Impact of PNPLA3 and TM6SF2 polymorphisms on the prognosis of patients with MASLD and type 2 diabetes mellitus.

BACKGROUND/AIMS: Longitudinal studies assessing the impact of genetic polymorphisms on outcomes in patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) are scarce. This study aimed to evaluate the effect of PNPLA3 and TM6SF2 risk alleles on hepatic and extrahepatic outcomes in T2DM-MASLD individuals. METHODS: Patients' polymorphisms were analysed as follows: PNPLA3 CC, CG and GG; TM6SF2 CC and CT + TT; combined comparing no mutant allele, one allele G or T or ≥2 alleles G or T. Hierarchical models were built to assess associations between polymorphisms and outcomes, independently of confounding factors. Multivariate logistic regression was used for cirrhosis and its complications and extrahepatic cancer, and Cox regression for cardiovascular events (CVEs) and all-cause mortality. RESULTS: In total, 407 T2DM-MASLD patients (62.1 ± 10.5 years, 67.6% women) were followed for 11 (6-13) years. Having at least one G or T allele independently increased the risk of cirrhosis in the separate analysis of PNPLA3 and TM6SF2. Combined polymorphism analysis demonstrated an even higher risk of cirrhosis if two or more risk alleles were present (OR 18.48; 95% CI 6.15-55.58; p < .001). Regarding cirrhosis complications, the risk was higher in PNPLA3 GG and TM6SF2 CT + TT, also with an even higher risk when two or more risk alleles were present in the combined evaluation (OR 27.20; 95% CI 5.26-140.62; p < .001). There were no associations with CVEs or mortality outcomes. CONCLUSION: In T2DM, PNPLA3 and TM6SF2 polymorphisms, individually and additively, impact MASLD severity, with an increased risk of cirrhosis and its complications.

Parental History of Type 2 Diabetes Mellitus and PNPLA3 Polymorphism Increase the Risk of Severe Stages of Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: In non-alcoholic fatty liver disease (NAFLD), the influence of parental history of type 2 diabetes (T2D) allied to single nucleotide polymorphisms (SNPs) in the offspring is not known. We aimed to investigate the impact of the parental history of T2D, PNPLA3 and TM6SF2 polymorphisms in liver steatosis and fibrosis. METHODS: This was a case-control study involving the offspring of T2D patients and controls without a parental history of T2D. Participants underwent clinical and laboratory evaluation, transient elastography (TE) by Fibroscan® (Echosens, Fr) and genotyping for PNPLA3 and TM6SF2. Multivariate logistic regression evaluated the influence of parental history of T2D on liver steatosis and fibrosis, controlled for age, gender, metabolic traits and SNPs. RESULTS: 161 T2D offspring and 78 controls, 10-46 years old, were included. The offspring of T2D had higher prevalences of obesity, T2D, arterial hypertension and sedentarism. Parental history of T2D was associated with fibrosis ≥ F2 (OR 8.89, CI 95% 1.09-72.01, p = 0.041) after adjustment for age, gender, metabolic traits and SNPs. PNPLA3 GG genotype was independently associated with steatosis ≥ S1 (OR 8.15, CI 95% 1.93-34.38, p = 0.004) and fibrosis ≥ F2 (OR 4.31, CI 95% 1.11-16.61, p = 0.034). CONCLUSIONS: The offspring of T2D patients present a worse metabolic profile and the parental history of T2D confers an increased likelihood of hepatic fibrosis, independent of metabolic factors. PNPLA3 homozygous GG, but not TM6SF2 genotypes, also impacts on this phenotype.

Usefulness of the vibration perception thresholds measurement as a diagnostic method for diabetic peripheral neuropathy: Results from the Rio de Janeiro type 2 diabetes cohort study.

AIMS: To investigate the associated factors with the vibration threshold perception (VPT) in patients with type 2 diabetes and to assess whether it is useful for detection of diabetic peripheral neuropathy (DPN). METHODS: VPTs were measured with Vibration Sensory Analyzer (VSA-3000) in 426 diabetic patients. The diagnosis of DPN was based on Neuropathy Symptom Score and Neuropathy Disability Score (NDS). ROC curve analysis and multiple linear and logistic regressions were performed to investigate the associations between VPT and DPN. RESULTS: Values of VPT were progressively higher according to NDS stages. Age, height, diabetes duration, and mean cumulative HbA1c exposure (partial correlation coefficients: 0.34; 0.27; 0.10; and 0.13; respectively) were the variables independently associated with VPT. Area under ROC curve of VPT for detection of DPN was 0.71 (95% CI: 0.66-0.75) and >8.9 µm was its best cut-off value. VPT, age, female sex, height, diabetes duration and mean HbA1c levels were the independent correlates of the presence of DPN. An increased VPT triplicate the likelihood of having DPN (OR: 3.24; 95% CI: 2.05-5.11). CONCLUSIONS: VPT, measured by an automatic device, shares common correlates with DPN and is strongly associated with its presence. VPT testing may be useful as a screening tool for DPN assessment.

Prognostic Value of C-Reactive Protein in Resistant Hypertension.

BACKGROUND: C-reactive protein (CRP) is a biomarker of systemic low-grade inflammation and a cardiovascular risk predictor in several clinical conditions. However, its prognostic value has never been examined in patients with resistant hypertension. METHODS: In a prospective study, 476 patients with resistant hypertension had CRP levels measured at baseline, together with other clinical laboratory variables, including ambulatory blood pressures (BPs). Primary end points were a composite of major fatal or nonfatal cardiovascular events, all-cause mortality, and cardiovascular mortality. Multiple Cox regression assessed the associations between CRP levels and end points. RESULTS: Median CRP was 3.8mg/l (interquartile range: 2.0-7.2mg/l). After a median follow-up of 9 years, 103 major cardiovascular events occurred, and 120 patients died, 62 from cardiovascular causes. Patients with CRP levels above the median value had a doubled excess risk of major cardiovascular events (95% confidence interval: 1.29-3.06; P = 0.002) and an 86% higher risk of cardiovascular death (95% confidence interval: 1.07-3.25; P = 0.029), after adjustments for potential confounders including traditional cardiovascular risk factors and ambulatory BP and dipping pattern. A high CRP equally predicted coronary (hazard ratio: 2.04; 95% confidence interval: 1.10-3.76; P = 0.023) and cerebrovascular events (hazard ratio: 2.72; 95% confidence interval: 1.30-5.67; P = 0.007). In interaction and sensitivity analyses, CRP levels were stronger predictors of worse cardiovascular outcomes in younger and obese patients, and in those with uncontrolled ambulatory BPs and with the nondipping pattern. CONCLUSIONS: In patients with resistant hypertension, elevated serum CRP levels is predictive of worse cardiovascular prognosis above and beyond other cardiovascular risk factors, including ambulatory BP levels and dipping patterns.

Serum biomarkers in type 2 diabetic patients with non-alcoholic steatohepatitis and advanced fibrosis.

AIM: Advanced stages of non-alcoholic fatty liver disease (NAFLD) are highly prevalent in type 2 diabetes (T2DM), however, no diabetes-related or biochemical variable seems to be predictive of severity of NAFLD. The aim of this study was to investigate the association of several serum biomarkers with the more severe histopathological stages of NAFLD in T2DM. METHODS: In a cross-sectional design, 84 T2DM patients with biopsy-proven NAFLD had adiponectin, tumor necrosis factor-α, transforming growth factor (TGF)-ß1, interleukin (IL)-6, -8 and -10, and C-reactive protein measured. NAFLD severity was evaluated by two hepatopathologists according to the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Independent associations of cytokines with NASH and advanced fibrosis were evaluated by multivariate logistic regressions. RESULTS: Sixty-six patients (78.6%) had NASH, and 52 patients (61.9%) had advanced fibrosis considering the highest score between the two pathologists. Patients with NASH or with advanced fibrosis had equal cytokine levels to those without NASH or with absent/light fibrosis, except for a lower serum adiponectin (8.59 vs 12.77 µg/mL; P = 0.015) in patients with NASH and a lower TGF-ß1 (170 vs 180 pg/mL; P = 0.026) in patients with advanced fibrosis. In multivariate analysis, lower adiponectin was independently associated with NASH (odds ratio = 7.7, 95% confidence interval = 1.5-39.9, P = 0.014, for the subgroup with adiponectin below the median value), whereas both lower adiponectin and lower TGF-ß1 levels were associated with advanced fibrosis. CONCLUSION: Low adiponectin and low TGF-ß1 are associated with severest NAFLD stages in T2DM and may be a valuable tool to support liver biopsy indication in this setting.

Prognostic impact of baseline and serial changes in electrocardiographic left ventricular hypertrophy in resistant hypertension.

BACKGROUND: The prognostic value of electrocardiographic left ventricular hypertrophy (ECG-LVH) in resistant hypertension (RH) is unknown. The aim was to evaluate the importance of baseline and serial changes in ECG-LVH as predictors of cardiovascular morbidity and mortality in patients with RH. METHODS: At baseline and during follow-up, 552 resistant hypertensive patients had 3 ECG-LVH criteria obtained: Sokolow-Lyon, Cornell voltage, and Cornell voltage-duration product. Primary end points were a composite of fatal and nonfatal cardiovascular events and all-cause and cardiovascular mortalities. Total strokes and coronary heart disease (CHD) events were secondary end points. Multiple Cox regression assessed the associations between time-varying ECG-LVH and subsequent end points. RESULTS: After a median follow-up of 4.8 years, 70 patients died, 46 from cardiovascular causes; and 109 total cardiovascular events occurred, 46 strokes, and 44 CHD events. After adjustment for several cardiovascular risk factors, baseline Cornell voltage and product, but not Sokolow-Lyon voltage, were independent predictors of the composite end point and of all-cause and cardiovascular mortalities. Reductions of all ECG-LVH criteria were protective factors for the composite end point: a 1-SD (1.1 mV) reduction in Sokolow-Lyon voltage was associated with a 35% lower risk (95% CI 10%-53%) of cardiovascular events, whereas prevention or regression of Cornell product LVH criterion implied a 40% lower risk (95% CI 11%-60%). Baseline and serial changes in Sokolow-Lyon voltage were independent predictors of strokes, whereas Cornell voltage was predictive of CHD events. CONCLUSIONS: Baseline and serial changes in ECG-LVH predict cardiovascular morbidity and mortality in RH patients. Antihypertensive treatment targeted at regression or prevention of ECG-LVH may improve prognosis.

Prognostic value of nocturnal blood pressure reduction in resistant hypertension.

BACKGROUND: The prognostic value of nocturnal blood pressure (BP) reduction in resistant hypertension (RH) is unknown. The objective of this prospective study was to evaluate its importance as a predictor of cardiovascular morbidity and mortality. METHODS: At baseline, 556 patients with RH underwent clinical and laboratory examinations and 24-hour ambulatory BP monitoring. The primary end points were a composite of fatal or nonfatal cardiovascular events, all-cause mortality, and cardiovascular mortality. Multiple Cox regression was used to assess associations between the nocturnal BP reduction and the subsequent end points. RESULTS: After a mean follow-up of 4.8 years (range, 1-103 months), 109 patients (19.6%) reached the composite end point, with 70 all-cause and 46 cardiovascular deaths. A nondipping pattern was present in 360 patients (65.0%). After adjustment for age, sex, body mass index, diabetes, smoking status, physical inactivity, dyslipidemia, previous cardiovascular disease, number of antihypertensive drugs in use, and office and 24-hour ambulatory BP readings, the nondipping pattern was an independent predictor of the composite end point (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12-2.71) and of cardiovascular mortality (HR, 2.31; 95% CI, 1.09-4.92). In subgroup analysis, the reduced (HR, 1.71; 95% CI, 1.03-2.83) and reverted (HR, 1.89; 95% CI, 1.04-3.43) dipping patterns were predictive of total cardiovascular events. The effect of the nondipping pattern on cardiovascular prognosis was stronger in younger patients and in those with true RH. CONCLUSIONS: The nocturnal BP variability patterns provide valuable prognostic information for stratification of cardiovascular morbidity and mortality risk in patients with RH, above and beyond other traditional cardiovascular risk factors and mean ambulatory BP levels.

Bioprótese mitral: avaliaçäo clínica, radiológica, eletrocardiográfica e ecocardiográfica / Mitral bioprosthesis: clinical, roentgenographic, electrocardiographic and echocardiographic evaluation

Foram estudados 26 pacientes portadores de doenç a mitral reumática submetidos a troca valvar por bioprótese, quanto à sua evoluçäo clínica, eletrocardiográfi, radiológica e ecocardiográfica. O tempo médio de implante foi de 53,65 meses. Na avaliaçäo clínica observamos melhora funcional em 25 pacientes e evidências de disfunçäo valvar em cinco (19,23%). Na avaliaçäo radiológica houve reduçäo significativa do índice cardiotorácico (p < 0,01) no pós-operat-orio. No estudo eletrocardiográfico observamos média (p < 0,05) do pós-operatório em relaçäo ao pré-operatório. No estudo ecocardiográfico observamos aspectos e medidas normais das biopróteses e confirmamos aspectos anormais nos pacientes com evidencias clínicas de disfunçäo protética, coincidentes com a literatura. A presença de sinais sugestivos de calcificaçäo dos folhetos foi a alteraçäo mais freqüente encontrada em oito (30,8%) dos pacientes estudados. Esse dado, presente tanto nos pacientes com sinais clínicos de disfunç äo protética como naqueles sem evidências de comprometimento da prótese, sugere que essa alteraçäo anteceda as demais alteraçöes estruturais e funcionais da bioprótese e possa ser incluída como critério de degeneraçäo tissular das próteses biológicas