Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin's quantity, response to progerin-targeted therapy, and relationship to patient survival. METHODS: Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children's Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization. RESULTS: The assay's dynamic detection range was 59 to 30 000 pg/mL (R2=0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2-71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1-17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children (P<0.0001). Progerin levels did not differ by sex (P=0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P<0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival (P<0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration. CONCLUSIONS: A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy. REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifiers: NCT00879034 and NCT00916747.

Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin.

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.

Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.

BACKGROUND: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. METHODS: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. RESULTS: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004). CONCLUSIONS: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial.

BACKGROUND: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. METHODS: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033. FINDINGS: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (pinteraction=0·012 [≥29·7 mL/m2, worse outcomes]), and sex (pinteraction=0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11). INTERPRETATION: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. FUNDING: Corvia Medical.

Blood levels of MCP-1 modulate the genetic risks of Alzheimer's disease mediated by HLA-DRB1 and APOE for Alzheimer's disease.

INTRODUCTION: C-Reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) are both implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption. Since the blood CRP level increases Alzheimer's disease (AD) risk depending on the apolipoprotein E (APOE) genotype, we hypothesized that the blood MCP-1 level exerts different effects on the AD risk depending on the genotypes. METHODS: Using multiple regression analyses, data from the Framingham Heart Study (n = 2884) and Alzheimer's Disease Neuroimaging Initiative study (n = 231) were analyzed. RESULTS: An elevated blood MCP-1 level was associated with AD risk in major histocompatibility complex, Class II, DR beta 1 (HLA-DRB1) rs9271192-AC/CC (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 1.50-6.28, p = 0.002) and in APOE ε4 carriers (HR = 3.22, 95% CI = 1.59-6.53, p = 0.001). In contrast, among HLA-DRB1 rs9271192-AA and APOE ε4 noncarriers, blood MCP-1 levels were not associated with these phenotypes. DISCUSSION: Since HLA-DRB1 and APOE are expressed in the BBB, blood MCP-1 released in the peripheral inflammatory cascade may function as a mediator of the effects of HLA-DRB1 rs9271192-AC/CC and APOE ε4 genotypes on AD pathogenesis in the brain via the BBB pathways.

Midlife lipid and glucose levels are associated with Alzheimer's disease.

INTRODUCTION: It is unknown whether vascular and metabolic diseases assessed in early adulthood are associated with Alzheimer's disease (AD) later in life. METHODS: Association of AD with lipid fractions, glucose, blood pressure, body mass index (BMI), and smoking obtained prospectively from 4932 Framingham Heart Study (FHS) participants across nine quadrennial examinations was evaluated using Cox proportional hazard and Kaplan-Meier models. Age-, sex-, and education-adjusted models were tested for each factor measured at each exam and within three adult age groups (early = 35-50, middle = 51-60, and late = 61-70). RESULTS: A 15 mg/dL increase in high density lipoprotein (HDL) cholesterol was associated with decreased AD risk during early (15.4%, P = 0.041) and middle (17.9%, P = 0.014) adulthood. A 15 mg/dL increase in glucose measured during middle adulthood was associated with 14.5% increased AD risk (P = 0.00029). These findings remained significant after adjusting for treatment. DISCUSSION: Our findings suggest that careful management of cholesterol and glucose beginning in early adulthood can lower AD risk.

Standardized measurement of abdominal muscle by computed tomography: association with cardiometabolic risk in the Framingham Heart Study.

OBJECTIVES: To provide a standard for total abdominal muscle mass (TAM) quantification on computed tomography (CT) and investigate its association with cardiovascular risk in a primary prevention setting. METHODS: We included 3016 Framingham Heart Study participants free of cardiovascular disease (CVD) who underwent abdominal CT between 2002 and 2005. On a single CT slice at the level of L3/L4, we segmented (1) TAM-Area, (2) TAM-Index (= TAM-Area/height) and, (3) TAM-Fraction (= TAM-Area/total cross-sectional CT-area). We tested the association of these muscle mass measures with prevalent and incident cardiometabolic risk factors and incident CVD events during a follow-up of 11.0 ± 2.7 years. RESULTS: In this community-based sample (49% women, mean age: 50.0 ± 10.0 years), all muscle quantity measures were significantly associated with prevalent and incident cardiometabolic risk factors and CVD events. However, only TAM-Fraction remained significantly associated with key outcomes (e.g., adj. OR 0.68 [0.55, 0.84] and HR 0.73 [0.57, 0.92] for incident hypertension and CVD events, respectively) after adjustment for age, sex, body mass index, and waist circumference. Moreover, only higher TAM-Fraction was associated with a lower risk (e.g., adj. OR: 0.56 [0.36-0.89] for incident diabetes versus TAM-Area: adj. OR 1.26 [0.79-2.01] and TAM-Index: 1.09 [0.75-1.58]). CONCLUSION: TAM-Fraction on a single CT slice at L3/L4 is a novel body composition marker of cardiometabolic risk in a primary prevention setting that has the potential to improve risk stratification beyond traditional measures of obesity. KEY POINTS: • In this analysis of the Framingham Heart Study (n = 3016), TAM-F on a single slice CT was more closely associated with prevalent and incident cardiometabolic risk factors as compared to TAM alone or TAM indexed to body surface area. • TAM-F on a single abdominal CT slice at the level of L3/L4 could serve as a standard measure of muscle mass and improve risk prediction.

Sample size determination for the association between longitudinal and time-to-event outcomes using the joint modeling time-dependent slopes parameterization.

Given their improvements in bias reduction and efficiency, joint models (JMs) for longitudinal and time-to-event data offer great potential to clinical trials. However, for JM to become more widely used, there is a need for additional development of design considerations. To this end, Chen et al previously developed two closed-form sample size formulas in the JM setting. In this current work, we expand upon this framework by utilizing the time-dependent slopes parameterization, where the change in the longitudinal outcome influences the hazard, in addition to the current value of the longitudinal process. Our extended formula for the required number of events can be used when testing significance of the association between the longitudinal and time-to-event outcomes. We find that if the data indeed are generated such that not only the current value, but also the slope of the longitudinal outcome influence the hazard of the time-to-event process, it is advisable to use the current formula developed utilizing the time-dependent slopes parameterization. In this setting, our proposed formula will provide a more accurate estimate of power compared to the method by Chen et al. To illustrate our proposed method, we present power calculations of a biomarker qualification study for Hutchinson-Gilford progeria syndrome, an ultra-rare premature aging disease.

Calculating power for the Finkelstein and Schoenfeld test statistic for a composite endpoint with two components.

The Finkelstein and Schoenfeld (FS) test is a popular generalized pairwise comparison approach to analyze prioritized composite endpoints (eg, components are assessed in order of clinical importance). Power and sample size estimation for the FS test, however, are generally done via simulation studies. This simulation approach can be extremely computationally burdensome, compounded by increasing number of composite endpoints and with increasing sample size. Here we propose an analytical solution to calculate power and sample size for commonly encountered two-component hierarchical composite endpoints. The power formulas are derived assuming underlying distributions in each of the component outcomes on the population level, which provide a computationally efficient and practical alternative to the standard simulation approach. Monte Carlo simulation results demonstrate that performance of the proposed power formulas are consistent with that of the simulation approach, and have generally desirable objective properties including robustness to mis-specified distributional assumptions. We demonstrate the application of the proposed formulas by calculating power and sample size for the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial.

Perihematomal Edema and Clinical Outcome After Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.

BACKGROUND: Perihematomal edema (PHE) has been proposed as a radiological marker of secondary injury and therapeutic target in intracerebral hemorrhage (ICH). We conducted a systematic review and meta-analysis to assess the prognostic impact of PHE on functional outcome and mortality in patients with ICH. METHODS: We searched major databases through December 2020 using predefined keywords. Any study using logistic regression to examine the association between PHE or its growth and functional outcome was included. We examined the overall pooled effect and conducted secondary analyses to explore the impact of individual PHE measures on various outcomes separately. Study quality was assessed by three independent raters using the Newcastle-Ottawa Scale. Odds ratios (per 1-unit increase in PHE) and their confidence intervals (CIs) were log transformed and entered into a DerSimonian-Laird random-effects meta-analysis to obtain pooled estimates of the effect. RESULTS: Twenty studies (n = 6633 patients) were included in the analysis. The pooled effect size for overall outcome was 1.05 (95% CI 1.02-1.08; p < 0.00). For the following secondary analyses, the effect size was weak: mortality (1.01; 95% CI 0.90-1.14), functional outcome (1.04; 95% CI 1.02-1.07), both 90-day (1.06; 95% CI 1.02-1.11), and in-hospital assessments (1.04; 95% CI 1.00-1.08). The effect sizes for PHE volume and PHE growth were 1.04 (95% CI 1.01-1.07) and 1.14 (95% CI 1.04-1.25), respectively. Heterogeneity across studies was substantial except for PHE growth. CONCLUSIONS: This meta-analysis demonstrates that PHE volume within the first 72 h after ictus has a weak effect on functional outcome and mortality after ICH, whereas PHE growth might have a slightly larger impact during this time frame. Definitive conclusions are limited by the large variability of PHE measures, heterogeneity, and different evaluation time points between studies.

Assessing Cardiovascular Risk in People Living with HIV: Current Tools and Limitations.

PURPOSE OF REVIEW: To provide the current state of the development and application of cardiovascular disease (CVD) prediction tools in people living with HIV (PLWH). RECENT FINDINGS: Several risk prediction models developed on the general population are available to predict CVD risk, the most notable being the US-based pooled cohort equations (PCE), the Framingham risk functions, and the Europe-based SCORE (Systematic COronary Risk Evaluation). In validation studies in cohorts of PLWH, these models generally underestimate CVD risk, especially in individuals who are younger, women, Black race, or predicted to be at low/intermediate risk. An HIV-specific CVD prediction model, the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) model, is available, but its performance is modest, especially in US-based cohorts. Enhancing CVD prediction with novel biomarkers of inflammation or coronary artery calcification is of interest but has not yet been evaluated in PLWH. Finally, studies on CVD risk prediction are lacking in diverse PLWH globally. While available risk models for CVD prediction in PLWH remain suboptimal, clinicians should remain vigilant of higher CVD risk in this population and should use any of these risk scores for risk stratification to guide preventive interventions. Focus on established traditional risk factors such as smoking remains critical in PLWH. Risk prediction functions tailored to PLWH in diverse settings will enhance clinicians' ability to deliver optimal preventive care.

Use of the likelihood reduction factor in a path analysis framework to quantify surrogacy in clinical trials.

In clinical trials, surrogate endpoints are useful when the endpoint of interest is difficult to measure or requires a long follow-up time. Current methodology for validating surrogate endpoints encounters challenges in the presence of collinearity between the treatment and surrogate endpoint, which is often present in clinical trials. The proposed methods adapt current methodology in the structural framework of path analysis to quantify the validity of a surrogate endpoint. The path analysis framework provides an improved interpretation of treatment effect. Through derivation and simulation we show the proposed path likelihood reduction factor (LRF P ), is less biased and more robust than current methodology in cases of collinearity between the treatment and surrogate endpoint, with notable improvement when surrogacy is weak or moderate. LRF P can be expanded to evaluate multiple correlated surrogate endpoints, which as shown through simulation, is also less biased and more robust than current methodology in the case of collinearity between the treatment and surrogate endpoint.

A joint industry-sponsored data monitoring committee model for observational, retrospective drug safety studies in the real-world setting.

PURPOSE: To share better practice in establishing data monitoring committees (DMCs) for observational, retrospective safety studies with joint-industry sponsorship. METHODS: A DMC model was created to monitor data from an observational, retrospective, post-authorization safety study investigating risk of medullary thyroid cancer in patients treated with long-acting glucagon-like peptide-1 receptor agonists (LA GLP-1RAs) (NCT01511393). Sponsors reviewed regulatory guidelines, best practice and sponsors' standard operation procedures on DMCs. Discussions were held within the four-member consortium, assessing applicability to observational, retrospective, real-world studies. A DMC charter was drafted based on a sponsor-proposed, adapted DMC model. Thereafter, a kick-off meeting between sponsors and DMC members was held to receive DMC input and finalize the charter. RESULTS: Due to this study's observational, retrospective nature, assuring participant safety - central for traditional explanatory clinical trial models - was not applicable to our DMC model. The overall strategy and key indication for our real-world model included preserving study integrity and credibility. Therefore, DMC member independence and their contribution of expert knowledge were essential. To ensure between-sponsor data confidentiality, all study committees/corporations and sponsors, besides the DMC, received blinded data only (adapted to refer to data blinding that revealed the specific marketed LA GLP-1RA/sponsor). Communication and blinding/unblinding of these data were facilitated by the contract research organization, which also provided crucial operational oversight. CONCLUSIONS: To our knowledge, we have established the first DMC model for joint industry-sponsored, observational, retrospective safety studies. This model could serve as a precedent for others performing similar post-marketing, joint industry-sponsored pharmacovigilance activities.

COVID-19 and climatic factors: A global analysis.

BACKGROUND: It is unknown if COVID-19 will exhibit seasonal pattern as other diseases e.g., seasonal influenza. Similarly, some environmental factors (e.g., temperature, humidity) have been shown to be associated with transmission of SARS-CoV and MERS-CoV, but global data on their association with COVID-19 are scarce. OBJECTIVE: To examine the association between climatic factors and COVID-19. METHODS: We used multilevel mixed-effects (two-level random-intercepts) negative binomial regression models to examine the association between 7- and 14-day-lagged temperature, humidity (relative and absolute), wind speed and UV index and COVID-19 cases, adjusting for Gross Domestic Products, Global Health Security Index, cloud cover (%), precipitation (mm), sea-level air-pressure (mb), and daytime length. The effects estimates are reported as adjusted rate ratio (aRR) and their corresponding 95% confidence interval (CI). RESULTS: Data from 206 countries/regions (until April 20, 2020) with ≥100 reported cases showed no association between COVID-19 cases and 7-day-lagged temperature, relative humidity, UV index, and wind speed, after adjusting for potential confounders, but a positive association with 14-day-lagged temperature and a negative association with 14-day-lagged wind speed. Compared to an absolute humidity of <5 g/m3, an absolute humidity of 5-10 g/m3 was associated with a 23% (95% CI: 6-42%) higher rate of COVID-19 cases, while absolute humidity >10 g/m3 did not have a significant effect. These findings were robust in the 14-day-lagged analysis. CONCLUSION: Our results of higher COVID-19 cases (through April 20) at absolute humidity of 5-10 g/m3 may be suggestive of a 'sweet point' for viral transmission, however only controlled laboratory experiments can decisively prove it.

Baseline 10-Year Cardiovascular Risk Scores Predict Cognitive Function in Older Persons, and Particularly Women, Living With Human Immunodeficiency Virus Infection.

BACKGROUND: Cardiovascular disease (CVD) and associated comorbidities increase the risk of cognitive impairment in persons living with human immunodeficiency virus (PLWH). Given the potential composite effect of multiple cardiovascular risk factors on cognition, we examined the ability of the Atherosclerotic Cardiovascular Disease (ASCVD) risk score and the Framingham Heart Study Global CVD risk score (FRS) to predict future cognitive function in older PLWH. METHODS: We constructed linear regression models evaluating the association between baseline 10-year cardiovascular risk scores and cognitive function (measured by a summary z-score, the NPZ-4) at a year 4 follow-up visit. RESULTS: Among 988 participants (mean age, 52 years; 20% women), mean 10-year ASCVD risk score at entry into the cohort was 6.8% (standard deviation [SD], 7.1%) and FRS was 13.1% (SD, 10.7%). In models adjusted only for cognitive function at entry, the ASCVD risk score significantly predicted year 4 NPZ-4 in the entire cohort and after stratification by sex (for every 1% higher ASCVD risk, year 4 NPZ-4 was lower by 0.84 [SD, 0.28] overall, P = .003; lower by 2.17 [SD, 0.67] in women, P = .001; lower by 0.78 [SD, 0.32] in men, P = .016). A similar relationship was observed between FRS and year 4 NPZ-4. In multivariable models, higher 10-year ASCVD risk and FRS predicted lower NPZ-4 in women. CONCLUSIONS: Baseline 10-year ASCVD risk and FRS predicted future cognitive function in older PLWH with well-controlled infection. Cardiovascular risk scores may help to identify PLWH, especially women, who are at risk for worse cognition over time.

Alcohol Use Is Associated With Hepatic Steatosis Among Persons With Presumed Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Many individuals presumed to have nonalcoholic fatty liver disease (NAFLD) consume moderate amounts of alcohol. Little is known about patterns of alcohol use in patients with NAFLD or how drinking behaviors affect liver fat. METHODS: We conducted a cross-sectional study of 2475 participants of the Framingham Heart Study with hepatic steatosis, as determined by computed tomography. We performed multivariable-adjusted logistic regression models to evaluate the association between alcohol drinking patterns and hepatic steatosis. Models were adjusted for sociodemographic factors, diet, and the components of the metabolic syndrome. We excluded heavy alcohol users, defined as women who consume more than 14 alcohol drinks per week and men who consume more than 21 alcohol drinks per week. RESULTS: In our sample (mean age, 49.8 ± 10.2 y; 50.3% women), the prevalence of hepatic steatosis was 17.5%. The total number of alcohol drinks per week and the maximum drinks consumed per drinking day each were associated with hepatic steatosis (adjusted odds ratio [aOR], 1.15; 95% CI, 1.02-1.29 and aOR 1.15; 95% CI, 1.02-1.30). Binge drinking occurred in 25.4% of individuals with presumed NAFLD and was associated with an increased odds of hepatic steatosis (aOR, 1.45; 95% CI, 1.06-1.98) among alcohol users. In a beverage-specific analysis, alcohol use patterns were associated with hepatic steatosis among beer drinkers, but not among wine drinkers. CONCLUSIONS: In a cross-sectional study of participants of the Framingham Heart Study with hepatic steatosis, we observed an association between alcohol use and liver fat, even after excluding heavy alcohol users from our analysis. Alcohol use therefore appears to be a risk factor for NAFLD. Prospective studies are needed to validate these findings and determine if alcohol use should be a focus for research, prevention, and treatment of presumed NAFLD.

Increasing Liver Fat Is Associated With Incident Cardiovascular Risk Factors.

Nonalcoholic fatty liver disease (NAFLD) is associated with increased liver- and cardiovascular disease (CVD)-related morbidity and mortality. In cross-sectional analyses, NAFLD clusters with several cardiometabolic traits including obesity,1,2 hypertension,3 diabetes,1 and dyslipidemia.3 However, liver fat is dynamic and changes over time. Aside from limited prior studies evaluating diet or exercise interventions, little is known about the association between changes in liver fat and the incidence of CVD risk factors. Additionally, previous studies often have limited follow-up; evaluate only select populations, such as individuals with obesity4,5 or diabetes6-8; and may not account for changes in weight or body mass index (BMI). The aim of the present study was to examine, in a longitudinal cohort, the natural history of liver fat change and the association with the incidence of multiple CVD risk factors.

Transcatheter InterAtrial Shunt Device for the treatment of heart failure: Rationale and design of the pivotal randomized trial to REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP-HF II).

BACKGROUND: A randomized, sham-controlled trial in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40% demonstrated reductions in pulmonary capillary wedge pressure (PCWP) with a novel transcatheter InterAtrial Shunt Device (IASD). Whether this hemodynamic effect will translate to an improvement in cardiovascular outcomes and symptoms requires additional study. STUDY DESIGN AND OBJECTIVES: REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP HF-II) is a multicenter, prospective, randomized, sham-controlled, blinded trial designed to evaluate the clinical efficacy of the IASD in symptomatic HF and elevated left atrial pressures. Up to 608 HF patients age ≥ 40 years with LVEF ≥40%, PCWP ≥25 mm Hg during supine ergometer exercise, and PCWP ≥5 mm Hg higher than right atrial pressure will be randomized 1:1 to the IASD versus sham control. Key exclusion criteria include hemodynamically significant valvular disease, evidence of pulmonary arterial hypertension, and right heart dysfunction. The primary endpoint is a hierarchical composite, analyzed by the Finkelstein-Schoenfeld methodology, that includes (1) cardiovascular mortality or first nonfatal ischemic stroke through 12 months; (2) total (first plus recurrent) HF hospitalizations or healthcare facility visits for intravenous diuretics up to 24 months, analyzed when the last randomized patient completes 12 months of follow-up; and (3) change in Kansas City Cardiomyopathy Questionnaire overall summary score from baseline to 12 months. Follow-up echocardiography will be performed at 6, 12, and 24 months to evaluate shunt flow and cardiac chamber size/function. Patients will be followed for a total of 5 years after the index procedure. CONCLUSIONS: REDUCE LAP-HF II is designed to evaluate the clinical efficacy of the IASD device in patients with symptomatic HF with elevated left atrial pressure and LVEF ≥40%.

Increasing liver fat is associated with progression of cardiovascular risk factors.

BACKGROUND: Nonalcoholic fatty liver disease is associated with cardiovascular risk factors in cross-sectional analyses. However, less is known about how changes in liver fat associate with the progression of cardiovascular risk factors. METHODS: A substudy (n = 808) drawn from the Framingham Heart Study underwent serial computed tomography scans 6 years apart. We performed multivariable-adjusted regression to determine the association between changes in liver fat and progression of cardiovascular risk factors. RESULTS: Each standard deviation increase in liver fat was associated with adverse progression of systolic blood pressure, diastolic blood pressure, fasting glucose, high-density lipoprotein and log triglycerides. After adjusting for baseline cardiovascular risk, baseline body mass index (BMI), and change in BMI, increasing liver fat was significantly associated with adverse changes in fasting glucose and triglycerides. CONCLUSIONS: In a longitudinal cohort, increasing liver fat over 6 years was associated with progression of cardiovascular risk factors, even after accounting for BMI changes.

The association of non-alcoholic fatty liver disease and cardiac structure and function-Framingham Heart Study.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease confers increased risk for cardiovascular disease, including heart failure (HF), for reasons that remain unclear. Possible pathways could involve an association of liver fat with cardiac structural or functional abnormalities even after accounting for body size. METHODS: We analysed N = 2356 Framingham Heart Study participants (age 52 ± 12 years, 52% women) who underwent echocardiography and standardized computed tomography measures of liver fat. RESULTS: In cross-sectional multivariable regression models adjusted for age, gender, cohort and cardiovascular risk factors, liver fat was positively associated with left ventricular (LV) mass (ß = 1.45; 95% confidence interval (CI): 0.01, 2.88), LV wall thickness (ß = 0.01; 95% CI: 0.00, 0.02), mass volume ratio (ß = 0.02; 95% CI 0.01, 0.03), mitral peak velocity (E) (ß = 0.83; 95% CI 0.31, 1.36) and LV filling pressure (E/e' ratio) (ß = 0.16; 95% CI 0.09, 0.23); and inversely associated with global systolic longitudinal strain (ß = 0.20, 95% CI 0.07, 0.33), diastolic annular velocity (e') (ß = -0.12; 95% CI - 0.22, -0.03), and E/A ratio (ß = -0.01; 95% CI - 0.02, -0.00). After additional adjustment for body mass index (BMI), statistical significance was attenuated for all associations except for that of greater liver fat with increased LV filling pressure, a possible precursor to HF (ß = 0.11; 95% CI 0.03, 0.18). CONCLUSION: Increased liver fat was associated with multiple subclinical cardiac dysfunction measures, with most of associations mediated by obesity. Interestingly, the association of liver fat and LV filling pressure was only partially mediated by BMI, suggesting a possible direct effect of liver fat on LV filling pressure. Further confirmatory studies are needed.