Sex-related differences for uric acid in the prediction of cardiovascular events in essential hypertension. A population prospective study.

BACKGROUND: Uric acid (UA) is an independent prognostic factor for cardiovascular events, but there are no data demonstrating a different risk profile between women and men. Thus, we tested whether UA is associated with a possible sex-related difference in fatal and non-fatal cardiovascular events. METHODS: In this prospective population-based study we enrolled 1,650 never-treated Caucasian hypertensive outpatients referred to Catanzaro University Hospital (Italy). Inclusion criteria were newly diagnosed hypertensive patients, aged 20 years or more. Exclusion criteria were secondary form of hypertension, previous cardiovascular events, rheumatic and non-rheumatic valvular heart disease, prosthetic valves, cardiomyopathies, type-2 diabetes, chronic kidney disease, malignant diseases, gout arthritis and secondary forms of hyperuricemia, liver diseases, peripheral vascular diseases, and heart failure. Anthropometric, clinical, and biochemical parameters were measured. UA prognostic role was investigated by Cox regression analyses. Receiver-operating characteristic curve analyses and area under the curve were used to determine the predictive validity and the optimal cut-off point of UA. We investigated following endpoints: coronary events (fatal and nonfatal myocardial infarction, unstable angina, coronary revascularization procedures, coronary death); fatal and nonfatal stroke; all-cause mortality and major adverse cardiovascular events (MACE). RESULTS: We enrolled 830 males and 820 females aged 52.2 ± 11.3 years. During 9.5 ± 3.1 years follow-up, there were 424 new clinical events (2.71%): 250 coronary (1.59%), 118 (0.75%) cerebrovascular, and 56 (0.40%) deaths. Comparison between groups demonstrated a higher and significant difference in incidence rate in females for MACE (3.08 vs 2.33%, P = 0.001), coronary (1.82 vs 1.36%, P = 0.014) and cerebrovascular events (0.93 vs 0.57%, P = 0.006). UA at multiple Cox regression analysis resulted a strong and significant predictor of coronary events (HR = 1.493;95% CI 1.375-1.621), cerebrovascular events (HR = 1.256;95% CI 1.109-1.423), MACE (HR = 1.415;95% CI 1.328- 53 1.508), and all-cause mortality (HR = 1.469;95% CI 1.237-1.745) in the whole population and in both groups with a HR higher in females. The best estimated cut-off values of uric acid for males and females predicted these endpoints equally well, but it was always lower in females than males. CONCLUSIONS: We demonstrate, that UA operates with a sex-related impact and best cut-off value in predicting cardiovascular outcomes and all-cause mortality, reflecting a possible sex difference in disease pathophysiology.

Real-life glecaprevir/pibrentasvir in a large cohort of patients with hepatitis C virus infection: The MISTRAL study.

BACKGROUND AND AIMS: It is paramount to identify predictors of treatment failure with direct antiviral agents in 'field-practice' patients, including people who inject drugs (PWID). Data on the efficacy of glecaprevir/pibrentasvir (GLE/PIB) in a field-practice scenario are scant. The multicentre MISTRAL study enrolled 1177 patients, including PWID, to assess real-life efficacy and safety of GLE/PIB and to identify the predictive factors for this treatment. METHODS: This was a prospective, longitudinal study. The outcome variable was the rate of sustained virological response (SVR) at week 12. RESULTS: A total of 123 patients (10%) were infected from hepatitis C virus (HCV) 3. METAVIR fibrosis score was F4 in 104 subjects (9%); 118 patients (10%) were PWID. Overall, 1163/1177 (99%) patients achieved SVR. The baseline clinical factors discriminating between treatment success and treatment failure were age at treatment (P = 0.031) and creatinine level (P = 0.034). SVR rates were not influenced by gender, substance abuse, previous treatment, treatment duration, fibrosis or chronic kidney disease stage. Compared with non-substance users, the 118 PWID exhibited a significantly different genotype pattern distribution (χ2  < 0.001). A total of 40/118 (33.9%) of substance users were HCV3 compared to 83/1056 (7.9%) non-substance users. Only 6 patients (0.5%) reported a serious adverse event. CONCLUSIONS: The MISTRAL study provides evidence of GLE/PIB efficacy in a field-practice scenario in a highly epidemic HCV area in southern Italy; it unveiled significant differences in genotype distribution among the most underserved and difficult-to-treat patient subgroups including PWID.

Additive Effect of Non-Alcoholic Fatty Liver Disease on Metabolic Syndrome-Related Endothelial Dysfunction in Hypertensive Patients.

Metabolic syndrome (MS) is characterized by an increased risk of incident diabetes and cardiovascular (CV) events, identifying insulin resistance (IR) and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD) is bidirectionally linked with MS as a consequence of metabolic and inflammatory abnormalities. We addressed the question if the evolution in NAFLD might worsen endothelium-dependent vasodilating response in MS hypertensives. We recruited 272 Caucasian newly-diagnosed never-treated hypertensive outpatients divided into three groups according to the presence/absence of MS alone or in combination with NAFLD. MS and NAFLD were defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and non-invasive fatty liver index, respectively. We determined IR by using the homeostasis model assessment (HOMA) index. Vascular function, as forearm blood flow (FBF), was determined through strain-gauge plethysmography after intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside. MS+NAFLD+ group showed worse metabolic, inflammatory and vascular profiles compared with MS-NAFLD- and MS+NAFLD-. HOMA resulted in being the strongest predictor of FBF both in the MS+NAFLD- and in the MS+NAFLD+ groups, accounting for 20.5% and 33.2% of its variation, respectively. In conclusion, we demonstrated that MS+NAFLD+ hypertensives show a worse endothelium-dependent vasodilation compared with MS+NAFLD-, allowing for consideration of NAFLD as an early marker of endothelial dysfunction in hypertensives.

Chronic HCV infection increases cardiac left ventricular mass index in normotensive patients.

BACKGROUND & AIMS: Left ventricular hypertrophy (LVH), is an independent predictor for cardiovascular events. We investigated if chronic hepatitis C virus (HCV) infection and the related insulin resistance (IR)/hyperinsulinemia could influence the increase of left ventricular mass (LVM). METHODS: We enrolled 260 outpatients matched for age, body mass index, gender, ethnicity: 52 with never-treated uncomplicated chronic HCV infection (HCV(+)), 104 never-treated hypertensives (HT) and 104 healthy subjects (NT). LVM was calculated according to the Devereux formula and indexed for body surface area. The following laboratory parameters were measured: fasting plasma glucose and insulin, total, LDL- and HDL-cholesterol, triglyceride, creatinine, e-GFR-EPI, HOMA. Quantitative HCV-RNA was assessed by PCR. RESULTS: HCV(+) patients with respect to healthy normotensive subjects had an increased LVMI (100 ± 23 vs. 83 ± 15 g/m(2); p < 0.0001), similar to that observed in HT group (103 ± 25 g/m(2)). Regarding biochemical variables, HCV(+) patients, in comparison with normotensive healthy subjects, had higher triglyceride, creatinine, fasting insulin and HOMA (3.2 ± 1.3 vs. 2.5 ± 1.0; p < 0.0001). At linear regression analysis, the correlation between LVMI and HOMA was similar in HT (r = 0.528, p < 0.0001) and HCV(+) (r = 0.489, p < 0.0001) groups. At multiple regression analysis, HOMA resulted the major determinant of LMVI in all groups, explaining respectively 21.8%, 27.8%, and 23.9% of its variation in NT, HT and HCV(+). At correlational analysis HCV-RNA and HOMA demonstrated a strong and linear relationship between them, explaining the 72.4% of their variation (p = 0.022). CONCLUSIONS: We demonstrated a significant and direct correlation between HOMA and LVMI in patients with chronic HCV infection, similar to that observed in hypertensives.

Natural history and clinical response: "it's the virus, stupid, or is it the host?".

A major goal of modern medicine is the application of personalized therapies, consisting of decisions and practices tailored to the individual patient. Information about genetic variants, either mutant or polymorphic, represents the basis for the development of this clinical approach. Recently, several independent genome-wide association studies (GWAS) have identified two single nucleotide polymorphisms (SNPs) on the IL28B locus associated with HCV containment, spontaneous clearance, treatment response, and disease progression. In this minireview we will concisely discuss some critical genetic concepts that may have possible implications for clinical decisions in the treatment of HCV infection.

Direct-acting Antivirals Inducing HCV-RNA Sustained Suppression Improve Xerophthalmia in HCV-infected Patients.

BACKGROUND: Hepatitis C Virus (HCV) infection represents a global problem, and it is related to both hepatic and extra-hepatic manifestations (e.g., xerophthalmia). New direct-acting antivirals (DAAs), IFN-free treatments, are commonly used to manage HCV infection. However, the impact of new DAAs on dry eyes (xerophthalmia) is lacking. In this study, we evaluated its incidence in HCV patients and the effect of DAAs on this manifestation. METHODS: We performed an observational open-label non-randomized study in HCV patients from 01 April 2018 to 01 June 2020. RESULTS: Patients who satisfied the inclusion criteria underwent clinical and laboratory evaluation, Schirmer's test, and Break-up time test. Enrolled patients were divided in two groups: Group 1: HCV patients with xerophthalmia: 24 patients (16 male and 8 female), HCV-RNA 2,685,813 ± 1,145,698; Group 2: HCV patients without xerophthalmia: 35 patients (19 male and 16 female), HCV-RNA 2,614,757 ± 2,820,433. The follow-ups (3 and 6 months after the enrollment) documented an improvement in both eyes' manifestations and HCV-infection (HCV-RNA undetected). CONCLUSION: In conclusion, in this study, we reported that xerophthalmia could appear in HCV patients, and DAAs treatment reduces this manifestation without the development of adverse drug reactions.

Effects of Sacubitril-Valsartan on Clinical, Echocardiographic, and Polygraphic Parameters in Patients Affected by Heart Failure With Reduced Ejection Fraction and Sleep Apnea.

Background: Heart failure with reduced ejection fraction (HFrEF) is a clinical condition frequently diagnosed in clinical practice. In patients affected by HFrEF, sleep apnea (SA) can be detected among the most frequent comorbidities. Sacubitril-valsartan (sac/val) association has been proven to be effective in reducing disease progression and all-cause mortality in HFrEF patients. Sac/val treatment can potentially attenuate SA development via several pathophysiologic mechanisms, including improvement of global hemodynamics, reduction of extracellular fluid overload, and decrease of sympathetic neural activity. Methods: We recruited 132 patients affected by HFrEF and SA, already under treatment with continuous positive airway pressure (CPAP), which was discontinued 24 h before the scheduled study timepoints. Physical examination, echocardiography, nocturnal cardio-respiratory monitoring, and laboratory tests were performed in each patient at baseline and after a 6-month treatment with sac/val. Results: After 6 months, sac/val induced statistically significant changes in clinical, hemodynamic, biohumoral (NT-proBNP, serum electrolytes, creatinine, and uric acid), and echocardiographic parameters. In particular, cardiac index (CI), both atrial and ventricular volumes and global longitudinal strain (GLS) improved. Moreover, polysomnography, carried out during a temporary CPAP interruption, revealed a significant reduction in global apnea-hypopnea index (AHI) value (p < 0.0001), central AHI (p < 0.0001), obstructive AHI (p < 0.0001), oxygen desaturation index (ODI) (p < 0.0001), and percentage time of saturation below 90% (TC90) (p < 0.0001). The changes of CI, estimated glomerular filtration rate (eGFR), NT-proBNP, and tricuspid annular plane excursion (TAPSE) contributed to 23.6, 7.6, 7.3, and 4.8% of AHI variability, respectively, and the whole model accounted for a 43.3% of AHI variation. Conclusions: Our results suggest that treatment with sac/val is able to significantly improve the cardiorespiratory performance of patients with HFrEF and SA, integrating the positive impact of CPAP. Thus, both CPAP and sac/val therapy may synergistically contribute to lower the risks of both cardiac and pulmonary complications in HFrEF patients with SA.

Decreased Pulse Wave Velocity in a Systemic Sclerosis Population: Preliminary Results from a Cross-Sectional Study.

Systemic Sclerosis (SSc) is an autoimmune disorder characterized by organ and tissue fibrosis in which the incidence of atherosclerosis and cardiovascular events is increased, although the exact underlying mechanism remains unclear. Arterial stiffness is a marker of vascular damage that can predict cardiovascular events; therefore, this study aimed to assess the augmentation index (AIx) and pulse wave velocity (PWV), markers of stiffness, in a Systemic Sclerosis population and to detect potentially associated variables. Fourteen female Systemic Sclerosis patients and 14 age- and sex-matched controls were enrolled. Demographic, anthropometric, sero-hematological parameters and disease characteristics were collected for each participant. Arterial stiffness was evaluated using an applanation tonometry system. No differences were found between groups, except for BMI, fasting blood glucose, red blood cells count, hemoglobin, and treatment. Patients had increased augmentation index than the controls (p = 0.008). PWV was significantly decreased in SSc patients compared with the controls (p = 0.007). PWV was correlated with age (r = 0.462; p = 0.048) and BMI (r = 0.458; p = 0.050). Finally, patients with no specific auto-antibody pattern had greater AIx than those expressing anticentromere antibodies. Our study demonstrated that SSc patients had greater AIx, but lower PWV than the controls. In addition, few variables were correlated to arterial stiffness. Further studies are necessary to validate these findings and to establish medication's role in modifying cardiovascular risk.

COPD significantly increases cerebral and cardiovascular events in hypertensives.

Essential hypertension and chronic obstructive pulmonary disease often coexist in the same patient. The aim of this study was to evaluate whether the addition of chronic obstructive pulmonary disease modifies the risk of cardiovascular events in hypertensives. We enrolled 1728 hypertensives. Study outcomes included fatal and non-fatal cardiovascular stroke and myocardial infarction, and cardiovascular death. During a mean follow-up of 57 months there were 205 major adverse cardiovascular events (2.47 per 100 pts/yr): cardiac (n117; 1.41 per 100 pts/yr) and cerebrovascular (n = 77; 0.93 per 100 pts/yr). In hypertensives with chronic obstructive pulmonary disease we observed a greater number of cardiovascular events than in hypertensives without respiratory disease (133 [5.55 per 100 pts/yr) vs 72 [1.22 per 100 pts/yr], respectively. The addition of chronic obstructive pulmonary disease to hypertension increased the incidence of total and non-fatal stroke of more than nine- (2.42 vs 0.32 per 100 pts/yr) and 11-fold (2.09 vs 0.22 per 100 pts/yr), respectively. The same trend was observed for total (2.88 vs 0.81 per 100 pts/yr) and non-fatal (2.67 vs 0.79 per 100 pts/y) myocardial infarction. The presence of chronic obstructive pulmonary disease in hypertensives significantly increases the risk of stroke, myocardial infarction and major adverse cardiovascular events.

Continuous Positive Airway Pressure Improves Renal Function in Obese Patients With Obstructive Sleep Apnea Syndrome.

Background: Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular morbidity and mortality, and it has a detrimental effect on renal function. Obesity is the major risk factor for OSAS, and represents a risk factor for chronic kidney disease. Continuous positive airway pressure (CPAP) is the suggested therapy for moderate-to-severe OSAS. We designed this study to evaluate the effect of CPAP on estimated glomerular filtration rate (e-GFR) in a cohort of obese patients with moderate-to-severe OSAS and normal renal function. Methods: We enrolled 198 obese subjects, divided into two groups (OSAS+ and OSAS-), on the basis of cardiorespiratory monitoring; mild OSAS patients (n = 33) were excluded from the study, thus the analyses were conducted on 165 patients. Comparisons between groups were made by Student t-test or χ2 test as appropriate. Linear regression analyses were used to assess the relationship between baseline e-GFR and different covariates and, in the OSAS+ group, between Δe-GFR and different covariates. A multivariate regression analysis was performed to determinate the independent predictor of the Δe-GFR. Results: OSAS+ subjects showed significantly increased values of systolic blood pressure, HOMA, pulse wave velocity, high-sensitivity C reactive protein and uric acid compared with OSAS- group. OSAS+ group showed significantly lower values of e-GFR and increased values of microalbuminuria. At linear regression analysis e-GFR resulted significantly and inversely related to AHI in the whole study population and in the two groups. After 6 months of CPAP therapy, OSAS+ subjects showed an improvement in respiratory parameters, as well as a significant increase in e-GFR values (104.2 + 19.0 vs. 84.0 + 13.1 ml/min/1.73 m2, P < 0.0001). At multiple regression analysis, Δ apnea/hypopnea index (AHIa) resulted the main independent predictor of Δe-GFR explaining 22% of its variation. Conclusions: Obese OSAS patients show significantly lower values of e-GFR, even if in the normal range, compared with obese non-OSAS subjects. After 6 months of CPAP, e-GFR significantly improved (+20 ml/min/1.73 m2) and ΔAHIa resulted the most important independent predictor of Δe-GFR.