreadful complications during AMI, requiring early diagnosis and urgent surgery. However, medical (90%) and surgical (50%) mortality remain elevated. We report a case of a 59 years old patient with infero-posterior AMI complicated by ISR after thrombolysis. Despite early recognition of this complication by trans-thoracic echocardiography at bedside and prompt surgical intervention the patient died on the second post-surgical day.

Left ventricular early myocardial dysfunction after chronic misuse of anabolic androgenic steroids: a Doppler myocardial and strain imaging analysis.

BACKGROUND: Anabolic androgenic steroids (AAS) are sometimes used by power athletes to improve performance by increasing muscle mass and strength. Recent bioptical data have shown that in athletes under the pharmacological effects of AAS, a focal increase in myocardial collagen content might occur as a repair mechanism against myocardial damage. OBJECTIVE: To investigate the potential underlying left ventricular myocardial dysfunction after chronic misuse of AAS in athletes by use of Doppler myocardial imaging (DMI) and strain rate imaging (SRI). METHODS: Standard Doppler echocardiography, DMI, SRI and ECG treadmill test were undertaken by 45 bodybuilders, including 20 athletes misusing AAS for at least 5 years (users), by 25 anabolic-free bodybuilders (non-users) and by 25 age-matched healthy sedentary controls, all men. The mean (SD) number of weeks of AAS use per year was 31.3 (6.4) in users, compared with 8.9 (3.8) years in non-users, and the mean weekly dosage of AAS was 525.4 (90.7) mg. RESULTS: The groups were matched for age. Systolic blood pressure was higher in athletes (145 (9) vs 130 (5) mm Hg) than in controls. Left ventricular mass index did not significantly differ between the two groups of athletes. In particular, both users and non-users showed increased wall thickness and relative wall thickness compared with controls, whereas left ventricular ejection fraction, left ventricular end-diastolic diameter and transmitral Doppler indexes were comparable for the three groups. Colour DMI analysis showed significantly lower myocardial early: myocardial atrial diastolic wave ratios in users at the level of the basal interventricular septum (IVS) and left ventricular lateral wall (p<0.01), in comparison with both non-users and controls. In addition, in users, peak systolic left ventricular strain rate and strain were both reduced in the middle IVS (both p<0.001) and in the left ventricular lateral free wall (both p<0.01). By stepwise forward multivariate analyses, the sum of the left ventricular wall thickness (beta coefficient = -0.32, p<0.01), the number of weeks of AAS use per year (beta = -0.42, p<0.001) and the weekly dosage of AAS (beta = -0.48, p<0.001) were the only independent determinants of middle IVS strain rate. In addition, impaired left ventricular strain in users was associated with a reduced performance during physical effort (p<0.001). CONCLUSIONS: Several years after chronic misuse of AAS, power athletes show a subclinical impairment of both systolic and diastolic myocardial function, strongly associated with mean dosage and duration of AAS use. The combined use of DMI and SRI may therefore be useful for the early identification of patients with more diffused cardiac involvement, and eventually for investigation of the reversibility of such myocardial effects after discontinuation of the drug.

A nested-epidemic model for the spread of hepatitis C among injecting drug users.

Injecting drug users (IDUs) are the largest risk group for HCV infection. Studying injecting by classical epidemiological methods is no easy task, largely due to its hidden nature and low prevalence in general population terms. Thus, mathematical modelling can be of major help in performing a qualitative and quantitative evaluation of the costs and possible impact of the various interventions and to produce forecasts of both injecting drug use and HCV spread among IDUs. In the present paper an epidemic Mover-Stayer model for the spread of drug use, which has been recently proposed, is extended to mirror the spread of an infectious disease, in particular hepatitis C, among the injecting drug user population. In order to model the spread of a disease (HCV) among a population evolving following a different epidemic (injecting drug use) all the compartments of the 'external epidemic' (injecting drug use) are subdivided into two sub-compartments: the first one comprising individuals who are not affected by HCV and the second one comprising individuals affected. The resulting model may be defined the 'two epidemics' or, better, the 'nested epidemics' model. The model is a Mover-Stayer model for what concerns the 'external epidemic' (injecting drug use) but is a homogeneous epidemic model for HCV (all individuals are at risk of HCV the same). In the following, the dynamic equations are derived. Some qualitative analysis is performed in order to evaluate the asymptotic behaviour and the impact of possible prevention or harm reduction interventions. The results of a scenario analysis are also presented. The model, though simple, seems to be a very valuable tool for policy makers.

[Assessment of the potential impact in Italy of extensive varicella vaccination programs based on a mathematical model]. / Valutazione del potenziale impatto in Italia di programmi estesi di vaccinazione antivaricella secondo un modello matematico.

A mathematical model has been developed in order to assess the effect of extended programs of varicella vaccination on the epidemiology of the disease in Italy. The effect of different vaccination options have been estimated by the change in incidence of the disease and age distribution of cases over a short and long period of time. The developed mathematical model reproduces chickenpox transmission and immunisation; five strategies different for target age of vaccination and/or proportion of vaccinated subjects have been considered. In all scenarios the model pointed out an initial decrease of case frequency observed in the first 3-5 years, followed by a series of epidemic peaks, variable in number and size by vaccination strategy. Moreover, as the number of cases among infants decreases, the number of cases among adults increases. Such event is minimised only by very high vaccination coverage (80% in the first year of life and 50% at 12 years of age). Extensive programmes of vaccination against chickenpox must reach a high coverage as soon as possible in order to avoid undesirable effects that may move forward the age of cases and therefore should be offered to target age groups easy to reach.

Different involvement of right ventricular myocardial function in either physiologic or pathologic left ventricular hypertrophy: a Doppler tissue study.

The aim of the study was to analyze right ventricular (RV) myocardial function in patients with left ventricular (LV) hypertrophy secondary to either hypertrophic cardiomyopathy (HC) or athletic endurance training. Doppler echocardiography and pulsed Doppler tissue imaging of the posterior septal wall, and mitral and tricuspid annulus were performed in 32 top-level endurance athletes (AT) and in 27 patients with HC, all men. LV mass index was comparable between the 2 groups. All transmitral Doppler indexes were higher in AT, whereas only tricuspid inflow peak E and E/A ratio were slightly decreased in the HC group. In the HC group, Doppler tissue analysis showed lower myocardial systolic and early-diastolic (Em) peak velocities, and longer time intervals at the level of all the analyzed segments, even after correction for age, heart rate, and LV mass index. Distinct multiple linear regression models revealed an independent positive association between RV peak Em velocity and LV end-diastolic diameter (beta coefficient = 0.72, P <.0001) in AT, and an independent inverse correlation of the same peak Em velocity of tricuspid annulus with septal thickness (beta = - 0.65, P <.001) in the HC group. Of interest, a RV Em peak velocity < 0.16 m/s differentiated AT and HC groups better than tricuspid Doppler (89% sensitivity and 93% specificity). In conclusion, Em RV myocardial function is positively influenced by preload increase in AT and negatively associated to increased septal thickness in patients with HC. Therefore, Doppler tissue imaging may represent a useful tool in the differential diagnosis between athlete's heart and HC, underlining the different involvement of RV myocardial function in either physiologic or pathologic LV hypertrophy.