Alterations of cholesterol synthesis and absorption in obstructive sleep apnea: Influence of obesity and disease severity

Background and aimsObstructive sleep apnea (OSA) is closely linked to obesity and related adverse metabolic changes, including dyslipidemia. However, it is not clear whether OSA is an independent contributing factor to dyslipidemia, or the observed association is a reflection of a concomitant presence of obesity. Additionally, dyslipidemia is usually evaluated through measurement of parameters of routine lipid status, while more precise evaluation of lipid homeostasis is rarely performed in OSA. In this study, we analyzed markers of cholesterol synthesis and absorption in patients with OSA with respect to the presence of obesity and the disease severity.Methods and resultsThis study enrolled 116 OSA patients. Concentrations of non-cholesterol sterols (NCS), measured by LC-MS/MS, were used as markers of cholesterol synthesis and absorption. Apnea-hypopnea index (AHI) and oxygen saturation (SaO₂) were utilized as markers of OSA severity. Serum lipid status parameters were determined by routine enzymatic methods. Markers of cholesterol synthesis were increased (P = 0.005), whilst markers of cholesterol absorption decreased (P = 0.001) in obese OSA patients. Cholesterol synthesis/absorption ratio was elevated in obese subjects (P < 0.001). Concentration of cholesterol synthesis marker lathosterol was significantly higher in subjects with severe OSA (P = 0.014) and we observed a trend of decreased cholesterol absorption in these patients. AHI was revealed as an independent determinant of lathosterol concentration (P = 0.022).ConclusionsOur results suggest that the presence of obesity and severe forms of OSA is characterized by elevated endogenous cholesterol synthesis. AHI was singled out as an independent determinant of the serum level of cholesterol synthesis marker lathosterol.     

Prevalence of pulmonary embolism in patients with obstructive sleep apnea and chronic obstructive pulmonary disease: The overlap syndrome

ObjectiveGrowing evidence indicates that both obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) may be closely associated with the prevalence of pulmonary embolism (PE). However, the relationship of overlap syndrome (OS) (coexistence of OSA and COPD) with PE is unclear. The purpose of this study was to investigate whether OS were associated with increased PE prevalence.MethodsWe performed a retrospective chart review of patients who underwent sleep study at Beijing An Zhen Hospital from 2011 to 2014. The association of OS with PE prevalence was estimated by using logistic regression models.ResultsIn contrast to control patients (neither OSA nor COPD), those subjects with OS had higher odds of PE (OR9.61; 95%CI 4.02–21.31, p < 0.001) with significance persisting after adjusting for covariates (OR 5.66; 95%CI 1.80–16.18, p = 0.004). Meanwhile, patients with OS compared with those with isolated OSA also had significantly higher odds of PE in univariate (OR 4.79; 95%CI 2.04–10.33, p = 0.0007) and adjusted models (OR 3.89; 95%CI 1.27–10.68, p = 0.019). In subgroup analysis, patients with OS had higher odds of PE than control group among male subjects (OR 8.12, 95%CI1.86–31.87, p = 0.007) and patients ≥ 58years (OR 5.50, 95%CI 1.51–18.14, p = 0.012) in multivariable models. Percentage of total sleep time with saturation lower than 90% (T90) ≥ 2.6% was significantly associated with prevalence of PE (OR 4.72, 95%CI1.34–19.83, p = 0.015) in subgroup of patients older than 58.ConclusionsOS is independently associated with PE prevalence. Longitudinal studies are needed to better understand the relationship with incident PE.     

The impact of obstructive sleep apnea and PAP therapy on all-cause and cardiovascular mortality based on age and gender – a literature review

BackgroundObstructive sleep apnea (OSA) is a common sleep disorder which negatively impacts different body systems, especially the cardiovascular system. The correlation between sleep related breathing disorders and cardiovascular diseases has been well studied. However, the impact of OSA on cardiovascular related mortality and the role of positive airway pressure therapy in decreasing mortality is unclear. We reviewed studies investigating the impact of OSA on all-cause and cardiovascular related mortality in both genders, and in different age groups.MethodsA literature search (PubMed) using two phrases “obstructive sleep apnea and co-morbidities in males and females” and “obstructive sleep apnea and co-morbidities by age” yielded a total of 214 articles. Nineteen articles met the inclusion criteria.ResultsThe studies reviewed showed conflicting results. Some showed that OSA increases all cause and cardiovascular related mortality predominantly in the middle-aged group (40–65) followed by a plateau or a reduction in mortality. Other studies showed a positive linear correlation between OSA and mortality up to the age of 80. The same controversy was noted for gender; some studies did not observe an increase in mortality in females with OSA, while others observed a trend for an increase in mortality in females.ConclusionThere is a debate in the literature regarding the impact of OSA on all-cause and cardiovascular mortality in both genders and in different age groups. However, the variation in results might be related to different study designs and significant epidemiological prevalence of OSA in males and females.     

The release of phosphorylated-HSP27 from activated platelets of obstructive sleep apnea syndrome (OSAS) patients

BackgroundObstructive sleep apnea syndrome (OSAS) is a well known risk of arterial thrombosis that results in cardiovascular morbidity. It has been reported that platelet aggregability is enhanced in patients with OSAS. In the present study, we investigated whether phosphorylated-HSP27 is released from the activated platelets of OSAS patients.MethodsPatients diagnosed with OSAS (n = 21) were recruited, and platelet-rich plasma (PRP) was stimulated by ADP, ristosetin, collagen, and thrombin receptor-activating peptide. Platelet aggregation was measured using an aggregometer with a laser-scattering system. The levels of protein phosphorylation and the released levels of phosphorylated-HSP27 were determined by Western blot analysis and an ELISA, respectively.ResultsThe phosphorylation of HSP27 in the platelets was induced by the stimulators. The released levels of phosphorylated-HSP27 was correlated with the levels of phosphorylated-HSP27 stimulated by ADP or collagen. The levels of ADP-induced phosphorylated-HSP27 were correlated with those of both phosphorylated-protein kinase B (Akt) and phosphorylatd-p38 mitogen-activated protein kinase; however, the levels of phosphorylated-HSP27 stimulated by collagen were correlated with phosphorylated-Akt levels only. The ED₅₀ value of ADP on the platelet aggregation in OSAS (1.067 ± 0.128 μM) was lower than that in healthy subjects (1.778 ± 0.122 μM) and was inversely correlated with both the value of minimum SpO₂ and the released level of phosphorylated-HSP27 stimulated by ADP.ConclusionThe results strongly suggest that phosphorylated-HSP27 is released from the activated platelets of OSAS patients.     

Rapid eye movement related obstructive sleep apnea: Where do we stand?

Rapid eye movement (REM) related obstructive sleep apnea (OSA) is defined by the presence of episodes of apnea or hypopnea predominantly or exclusively during REM sleep. Epidemiology of this disorder shows a complex interaction with age, sex, and body mass index. The prevalence is variable and depends on the criteria used to define this disorder. Moreover, the clinical significance of this entity remains poorly defined. However, episodes of apnea or hypopnea encountered during REM sleep are longer and are associated with a more profound drop in oxygen saturation than non-REM sleep. Likewise, this disorder may be independently associated with hypertension and poor glycemic control. More importantly, positive airway pressure therapy as currently prescribed may not treat the majority of apnea episodes during REM sleep. The treatment is further complicated by the different definitions used for the diagnosis of this disorder and the lack of consensus if patients with this diagnosis should be treated if their overall apnea-hypopnea index does not meet the threshold for the clinical diagnosis of OSA. The definition and treatment used for the diagnosis and management of REM-related OSA needs to be standardized. Moreover, a consensus needs to be developed as to whether patients with this disorder should be treated if their overall apnea-hypopnea index does not meet the threshold for the clinical diagnosis of OSA. Further investigation may help answer if this disorder is independently associated with neurocognitive and cardiometabolic adverse outcomes and help guide the therapeutic approach.     

Sustained improvements in the cardiometabolic profile of patients with obstructive sleep apnea after a weight-loss Mediterranean diet/lifestyle intervention: 12-month follow-up (6 months post-intervention) of the “MIMOSA” randomized clinical trial

Background and aimsObstructive sleep apnea (OSA) and the metabolic syndrome (MS) frequently coexist and lead to increased cardiometabolic morbidity. We aimed to explore the long-term cardiometabolic benefits of a weight-loss Mediterranean diet/lifestyle intervention in OSA.Methods and resultsAs many as 180 adults with overweight/obesity and polysomnography-diagnosed moderate-to-severe OSA were randomized to a standard care (SCG, n = 62), a Mediterranean diet (MDG, n = 59) or a Mediterranean lifestyle group (MLG, n = 59). All groups were prescribed with continuous positive airway pressure (CPAP), while intervention arms (MDG/MLG) additionally participated in a 6-month weight-loss intervention based on the Mediterranean diet/lifestyle. Cardiometabolic parameters were evaluated at baseline and 12 months (6 months post-intervention). Data were analyzed using the intention-to-treat method, and 12-month between-group differences were explored while adjusting for age, sex, baseline status and CPAP use. Compared to the SCG, intervention arms exhibited lower insulin, triglycerides and high-sensitivity C-reactive protein, and higher high-density lipoprotein cholesterol; the MDG also exhibited lower diastolic blood pressure, while the MLG exhibited lower glucose and systolic blood pressure (all P < 0.050). The relative risk (95% confidence interval) of MS was 0.60 (0.36, 0.99) in the MDG versus the SCG, 0.33 (0.20, 0.55) in the MLG versus the SCG and 0.55 (0.32, 0.93) in the MLG versus the MDG. The risk of MS remained lower in the MLG versus the other study groups (both P < 0.050) after additional adjustment for body weight change.ConclusionCardiometabolic benefits of a 6-month healthy dietary/lifestyle intervention are sustainable 6 months post-intervention in OSA.Trial registrationClinicalTrials.gov, NCT02515357, August 4, 2015.     

Quantitative computed tomography-based evaluation of skeletal muscle and presence of sarcopenia in patients with chronic obstructive pulmonary disease

Sarcopenia, or age-related muscle loss, is a common comorbidity in patients with chronic obstructive pulmonary disease (COPD) with multiple contributing factors. We hypothesized that the presence of sarcopenia can be estimated using quantitative computed tomography-based parameters in patients with COPD. We retrospectively evaluated 38 elderly (≥65 years) men with COPD for pooled data, including hand grip strength and gait speed. Sarcopenia was diagnosed based on the updated 2019 criteria set by the Asian Working Group for Sarcopenia. Cross-sectional area of the erector spinae muscle (ESM) and pectoralis muscle (PM) were quantitatively evaluated and adjusted by height (ESM-I, and PM-I). Sarcopenia was diagnosed in 11 (29%) patients. The mean ESM-I and PM-I were 11.0 and 9.5 cm²/m², respectively, and significantly correlated with height-adjusted appendicular skeletal muscle mass. The optimal cutoff ESM-I for the presence of sarcopenia was 9.41 cm²/m². ESM loss helped estimate sarcopenia in patients with COPD.     

Lipid profiles and the risk of new-onset hypertension in a Chinese community-based cohort

Background and aimsDyslipidemia and hypertension, key risk factors for cardiovascular disease, may share similar pathophysiological processes. A longitudinal association was reported between dyslipidemia and new-onset hypertension, but few data were published in Asian. We aimed to investigate the association of lipid profiles with new-onset hypertension in a Chinese community-based non-hypertensive cohort without lipid-lowering treatment (n = 1802).Methods and resultsNew-onset hypertension was defined as any self-reported history of hypertension, systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg, or receiving antihypertensive medications at follow-up. Logistic regression models were used to evaluate the associations. Participants were aged 53.97 ± 7.49 years, 31.19% were men, and 64.54% with dyslipidemia. During a median of 2.30 years follow-up, the incidence of new-onset hypertension was 12.99%. Multivariate adjusted risks of new-onset hypertension increased with triglyceride increases (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.03–1.27) and high-density lipoprotein cholesterol (HDL-C) decreases (OR = 0.47, 95% CI: 0.29–0.76) for one unit. However, threshold effects were observed for total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and non-HDL-C. Compared with subjects with hyperlipidemia, in those with normal concentrations of TC, LDL-C, and non-HDL-C increased risks of new-onset hypertension were observed with OR (95% CI) of 1.65 (1.10–2.46), 1.58 (1.07–2.33), and 1.57 (1.15–2.15) for one unit increasement, respectively, after adjusting for all covariates.ConclusionHigher TG and lower HDL-C increased the risk of new-onset hypertension, but for TC, LDL-C and non-HDLC, the risk of new-onset hypertension was increased only at normal concentrations in a Chinese community-based cohort.     

Trends in lipid profiles and control of LDL-C among adults with diabetes in the United States: An analysis of NHANES 2007–2018

Background and aimTo determine trends in lipid profiles and lipid control in US adults with diabetes and assess variation in these trends across sex and race/ethnicity from 2007 to 2018.Methods and resultsSerial cross-sectional analysis of data from diabetic adults participating in the National Health and Nutrition Examination Survey (NHANES; 2007–2008 to 2017–2018). Among the 6116 participants included (weighted mean age, 61.0 years; 50.7% men), age-adjusted TC (p for trend < 0.001), LDL-C (p for trend < 0.001), TG (p for trend = 0.006), TG/HDL-C (p for trend = 0.014) and VLDL-C (p for trend = 0.015) decreased significantly. Age-adjusted LDL-C levels were consistently higher in women than in men over the study period. Age-adjusted LDL-C improved significantly for diabetic whites and blacks but did not change significantly for the other races/ethnicity. Lipid parameters improved for non-coronary heart disease (CHD) diabetic adults, except for HDL-C, while no lipid parameter significantly changed for diabetic adults with concomitant CHD. Among diabetic adults receiving statin therapy, age-adjusted lipid control remained unchanged from 2007 to 2018, as did adults with concomitant CHD. However, age-adjusted lipid control improved significantly for men (p for trend < 0.01) and diabetic Mexican Americans (p for trend < 0.01). In 2015–2018, female diabetic participants receiving statins had lower odds of achieving lipid control (OR: 0.55; 95% CI: 0.35–0.84; P = 0.006) than men. Differences in lipid control across different races/ethnicities no longer existed.ConclusionsLipid profiles improved in the US adults with diabetes from 2007 to 2018. Although rates of lipid control did not improve nationally in adults receiving statins, these patterns varied by sex and race/ethnicity.     

Association between the severity of chronic spontaneous urticaria and sleep-disordered breathing

BackgroundChronic spontaneous urticaria (CSU) is a common mast cell-driven disease, presenting with wheals, angioedema, or both. Sleep-disordered breathing (SDB) is also a common condition and contributes to various diseases by causing chronic inflammation. Recent studies have suggested an association between CSU and SDB.MethodsTo determine the association between the severity of SDB and that of CSU, we studied consecutive patients with CSU who visited the Sagamihara National Hospital allergy department or dermatology department between April 1 and October 31, 2018. The severity of CSU and SDB was evaluated based on the urticaria activity score 7 (UAS7) and peripheral arterial tone apnea-hypopnea index (pAHI) derived from out-of-center sleep testing (OCST) findings, respectively; their correlation was examined.ResultsOf the 37 patients studied, 19 had symptom-free-to-mild CSU (UAS7 ≤15) and 18 had moderate-to-severe CSU (UAS7 ≥16). The pAHI in the latter group was significantly higher than that in the former group (18 vs. 4.2, p = 0.001). In multivariate logistic analysis, moderate-to-severe SDB (pAHI ≥15) was significantly associated with moderate-to-severe CSU even after adjusting for the BMI (adjusted odds ratio 22 [95% confidence interval, 1.7–285]).ConclusionsThe severity of SDB is correlated with that of CSU independently of the BMI. Physicians should consider comorbid SDB when treating patients with CSU.     

Serum gasdermin D levels are associated with the chest computed tomography findings and severity of COVID-19

BackgroundThe role of programmed cell death, especially pyroptosis and apoptosis, in unfavorable immune responses in COVID-19 remains to be elucidated.MethodsWe conducted a cross-sectional analysis to investigate the association between the serum gasdermin D (GSDMD) levels, a pyroptotic marker, and caspase-cleaved cytokeratin 18 fragment (M30), an apoptotic marker, and the clinical status and abnormal chest computed tomography (CT) findings in patients with COVID-19.ResultsIn this study, 46 patients diagnosed with COVID-19 were divided into the following three groups according to the disease severity: mild to moderate group (n = 10), severe group (n = 14), and critical group (n = 22). The serum GSDMD levels were higher in the critical group than in the mild to moderate group (P = 0.016). In contrast, serum M30 levels were lower in the critical group than in the severe group (P = 0.048). Patients who required mechanical ventilation or died had higher serum GSDMD levels than those who did not (P = 0.007). Area of consolidation only and of ground glass opacity plus consolidation positively correlated with serum GSDMD levels (r = 0.56, P < 0.001 and r = 0.53, P < 0.001, respectively).ConclusionHigher serum GSDMD levels are associated with critical respiratory status and the consolidation area on chest CT in patients with COVID-19, suggesting that excessive activation of pyroptosis may affect the clinical manifestations in patients with COVID-19.     

Associations between major dietary patterns and blood pressure among Southwest Chinese: A cross-sectional analysis based on the China Multi-Ethnic Cohort (CMEC) study

Background and aimsIn the less developed multi-ethnic regions (LEMRs) of Southwest China, the associations between dietary patterns and blood pressure (BP) values remain unclear. We aimed to investigate such associations and related effect modifiers.Methods and resultsThis study included 81,433 participants from the China Multi-Ethnic Cohort Study. Dietary intakes during the year before the interview were measured with the Quantitative Food Frequency Questionnaire. Three major dietary patterns that were highly in line with geographical and ethnic distributions of the study population, i.e., “Sichuan Basin,” “Yunnan-Guizhou Plateau,” and “Qinghai-Tibet Plateau,” were derived using principal component factor analysis. The multilinear regression model combined with inverse probability of exposure weighting was used to estimate the associations between dietary patterns and BP values.Comparing the highest with the lowest quintiles, the Sichuan Basin dietary pattern (characterized by urban lifestyles) was associated with 2.67 mmHg lower systolic blood pressure (SBP) (95% CI: −3.07 to −2.27) and 0.89 mmHg lower diastolic blood pressure (95% CI: −1.12 to −0.65). In contrast, both the Yunnan-Guizhou Plateau (characterized by agricultural lifestyles) and the Qinghai-Tibet Plateau dietary patterns (characterized by nomadic lifestyles) showed positive associations with BP. In the stratified analysis, the associations between dietary patterns and SBP were significantly stronger in women than in men for all three kinds of dietary patterns.ConclusionBoth major dietary patterns and their associations with BP showed a substantial disparity in LEMRs of Southwest China. Dietary patterns in regions of higher socioeconomic status are more conducive to reducing the rising of BP, especially for women and urban residents, which might provide insights into the BP control in LEMRs of Southwest China.     

Lobar distribution of non-emphysematous gas trapping and lung hyperinflation in chronic obstructive pulmonary disease

BackgroundLung hyperinflation in chronic obstructive pulmonary disease (COPD) is closely associated with emphysema and non-emphysematous gas trapping, termed functional small airway disease (fSAD), on inspiratory and expiratory computed tomography (CT). Because the cranial-caudal emphysema distribution affects pulmonary function and fSAD may precede emphysema on CT, we tested the hypothesis that lobar fSAD distribution would affect lung hyperinflation differently in COPD with minimal and established emphysema.MethodsThe volume percentages of fSAD and emphysema (fSAD% and Emph%) over the upper and lower lobes were measured using inspiratory and expiratory CT in 70 subjects with COPD. Subjects were divided into those with minimal and established emphysema (n = 36 and 34) using a threshold of 10% Emph% in the whole lung.ResultsIn the minimal emphysema group, fSAD% in the upper and lower lobes was positively correlated with functional residual capacity (FRC) and residual volume to total lung capacity ratio (RV/TLC), and the correlation of fSAD% with RV/TLC was greater in the lower lobes. Conversely, in the established emphysema group, fSAD% in the upper and lower lobes was correlated with RV/TLC, but not with FRC. In multivariate analysis, fSAD% in the lower lobes, but not in the upper lobes, was associated with RV/TLC in subjects with minimal emphysema after adjusting for age, smoking status, and bronchodilator use.ConclusionNon-emphysematous gas trapping in the upper and lower lobes has a distinct physiological effect, especially in COPD with minimal emphysema. This local evaluation might allow sensitive detection of changes in lung hyperinflation in COPD.     

Lifestyle behaviors and cardiovascular risk profiles among parous women by gestational diabetes status, 2007–2018

Background and aimsWomen with prior gestational diabetes mellitus (GDM) are at elevated risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors among parous U.S. women ages 20–44 by history of GDM.Methods and resultsUsing data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018, 3537 parous women were classified by self-reported GDM history. We compared anthropometric measures, glycemia, blood pressure, lipids, lifestyle factors, cardiovascular health, and cardiometabolic disease prevalence by GDM status. NHANES survey design was taken into account. Women without history of GDM were younger and, after adjusting for age, race/ethnicity, and education, had more favorable cardiometabolic risk factor profiles for measures of anthropometry, glycemia, diabetes, many lipids, physical activity, diet, and overall cardiovascular health than women with history of GDM. Many patterns persisted after further adjustment for lifestyle factors. In analyses stratified by race/ethnicity, many patterns persisted, though there were key differences. Hypertension prevalence differed by GDM history only among Hispanic women. In women of other race/ethnicity, there was no difference in healthy eating or body mass index by GDM history. In non-Hispanic Black women, there was no difference in healthy eating by GDM history.ConclusionAmong parous U.S. women ages 20–44, those with history of GDM had less favorable cardiometabolic risk factor profiles than those without history of GDM. This highlights the importance of continued efforts to develop and test multilevel interventions to improve cardiometabolic risk factors among reproductive-age women with a history of GDM.     

Physical activity and metabolic syndrome severity among older adults at cardiovascular risk: 1-Year trends

Background and aimsModifiable lifestyle factors, such as physical activity (PA) and Mediterranean diet (MD), decrease metabolic syndrome (MetS). The aim was to assess 1-year changes of leisure-time physical activity (LTPA), sedentary behavior, and diet quality according to MetS severity in older population at high cardiovascular risk.Methods and resultsProspective analysis of 55–75-year-old 4359 overweight/obese participants with MetS (PREDIMED-Plus trial) categorized in tertiles according to 1-year changes of a validated MetS severity score (MetSSS). Anthropometrics, visceral adiposity index, triglycerides and glucose index, dietary nutrient intake, biochemical marker levels, dietary inflammatory index, and depression symptoms were measured. Diet quality was assessed by 17-item MD questionnaire. PAs were self-reported using the Minnesota-REGICOR Short Physical Activity Questionnaire and 30-s chair stand test. Sedentary behaviors were measured using the Spanish version of the Nurses’ Health Study questionnaire. After 1-year follow-up, decreasing MetSSS was associated with an anti-inflammatory dietary pattern, high intake of vegetables, fruits, legumes, nuts, whole grain cereals, white fish, and bluefish and low intake of refined cereals, red and processed meat, cookies/sweets, and snacks/ready-to-eat-meals. It resulted in high intake of polyunsaturated fatty acids, omega-3 fatty acids, protein, fiber, vitamins B1, B6, B9, C, D, potassium, magnesium, and phosphorus and low glycemic index and saturated fatty acid, trans fatty acid, and carbohydrates intake. Regarding PA and sedentary behavior, decreasing MetSSS was associated with increased moderate-to-vigorous LTPA, chair stand test, and decreased sedentary and TV-viewing time.ConclusionDecreasing MetSSS was associated with an anti-inflammatory dietary pattern, high LTPA, high MD adherence, low sedentary time, and low depression risk.     

Hierarchical cluster analysis based on disease-associated manifestations of patients with lymphangioleiomyomatosis: An analysis of the national database of designated intractable diseases of Japan

BackgroundLymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes.MethodsUsing cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations.ResultsFour clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required.ConclusionsHierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future.     

J-shaped relationship between serum zinc levels and the severity of hepatic necro-inflammation in patients with MAFLD

Background and aimsZinc is an essential trace element that plays an important role in maintaining health, and affecting gene expression, signal transduction and regulation of apoptosis. It is uncertain whether serum zinc levels are altered in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). We aimed to investigate the association between serum zinc levels and the severity of hepatic necro-inflammation (HN) in patients with MAFLD.Methods and resultsLiver disease severity was graded histologically using the NAFLD activity score. HN was defined as the sum of ballooning and lobular inflammation. We used a smooth function regression model to analyze the relationship between serum zinc levels and HN. A total of 561 (76.5% men) patients with biopsy-confirmed MAFLD were enrolled. They had a mean age of 41.3 years, and a mean serum zinc level of 17.0 ± 4.1 μmol/L. Compared to those with mild hepatic necro-inflammation (MHN, grades 0–2; n = 286), patients with severe hepatic necro-inflammation (SHN, grades 3–5; n = 275) had lower serum zinc concentrations (16.3 ± 4.2 vs. 17.6 ± 4.0 μmol/L; p < 0.001). However, a threshold saturation effect analysis showed that there was an inflection in serum zinc levels at 24 μmol/L. After adjustment for potential confounders, serum zinc levels <24 μmol/L were inversely associated with SHN (adjusted-odds ratio 0.88, 95%CI 0.83–0.93; p < 0.001), whereas serum zinc levels >24 μmol/L were positively associated with SHN (adjusted-odds ratio 1.42, 95%CI: 1.03–1.97; p = 0.035).ConclusionsThere is a J-shaped relationship between serum zinc levels and the severity of hepatic necro-inflammation in patients with biopsy-proven MAFLD.     

The Added Value of Coronary Calcium Score in Predicting Cardiovascular Events in Familial Hypercholesterolemia

ObjectivesThis study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH).BackgroundCommon cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD).MethodsREFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death.ResultsWe included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%.ConclusionsCAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH.     

Association between positivity of serum autoantibodies and liver disease severity in patients with biopsy-proven NAFLD

Background and aimsSome previous studies reported serum autoantibody positivity in patients with nonalcoholic fatty liver disease (NAFLD). The clinical significance of these findings remains uncertain. We aimed to investigate the association between the presence of serum autoantibodies and liver disease severity in NAFLD.Methods and resultsA total of 388 consecutive patients with biopsy-proven NAFLD were included in the study. Various serum autoantibodies (including also anti-nuclear antibodies [ANA]) were detected by indirect immunofluorescent or immunoblotting assays. Overall, 84 (21.6%) patients with biopsy-confirmed NAFLD had positivity for at least one of the measured serum autoantibodies. ANA positivity was present in 50 (12.9%) patients, whereas anti-U1RNP or pANCA antibodies were detectable in 9 (2.3%) and 6 (1.5%) patients, respectively. Multivariate logistic regression analysis showed that ANA positivity (adjusted-odds ratio: 4.51, 95%CI: 1.77–11.5; P = 0.002) or positivity of any serum autoantibodies (adjusted-odds ratio: 3.14, 95%CI: 1.30–7.62; P = 0.01) were independently associated with advanced liver fibrosis (stages F3–F4). In serum autoantibody/ANA-positive patients, the proportion of those with advanced fibrosis was also greater among carriers of PNPLA3 rs738409 GG or CG than among those carrying PNPLA3 rs738409 CC genotype.ConclusionsSerum autoantibody positivity was independently associated with advanced liver fibrosis in patients with biopsy-proven NAFLD. The presence of serum autoantibodies in patients with advanced fibrosis occurred more frequently amongst those carrying PNPLA3 rs738409 GG or CG genotypes.