Association of timing and agent for VTE prophylaxis in patients with severe traumatic brain injury on VTE, mortality, neurosurgical intervention, and discharge disposition.

BACKGROUND: Trauma patients are at increased risk for venous thromboembolism events (VTE). The decision of when to initiate VTE chemoprophylaxis (VTEP) and with what agent remains controversial in patients with severe traumatic brain injury (TBI). METHODS: This comparative effectiveness study evaluated the impact of timing and agent for VTEP on outcomes for patients with severe TBI (AIS Head = 3,4, or 5). Data was collected at 35 Level 1 and 2 trauma centers from January 1, 2017 to June 1, 2022. Patients were placed into analysis cohorts: No VTEP, low-molecular weight heparin (LMWH) ≤ 48 hours, LMWH>48 hours, Heparin≤48 hours, Heparin>48 hours. Propensity score matching accounting for patient factors and injury characteristics was used with logistic regression modeling to evaluate in-hospital mortality, VTE events, and discharge disposition. Neurosurgical intervention after initiation of VTEP was used to evaluate extension of intracranial hemorrhage. RESULTS: Of 12,879 patients, 32% had no VTEP, 36% LMWH, and 32% Heparin. Overall mortality was 8.3% and lowest among patients receiving LMWH≤48 hours (4.1%). VTE rates were lower with use of LMWH (1.6 vs 4.5%, OR 2.98, 95% CI 1.40-6.34, p = 0.005) without increasing mortality or neurosurgical interventions. VTE rates were lower with early prophylaxis (2.0 vs 3.5%, OR 1.76, 95% CI 1.15-2.71, p = 0.01) without increasing mortality (p = 1.0). Early VTEP was associated with more non-fatal intracranial operations (p < 0.001). However, patients undergoing neurosurgical intervention after VTEP initiation had no difference in rates of mortality, withdrawal of care, or unfavorable discharge disposition (p = 0.7, p = 0.1, p = 0.5). CONCLUSIONS: In patients with severe TBI, LMWH usage was associated with lower VTE incidence without increasing mortality or neurosurgical interventions. Initiation of VTEP≤48 hours decreased VTE incidence and increased non-fatal neurosurgical interventions without affecting mortality. LMWH is the preferred VTEP agent for severe TBI, and initiation ≤48 hours should be considered in relation to these risks and benefits. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level III.

High Variability of Body Mass Index Is Independently Associated With Incident Heart Failure.

BACKGROUND: Heart failure (HF) is a serious condition with increasing prevalence, high morbidity, and increased mortality. Obesity is an established risk factor for HF. Fluctuation in body mass index (BMI) has shown a higher risk of cardiovascular outcomes. We investigated the association between BMI variability and incident HF. METHODS AND RESULTS: In the UK Biobank, we established a prospective cohort after excluding participants with prevalent HF or cancer at enrollment. A total of 99 368 White participants with ≥3 BMI measures during >2 years preceding enrollment were included, with a median follow-up of 12.5 years. The within-participant variability of BMI was evaluated using standardized SD and coefficient of variation. The association of BMI variability with incident HF was assessed using Fine and Gray's competing risk model, adjusting for confounding factors and participant-specific rate of BMI change. Higher BMI variability measured in both SD and coefficient of variation was significantly associated with higher risk in HF incidence (SD: hazard ratio [HR], 1.05 [95% CI, 1.03-1.08], P<0.0001; coefficient of variation: HR, 1.07 [95% CI, 1.04-1.10], P<0.0001). CONCLUSIONS: Longitudinal health records capture BMI fluctuation, which independently predicts HF incidence.

Transcutaneous electrical nerve stimulation for the treatment of acute postoperative pain following spine surgery: a scoping review.

OBJECTIVE: Given the ubiquity and severity of postoperative pain following spine surgery, developing adequate pain management modalities is critical. Transcutaneous electrical nerve stimulation (TENS) is a promising noninvasive modality that is well studied for managing postoperative pain following a variety of surgeries, but data on using TENS for pain management in the acute postoperative period of spine surgery are limited. Therefore, this review aimed to recapitulate the existing evidence for the use of TENS in postoperative pain management for spine surgery and explore the potential of this modality moving forward. METHODS: A scoping review was conducted according to 2020 PRISMA guidelines. Two independently operating reviewers then conducted a systematic search of PubMed, Embase, and Scopus databases to identify studies that reported the use of TENS for the treatment of acute postoperative pain following spine surgery. The following data were abstracted from included studies: study type, sample size, demographics, surgery details, comparison group, assessment parameters, timing of postoperative assessment, TENS technical characteristics, relevant findings, length of hospital stay, complications with TENS, and notable limitations. RESULTS: Nine hundred thirty-two publications were screened, resulting in 6 studies included in this review, all of which were prospective clinical trials. The publication dates ranged from 1980 to 2011. Spine surgery types varied; the most common was posterior lumbar interbody fusion. No studies evaluated pain control in cervical- or thoracic-only surgeries. All 6 studies evaluated the level of postoperative pain directly. Five of the 6 studies that directly examined postoperative pain reported lower levels of pharmacological analgesia usage in the TENS groups compared with controls, with 4 of these studies reporting this difference as statistically significant. Length of hospital stay was evaluated in 2 studies, both of which reported decreases in mean length of stay, but these differences were not significant. Notably, every study reported distinct TENS administration parameters while also reporting similar results. CONCLUSIONS: This review concludes that TENS is effective at reducing postoperative pain in spine surgery. Further investigation is needed regarding the optimal settings for TENS administration, as well as efficacy in the thoracic and cervical spine.

Influenza Vaccine Immune Response in Patients With High-Risk Cardiovascular Disease: A Secondary Analysis of the INVESTED Randomized Clinical Trial.

Importance: High-dose trivalent compared with standard-dose quadrivalent influenza vaccine did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations in patients with high-risk cardiovascular disease in the INVESTED trial. Whether humoral immune response to influenza vaccine is associated with clinical outcomes is unknown. Objective: To examine the antibody response to high-dose trivalent compared with standard-dose quadrivalent inactivated influenza vaccine and its associations with clinical outcomes. Design, Setting, and Participants: This secondary analysis is a prespecified analysis of the immune response substudy of the randomized, double-blind, active-controlled INVESTED trial, which was conducted at 157 sites in the United States and Canada over 3 influenza seasons between September 2016 and January 2019. Antibody titers were determined by hemagglutination inhibition assays at randomization and 4 weeks during the 2017-2018 and 2018-2019 seasons. Eligibility criteria included recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor. Data were analyzed from February 2023 to June 2023. Main Outcomes and Measures: Mean antibody titer change, seroprotection (antibody titer level ≥1:40) and seroconversion (≥4-fold increase in titer) at 4 weeks, and the association between seroconversion status and the risk for adverse clinical outcomes. Interventions: High-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine, with revaccination up to 3 seasons. Results: Antibody data were available for 658 of 5260 randomized participants (12.5%; mean [SD] age, 66.2 [11.4] years; 507 male [77.1%], 151 female [22.9%]; 348 with heart failure [52.9%]). High-dose vaccine was associated with an increased magnitude in antibody titers for A/H1N1, A/H3N2, and B-type antigens compared with standard dose. More than 92% of all participants achieved seroprotection for each of the contained antigens, while seroconversion rates were higher in participants who received high-dose vaccine. Seroconversion for any antigen was not associated with the risk for cardiopulmonary hospitalizations or all-cause mortality (hazard ratio, 1.09; 95% CI, 0.79-1.53; P = .59), irrespective of randomized treatment (P = .38 for interaction). Conclusions and Relevance: High-dose vaccine elicited a more robust humoral response in patients with heart failure or prior myocardial infarction enrolled in the INVESTED trial, with no association between seroconversion status and the risk for cardiopulmonary hospitalizations or all-cause mortality. Vaccination to prevent influenza remains critical in high-risk populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Development and validation of an artificial intelligence model to accurately predict spinopelvic parameters.

OBJECTIVE: Achieving appropriate spinopelvic alignment has been shown to be associated with improved clinical symptoms. However, measurement of spinopelvic radiographic parameters is time-intensive and interobserver reliability is a concern. Automated measurement tools have the promise of rapid and consistent measurements, but existing tools are still limited to some degree by manual user-entry requirements. This study presents a novel artificial intelligence (AI) tool called SpinePose that automatically predicts spinopelvic parameters with high accuracy without the need for manual entry. METHODS: SpinePose was trained and validated on 761 sagittal whole-spine radiographs to predict the sagittal vertical axis (SVA), pelvic tilt (PT), pelvic incidence (PI), sacral slope (SS), lumbar lordosis (LL), T1 pelvic angle (T1PA), and L1 pelvic angle (L1PA). A separate test set of 40 radiographs was labeled by four reviewers, including fellowship-trained spine surgeons and a fellowship-trained radiologist with neuroradiology subspecialty certification. Median errors relative to the most senior reviewer were calculated to determine model accuracy on test images. Intraclass correlation coefficients (ICCs) were used to assess interrater reliability. RESULTS: SpinePose exhibited the following median (interquartile range) parameter errors: SVA 2.2 mm (2.3 mm) (p = 0.93), PT 1.3° (1.2°) (p = 0.48), SS 1.7° (2.2°) (p = 0.64), PI 2.2° (2.1°) (p = 0.24), LL 2.6° (4.0°) (p = 0.89), T1PA 1.1° (0.9°) (p = 0.42), and L1PA 1.4° (1.6°) (p = 0.49). Model predictions also exhibited excellent reliability at all parameters (ICC 0.91-1.0). CONCLUSIONS: SpinePose accurately predicted spinopelvic parameters with excellent reliability comparable to that of fellowship-trained spine surgeons and neuroradiologists. Utilization of predictive AI tools in spinal imaging can substantially aid in patient selection and surgical planning.

Atrial fibrillation and risk of adverse outcomes in heart failure with reduced, mildly reduced, and preserved ejection fraction: A systematic review and meta-analysis.

INTRODUCTION: Heart failure (HF) and atrial fibrillation (AF) frequently co-exist. Contemporary classification of HF categorizes it into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). Aggregate data comparing the risk profile of AF between these three HF categories are lacking. METHODS: We conducted a systematic review and meta-analysis aimed at determining any significant differences in AF-associated all-cause mortality, HF hospitalizations, cardiovascular mortality (CV), and stroke between HFrEF, HFmrEF, and HFpEF. A systematic search of PubMed, EMBASE, and Cochrane Library databases until February 28, 2023. Data were combined using DerSimonian-Laird random effects model. RESULTS: A total of 22 studies comprising 248 323 patients were retained: HFrEF 123 331 (49.7%), HFmrEF 40 995 (16.5%), and HFpEF 83 997 (33.8%). Pooled baseline AF prevalence was 36% total population, 30% HFrEF, 36% HFmrEF, and 42% HFpEF. AF was associated with a higher risk of all-cause mortality in the total population with pooled hazard ratio (HR) = 1.13 (95% confidence interval [CI] = 1.07-1.21), HFmrEF (HR = 1.25, 95% CI = 1.05-1.50) and HFpEF (HR = 1.16, 95% CI = 1.09-1.24), but not HFrEF (HR = 1.03, 95% CI = 0.93-1.14). AF was associated with a higher risk of HF hospitalizations in the total population (HR = 1.29, 95% CI = 1.14-1.46), HFmrEF (HR = 1.64, 95% CI = 1.20-2.24), and HFpEF (HR = 1.46, 95% CI = 1.17-1.83), but not HFrEF (HR = 1.01, 95% CI = 0.87-1.18). AF was only associated with CV in the HFpEF subcategory but was associated with stroke in all three HF subtypes. CONCLUSIONS: AF appears to be associated with a higher risk of all-cause mortality and HF hospitalization in HFmrEF and HFpEF. With these findings, the paucity of data and treatment guidelines on AF in the HFmrEF subgroup becomes even more significant and warrant further investigations.

Sex-stratified genome-wide association and transcriptome-wide Mendelian randomization studies reveal drug targets of heart failure.

The prevalence of heart failure (HF) subtypes, which are classified by left ventricular ejection fraction (LVEF), demonstrate significant sex differences. Here, we perform sex-stratified genome-wide association studies (GWASs) on LVEF and transcriptome-wide Mendelian randomization (MR) on LVEF, all-cause HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF). The sex-stratified GWASs of LVEF identified three sex-specific loci that were exclusively detected in the sex-stratified GWASs. Three drug target genes show sex-differential effects on HF/HFrEF via influencing LVEF, with NPR2 as the target gene for the HF drug Cenderitide under phase 2 clinical trial. Our study highlights the importance of considering sex-differential genetic effects in sex-balanced diseases such as HF and emphasizes the value of sex-stratified GWASs and MR in identifying putative genetic variants, causal genes, and candidate drug targets for HF, which is not identifiable using a sex-combined strategy.

Persistence of significant secondary mitral regurgitation post-cardiac resynchronization therapy and survival: a systematic review and meta-analysis : Mitral regurgitation and mortality post-CRT.

Cardiac resynchronization therapy (CRT) significantly reduces secondary mitral regurgitation (MR) in patients with severe left ventricular systolic dysfunction. However, uncertainty remains as to whether improvement in secondary MR correlates with improvement with mortality seen in CRT. We conducted a meta-analysis to determine the association of persistent unimproved significant secondary MR (defined as moderate or moderate-to-severe or severe MR) compared to improved MR (no MR or mild MR) post-CRT with all-cause mortality, cardiovascular mortality, and heart failure hospitalization. A systematic search of PubMed, EMBASE, and Cochrane Library databases till July 31, 2022 identified studies reporting clinical outcomes by post-CRT secondary MR status. In 12 prospective studies of 4954 patients (weighted mean age 66.8 years, men 77.8%), the median duration of follow-up post-CRT at which patients were re-evaluated for significant secondary MR was 6 months and showed significant relative risk reduction of 30% compared to pre-CRT. The median duration of follow-up post-CRT for ascertainment of main clinical outcomes was 38 months. The random effects pooled hazard ratio (95% confidence interval) of all-cause mortality in patients with unimproved secondary MR compared to improved secondary MR was 2.00 (1.57-2.55); p < 0.001). There was insufficient data to evaluate secondary outcomes in a meta-analysis, but limited data that examined the relationship showed significant association of unimproved secondary MR with increased cardiovascular mortality and heart failure hospitalization. The findings of this meta-analysis suggest that lack of improvement in secondary MR post-CRT is associated with significantly elevated risk of all-cause mortality and possibly cardiovascular mortality and heart failure hospitalization. Future studies may investigate approaches to address persistent secondary MR post-CRT to help improved outcome in this population.

Virtual Reality-Enabled Resident Education of Lateral-Access Spine Surgery.

OBJECTIVE: Lateral-access spine surgery has many benefits, but adoption has been limited by a steep learning curve. Virtual reality (VR) is gaining popularity and lends itself as a useful tool in enhancing neurosurgical resident education. We thus sought to assess whether VR-based simulation could enhance the training of neurosurgery residents in lateral spine surgery. METHODS: Neurosurgery residents completed a VR-based lateral spine module on lateral patient positioning and performing lateral lumbar interbody fusion using the PrecisionOS VR system on the Meta Quest 2 headset. Simulation occurred 1×/week every other week for a total of 3 simulations over 6 weeks. Pre- and postintervention surveys as well as intrasimulation performance metrics were assessed over time. RESULTS: The majority of resident participants showed improvement in performance scores, including an automated PrecisionOS precision score, number of radiographs used within the simulation, and time to completion. All participants showed improvement in comfort with anatomic landmarks for lateral access surgery, confidence performing lateral surgery without direct supervision, and assessing fluoroscopy in spine surgery for hardware placement and image interpretation. Participant perception on the utility of VR as an educational tool also improved. CONCLUSIONS: VR-based simulation enhanced neurosurgical residents' ability to understand lateral access surgery. Immersive surgical simulation resulted in improved resident confidence with surgical technique and workflow, perceived improvement in anatomical knowledge, and simulation performance scores. Trainee perceptions on virtual simulation and training as a curriculum supplement also improved following completion of VR training.

Correction for Collider Bias in the Genome-wide Association Study of Diabetes-Related Heart Failure due to Bidirectional Relationship between Heart Failure and Type 2 Diabetes.

Aims: Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) across demographic groups. On the other hand, metabolic impairment, including elevated T2D incidence is a hallmark of HF pathophysiology. We investigated the bidirectional relationship between T2D and HF, and identified genetic associations with diabetes-related HF after correction for potential collider bias. Methods: We performed a genome-wide association study (GWAS) of HF to identify genetic instrumental variables (GIVs) for HF, and to enable bidirectional Mendelian Randomization (MR) analysis between T2D and HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted GWAS of diabetes-related HF with correction for collider bias. Results: We first identified 61 genomic loci, including 24 novel loci, significantly associated with all-cause HF in 114,275 HF cases and over 1.5 million controls of European ancestry. Combined with the summary statistics of a T2D GWAS, we obtained 59 and 82 GIVs for HF and T2D, respectively. Using a two-sample bidirectional MR approach, we estimated that T2D increased HF risk (OR 1.07, 95% CI 1.04-1.10), while HF also increased T2D risk (OR 1.60, 95% CI 1.36-1.88). Then we performed a GWAS of diabetes-related HF corrected for collider bias due to prevalent HF affecting incidence of T2D. After removing the spurious association of TCF7L2 locus due to collider bias, we identified two genome-wide significant loci close to PITX2 (chromosome 4) and CDKN2B-AS1 (chromosome 9) associated with diabetes-related HF in the Million Veteran Program, and replicated the associations in the UK Biobank study. Conclusion: We identified novel HF-associated loci to enable bidirectional MR study of T2D and HF. Our MR findings support T2D as a HF risk factor and provide strong evidence that HF increases T2D risk. As a result, collider bias leads to spurious genetic associations of diabetes-related HF, which can be effectively corrected to identify true positive loci. Evaluation of collider bias should be a critical component when conducting GWAS of complex disease phenotypes such as diabetes-related cardiovascular complications.

Impact of Low-Level Laser Therapy on Orthodontic Tooth Movement and Various Cytokines in Gingival Crevicular Fluid: A Split-Mouth Randomized Study.

BACKGROUND AND OBJECTIVES: A few investigations have detailed the influence of low-level laser therapy (LLLT) on orthodontic tooth movement (OTM), with varying results. The objectives of this study were twofold: to assess the impact of LLLT on OTM and various cytokine levels in gingival crevicular fluid and to contrast the pain levels experienced by patients receiving orthodontic treatment with and without LLLT. MATERIALS AND METHODS: This split-mouth randomized controlled prospective study comprised 40 patients with an average age of 19.7±2.4 years with Angle Class I malocclusion combined with bimaxillary protrusion who were advised for extraction of the maxillary first premolar and bilateral canine distalization. The control-side canine was distalized solely by the coil spring. On the test arm, a low-level gallium-aluminum-arsenide semiconductor diode laser operating at 980 nm and 100 mW with a continuous-wave energy of 8 J/cm2 was used. The canine distalization on either side was measured with a digital caliper following the first premolar extraction (TO), one month after treatment (TOTM1), two months later (TOTM2), and three months later (TOTM3). The gingival index and the level of various cytokines were determined by an enzyme-linked immunosorbent assay at the beginning of the study, on the third and seventh days, and at four, eight, and 12 weeks following the canine distalization. The intra-group and inter-group comparisons were carried out using one-way analysis of variance (ANOVA) and t-tests, respectively, at a 5% significance level. RESULTS: The results show a highly statistically significant difference in the extent of canine distalization in the test group (TOTM1=2.92±0.44; TOTM2=1.04±0.1; TOTM3​=0.62±0.21 mm) in contrast to the control group (TOTM1=3.23±0.8; TOTM2=2.65±0.2; TOTM3​​​​=2.11±0.24 mm) (p<0.01). After three months of canine distalization, the laser and control group had 34 and 27 patients with mild gingivitis, respectively. Interleukin-1ß and interleukin-6 concentrations surged with values of 0.74±0.13 and 0.049±0.001 pg/g at seven days following treatment in the laser group, respectively. The difference in tumor necrosis factor concentration between the groups was shown to be highly statistically significant in all treatment phases (p<0.001). The differences in the epidermal growth factor and microglobulin levels were found to be statistically significant within both groups from T0 to T5. The average visual analog scale (VAS) scores at several subsequent evaluations of the laser and control groups were found to be highly statistically significant. CONCLUSION: The findings imply that when the periodontal microenvironment is stimulated by orthodontic force, several paramount cytokines are released, triggering an ordered sequence of biological processes that appear to expedite OTM with reduced associated pain.

Evaluating the state of non-invasive imaging biomarkers for traumatic brain injury.

Non-invasive imaging biomarkers are useful for prognostication in patients with traumatic brain injury (TBI) at high risk for morbidity with invasive procedures. The authors present findings from a scoping review discussing the pertinent biomarkers. Embase, Ovid-MEDLINE, and Scopus were queried for original research on imaging biomarkers for prognostication of TBI in adult patients. Two reviewers independently screened articles, extracted data, and evaluated risk of bias. Data was synthesized and confidence evaluated with the linked evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. Our search yielded 3104 unique citations, 44 of which were included in this review. Study populations varied in TBI severity, as defined by Glasgow Coma Scale (GCS), including: mild (n=9), mild and moderate (n=3), moderate and severe (n=7), severe (n=6), and all GCS scores (n=17). Diverse imaging modalities were used for prognostication, predominantly computed tomography (CT) only (n=11), magnetic resonance imaging (MRI) only (n=9), and diffusion tensor imaging (DTI) (N=9). The biomarkers included diffusion coefficient mapping, metabolic characteristics, optic nerve sheath diameter, T1-weighted signal changes, cortical cerebral blood flow, axial versus extra-axial lesions, T2-weighted gradient versus spin echo, translocator protein levels, and trauma imaging of brainstem areas. The majority (93%) of studies identified that the imaging biomarker of interest had a statistically significant prognostic value; however, these are based on a very low to low level of quality of evidence. No study directly compared the effects on specific TBI treatments on the temporal course of imaging biomarkers. The current literature is insufficient to make a strong recommendation about a preferred imaging biomarker for TBI, especially considering GRADE criteria revealing low quality of evidence. Rigorous prospective research of imaging biomarkers of TBI is warranted to improve the understanding of TBI severity.

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease: Secondary Analysis of a Randomized Clinical Trial.

Importance: Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial. Objective: To evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity. Design, Setting, and Participants: This study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)-reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US. Intervention: Participants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons. Main Outcomes and Measures: The primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state. Results: Among 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P < .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P < .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P > .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum.

Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (p < 5×10-8). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes (MYBPC3, BAG3), as well as regulators of lipoprotein (LPL) and glucose metabolism (GIPR, GLP1R), and are enriched in cardiac, muscle, nerve, and vascular tissues, as well as myocyte and adipocyte cell types. Gene burden studies across three biobanks (PMBB, UKB, AOU) including 27,208 individuals with HF and 349,126 without uncover exome-wide significant (p < 3.15×10-6) associations for HF and rare predicted loss-of-function (pLoF) variants in TTN, MYBPC3, FLNC, and BAG3. Total burden heritability of rare coding variants (2.2%, 95% CI 0.99-3.5%) is highly concentrated in a small set of Mendelian cardiomyopathy genes, and is lower than heritability attributable to common variants (4.3%, 95% CI 3.9-4.7%) which is more diffusely spread throughout the genome. Finally, we demonstrate that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. These findings suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.

Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.

Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure.

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

High Variability of Body Mass Index Independently Associated with Incident Heart Failure.

Background: Heart failure (HF) is a serious condition with increasing prevalence, high morbidity, and increased mortality. Obesity is an established risk factor for cardiovascular diseases, including HF. Fluctuation in body mass index (BMI) has shown a higher risk of cardiovascular outcomes. We investigated the association between BMI variability and incident HF. Methods: In the UK Biobank, we established a prospective cohort after excluding participants with prevalent HF or cancer at enrollment. A total of 99,368 White (British, Irish, and any other white background) participants with ≥ 3 BMI measures during > 2 years preceding enrollment were included, with a median follow-up of 12.5 years. The within-participant variability of BMI was evaluated using standardized standard deviation (SD) and coefficient of variation (CV). The association of BMI variability with incident HF was assessed using Fine and Gray's competing risk model, and adjusted for age, sex, smoking history, alcohol consumption, diabetes, hypertension, history of heart attack, stroke, atrial fibrillation, lipids, estimated glomerular filtration rate and mean BMI per individual. Results: In the fully adjusted model, higher BMI variability measured in both SD and CV were significantly associated with higher risk in HF incidence (SD: Hazard Ratio [HR] 1.05, 95% Confidence Interval [CI] 1.02 - 1.07, p = 0.0002; CV: HR 1.06, 95% CI 1.04 - 1.09, p < 0.0001). Conclusions: Longitudinal health records capture BMI fluctuation, which independently predicts HF incidence. Integration of long-term BMI and other routinely measured health factors may improve risk prediction of HF and other cardiovascular outcomes.

Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale.

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site-reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

Association of post-vaccination adverse reactions after influenza vaccine with mortality and cardiopulmonary outcomes in patients with high-risk cardiovascular disease: the INVESTED trial.

AIMS: Influenza vaccination is associated with reduced cardiopulmonary morbidity and mortality among patients with heart failure or recent myocardial infarction. The immune response to vaccination frequently results in mild adverse reactions (AR), which leads to vaccine hesitancy. This post hoc analysis explored the association between vaccine-related AR and morbidity and mortality in patients with high-risk cardiovascular disease. METHODS AND RESULTS: The INVESTED trial randomized 5260 patients with recent heart failure hospitalization or acute myocardial infarction to high-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine. We examined the association between vaccine-related AR and adverse clinical outcomes across both treatment groups in propensity-adjusted models. Among 5210 participants with available information on post-vaccination symptoms, 1968 participants (37.8%) experienced a vaccine-related AR. Compared to those without AR, post-vaccination AR, most commonly injection site pain (60.3%), were associated with lower risk for the composite of all-cause death or cardiopulmonary hospitalization (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75-0.92, p < 0.001), cardiopulmonary hospitalizations (HR 0.85 [95% CI 0.76-0.95], p = 0.003), all-cause death (HR 0.77 [95% CI 0.62-0.96], p = 0.02), cardiovascular hospitalizations (HR 0.88 [95% CI 0.78-0.99], p = 0.03) and non-cardiopulmonary hospitalizations (HR 0.80 [95% CI 0.69-0.92], p = 0.003). While mild (76.4%) and moderate (20.6%) AR were most common and together associated with lower risk for the primary outcome (HR 0.81 [95% CI 0.74-0.90], p < 0.001), severe AR (2.9%) were related to increased risk (HR 1.68 [95% CI 1.17-2.42], p = 0.005). CONCLUSION: Mild to moderate post-vaccination reactions after influenza vaccine were associated with reduced risk of cardiopulmonary hospitalizations and all-cause mortality in patients with high-risk cardiovascular disease, while severe reactions may indicate increased risk. Mild to moderate AR to influenza vaccination may be a marker of immune response and should not deter future vaccinations.