Cardiovascular Risk Estimation Is Suboptimal in People With HIV.

BACKGROUND: Established cardiovascular disease (CVD) risk prediction functions may not accurately predict CVD risk in people with HIV. We assessed the performance of 3 CVD risk prediction functions in 2 HIV cohorts. METHODS AND RESULTS: CVD risk scores were calculated in the Mass General Brigham and Kaiser Permanente Northern California HIV cohorts, using the American College of Cardiology/American Heart Association atherosclerotic CVD function, the FHS (Framingham Heart Study) hard coronary heart disease function and the Framingham Heart Study hard CVD function. Outcomes were myocardial infarction or coronary death for FHS hard coronary heart disease function; and myocardial infarction, stroke, or coronary death for American College of Cardiology/American Heart Association and FHS hard CVD function. We calculated regression coefficients and assessed discrimination and calibration by sex; predicted to observed risk of outcome was also compared. In the combined cohort of 9412, 158 (1.7%) had a coronary heart disease event, and 309 (3.3%) had a CVD event. Among women, CVD risk was generally underestimated by all 3 risk functions. Among men, CVD risk was underestimated by the American College of Cardiology/American Heart Association and FHS hard CVD function, but overestimated by the FHS hard coronary heart disease function. Calibration was poor for women using the FHS hard CVD function and for men using all functions. Discrimination in all functions was good for women (c-statistics ranging from 0.78 to 0.90) and moderate for men (c-statistics ranging from 0.71 to 0.72). CONCLUSIONS: Established CVD risk prediction functions generally underestimate risk in people with HIV. Differences in model performance by sex underscore the need for both HIV-specific and sex-specific functions. Development of CVD risk prediction models tailored to HIV will enhance care for aging people with HIV.

PCI vs. CABG in left main with multi-vessel coronary artery disease and diabetes: Case report.

This case challenges the conventional preference for coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) in patients with diabetes, left main coronary artery disease (LMCAD) and multivessel disease. Current guidelines generally recommend CABG, especially in the context of LMCAD. However, our case involves a male patient with diabetes with LMCAD and extensive multivessel disease who was successfully treated with PCI, demonstrating a favorable outcome. Despite the high-risk profile, including a SYNTAX score of 28, the PCI approach was selected. This decision was supported by evidence suggesting comparable outcomes between PCI and CABG in similar patients. Our case highlights the potential of PCI as not just a viable, but potentially superior alternative in specific high-risk patients with diabetes, contrary to the prevailing belief in favor of CABG for all patients with left main involvement.

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.

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.

Distribution, Determinants and Normal Reference Values of Aortic Arch Width: Thoracic Aortic Geometry in the Framingham Heart Study.

Study Objective: Aortic arch geometry changes with age, including an increase in aortic arch width (AAW). High AAW is a predictor of incident adverse cardiovascular disease (CVD) events, but its distribution and determinants are unknown. We hypothesized that traditional CVD risk factors, in addition to age, are associated with increased AAW in community-dwelling adults. Study Design: Framingham Offspring and Third Generation cohort participants (N=3026, 52% Men) underwent thoracic multidetector computed tomography (MDCT). A referent group (733M, 738W) free of clinical CVD, hypertension, dyslipidemia, smoking, and diabetes was used to generate sex and 10-year age-group specific upper 90th percentile (P90) cut-points for AAW. AAW was measured as the distance between the cross-sectional centroids of the ascending and descending thoracic aorta. Multivariable logistic regression models were used to identify clinical correlates of high AAW (≥referent P90) in the overall study group. Results: Among referent participants, AAW increased with greater age-group, p for trend <0.0001 in each sex. Overall and within each age group, AAW was greater in men than women, p<0.0001 all comparisons. Across all participants, high AAW was associated with greater age (odds ratio, OR=1.34/10y; 95% confidence interval 1.20 - 1.50), body surface area (OR=1.97/SD; 1.62 - 2.40), diastolic blood pressure (OR=1.59/10mmHg; 1.40 - 1.81), pack-years smoked (OR=1.07; 1.02 - 1.13), and prevalent CVD (OR=1.64; 1.08 - 2.49). Conclusion: AAW increases with greater age, body size, diastolic blood pressure and burden of smoking. High AAW (≥referent P90) is also associated with prevalent (clinically apparent) CVD. AAW is often seen on and easily measured from tomographic thoracic images and has prognostic value.

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.

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.

The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer's disease.

Apolipoprotein ε4 (APOE ε4) is the most significant genetic risk factor for late-onset Alzheimer's disease (AD). Elevated blood C-reactive protein (CRP) further increases the risk of AD for people carrying the APOE ε4 allele. We hypothesized that CRP, as a key inflammatory element, could modulate the impact of other genetic variants on AD risk. We selected ten single nucleotide polymorphisms (SNPs) in reported AD risk loci encoding proteins related to inflammation. We then tested the interaction effects between these SNPs and blood CRP levels on AD incidence using the Cox proportional hazards model in UK Biobank (n = 279,176 white participants with 803 incident AD cases). The five top SNPs were tested for their interaction with different CRP cutoffs for AD incidence in the Framingham Heart Study (FHS) Generation 2 cohort (n = 3009, incident AD = 156). We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD-associated genes (SPI1, CD33, and CLU). Using the Cox model in stratified genotype analysis, the hazard ratios (HRs) for the association between a higher CRP level (≥10 vs. <10 mg/L) and the risk of incident AD were 1.94 (95% CI: 1.33-2.84, p < 0.001) for the SPI1 rs1057233-AA genotype, 1.75 (95% CI: 1.20-2.55, p = 0.004) for the CD33 rs3865444-CC genotype, and 1.76 (95% CI: 1.25-2.48, p = 0.001) for the CLU rs9331896-C genotype. In contrast, these associations were not observed in the other genotypes of these genes. Finally, two SNPs were validated in 321 Alzheimer's Disease Neuroimaging (ADNI) Mild Cognitive Impairment (MCI) patients. We observed that the SPI1 and CD33 genotype effects were enhanced by elevated CRP levels for the risk of MCI to AD conversion. Furthermore, the SPI1 genotype was associated with CSF AD biomarkers, including t-Tau and p-Tau, in the ADNI cohort when the blood CRP level was increased (p < 0.01). Our findings suggest that elevated blood CRP, as a peripheral inflammatory biomarker, is an important moderator of the genetic effects of SPI1 and CD33 in addition to APOE ε4 on AD risk. Monitoring peripheral CRP levels may be helpful for precise intervention and prevention of AD for these genotype carriers.

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.

Evaluating the Cardiovascular Risk in an Aging Population of People With HIV: The Impact of Hepatitis C Virus Coinfection.

Background People with HIV (PWH) are at an increased risk of cardiovascular disease (CVD) with an unknown added impact of hepatitis C virus (HCV) coinfection. We aimed to identify whether HCV coinfection increases the risk of type 1 myocardial infarction (T1MI) and if the risk differs by age. Methods and Results We used data from NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) from January 1, 2000, to December 31, 2017, PWH (aged 40-79 years) who had initiated antiretroviral therapy. The primary outcome was an adjudicated T1MI event. Those who started direct-acting HCV antivirals were censored at the time of initiation. Crude incidence rates per 1000 person-years were calculated for T1MI by calendar time. Discrete time-to-event analyses with complementary log-log models were used to estimate adjusted hazard ratios and 95% CIs for T1MI among those with and without HCV. Among 23 361 PWH, 4677 (20%) had HCV. There were 89 (1.9%) T1MIs among PWH with HCV and 314 (1.7%) among PWH without HCV. HCV was not associated with increased T1MI risk in PWH (adjusted hazard ratio, 0.98 [95% CI, 0.74-1.30]). However, the risk of T1MI increased with age and was amplified in those with HCV (adjusted hazard ratio per 10-year increase in age, 1.85 [95% CI, 1.38-2.48]) compared with those without HCV (adjusted hazard ratio per 10-year increase in age,1.30 [95% CI, 1.13-1.50]; P<0.001, test of interaction). Conclusions HCV coinfection was not significantly associated with increased T1MI risk; however, the risk of T1MI with increasing age was greater in those with HCV compared with those without, and HCV status should be considered when assessing CVD risk in aging PWH.

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.

Fostering eating after stroke (FEASt) trial for improving post-stroke dysphagia with non-invasive brain stimulation.

Dysphagia is a serious stroke complication but lacks effective therapy. We investigated safety and preliminary efficacy of anodal transcranial direct current stimulation (atDCS) paired with swallowing exercises in improving post-stroke dysphagia from an acute unilateral hemispheric infarction (UHI). We conducted a double-blind, early phase-2 randomized controlled trial, in subjects (n = 42) with moderate-severe dysphagia [Penetration and Aspiration Scale (PAS) score ≥ 4], from an acute-subacute UHI. Subjects were randomized to Low-Dose, High-Dose atDCS or Sham stimulation for 5 consecutive days. Primary safety outcomes were incidence of seizures, neurological, motor, or swallowing function deterioration. Primary efficacy outcome was a change in PAS scores at day-5 of intervention. Main secondary outcome was dietary improvement at 1-month, assessed by Functional Oral Intake (FOIS) score. No differences in pre-defined safety outcomes or adjusted mean changes in PAS, FOIS scores, between groups, were observed. Post-hoc analysis demonstrated that 22 /24 subjects in the combined atDCS group had a clinically meaningful dietary improvement (FOIS score ≥ 5) compared to 8 /14 in Sham (p = 0.037, Fisher-exact). atDCS application in the acute-subacute stroke phase is safe but did not decrease risk of aspiration in this early phase trial. The observed dietary improvement is promising and merits further investigation.

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.

Advances in Our Clinical Understanding of Autonomic Regulation Therapy Using Vagal Nerve Stimulation in Patients Living With Heart Failure.

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery.

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.

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.

Is dietary choline intake related to dementia and Alzheimer's disease risks? Results from the Framingham Heart Study.

BACKGROUND: The positive association of choline for cognition has been reported in both animal and human studies, yet the associations of choline with the risks of incident dementia or Alzheimer's disease (AD) in humans is unclear. OBJECTIVES: Our objective was to test the hypothesis that lower or higher dietary choline intake is associated with increased or decreased, respectively, risks of incident dementia and AD. METHODS: Data from the Framingham Heart Study Offspring Cohort exam 5 to exam 9 were used. Participants were free of dementia and stroke, with a valid self-reported 126-item Harvard FFQ at exam 5. The intakes of total choline, its contributing compounds, and betaine were estimated based on a published nutrient database. The intakes were updated at each exam to represent the cumulative average intake across the 5 exams. The associations between dietary choline intakes and incident dementia and AD were examined in mixed-effect Cox proportional hazard models, adjusting for covariates. RESULTS: A total of 3224 participants (53.8% female; mean ± SD age, 54.5 ± 9.7 y) were followed up for a mean ± SD of 16.1 ± 5.1 y (1991-2011). There were 247 incident dementia cases, of which 177 were AD. Dietary choline intake showed nonlinear relationships with incident dementia and AD. After adjusting for covariates, low choline intake (defined as ≤ 219 and ≤ 215 mg/d for dementia and AD, respectively) was significantly associated with incident dementia and incident AD. CONCLUSIONS: Low choline intake was associated with increased risks of incident dementia and AD.