Primary Atriopathy in Mitral Valve Prolapse: Echocardiographic Evidence and Clinical Implications.

BACKGROUND: Prominent multi-scallop systolic leaflet displacement toward the left atrium (atrialization) is typically observed in bileaflet mitral valve prolapse (MVP) with mitral annular disjunction. We hypothesized that mitral leaflet atrialization is associated with an underlying left atrial (LA) myopathy characterized by progressive structural and functional abnormalities, irrespective of mitral regurgitation (MR) severity. METHODS: We identified 334 consecutive patients with MVP, no prior atrial fibrillation, and comprehensive clinical and echocardiographic data. LA function was assessed by LA reservoir strain, LA function index, and LA emptying fraction. We also classified the stage of LA remodeling based on LA enlargement and LA reservoir strain (stage 1: no remodeling; stage 2: mild remodeling; stage 3: moderate remodeling; and stage 4: severe remodeling). The primary end point was the composite risk of sudden arrhythmic death, heart failure hospitalization, or the new onset of atrial fibrillation. RESULTS: Bileaflet MVP with no or mild MR had a lower LA reservoir strain (P=0.04) and LA function index (P<0.001) compared with other MVP subtypes. In multivariable linear regression adjusted for cardiovascular risk factors and MR ≥moderate, bileaflet MVP remained significantly associated with lower LA function parameters (all P<0.05). There was a significant increase in the risk of events as the LA reservoir strain and LA remodeling stage increased (P<0.001). In multivariable analysis, stage 4 of LA remodeling remained significantly associated with a higher risk of events compared with stage 1 (hazard ratio, 6.09 [95% CI, 1.69-21.9]; P=0.006). CONCLUSIONS: In a large MVP registry, bileaflet involvement is associated with reduced LA function regardless of MR severity, suggesting a primary atriopathy in this MVP subtype. Abnormal LA function, particularly when assessed through a multiparametric approach, is linked to a higher risk of cardiovascular events and may improve risk stratification in MVP, even in those without significant MR.

Identifying Mitral Valve Prolapse at Risk for Arrhythmias and Fibrosis From Electrocardiograms Using Deep Learning.

BACKGROUND: Mitral valve prolapse (MVP) is a common valvulopathy, with a subset developing sudden cardiac death or cardiac arrest. Complex ventricular ectopy (ComVE) is a marker of arrhythmic risk associated with myocardial fibrosis and increased mortality in MVP. OBJECTIVES: The authors sought to evaluate whether electrocardiogram (ECG)-based machine learning can identify MVP at risk for ComVE, death and/or myocardial fibrosis on cardiac magnetic resonance (CMR) imaging. METHODS: A deep convolutional neural network (CNN) was trained to detect ComVE using 6,916 12-lead ECGs from 569 MVP patients from the University of California-San Francisco between 2012 and 2020. A separate CNN was trained to detect late gadolinium enhancement (LGE) using 1,369 ECGs from 87 MVP patients with contrast CMR. RESULTS: The prevalence of ComVE was 28% (160/569). The area under the receiver operating characteristic curve (AUC) of the CNN to detect ComVE was 0.80 (95% CI: 0.77-0.83) and remained high after excluding patients with moderate-severe mitral regurgitation [0.80 (95% CI: 0.77-0.83)] or bileaflet MVP [0.81 (95% CI: 0.76-0.85)]. AUC to detect all-cause mortality was 0.82 (95% CI: 0.77-0.87). ECG segments relevant to ComVE prediction were related to ventricular depolarization/repolarization (early-mid ST-segment and QRS from V1, V3, and III). LGE in the papillary muscles or basal inferolateral wall was present in 24% patients with available CMR; AUC for detection of LGE was 0.75 (95% CI: 0.68-0.82). CONCLUSIONS: CNN-analyzed 12-lead ECGs can detect MVP at risk for ventricular arrhythmias, death and/or fibrosis and can identify novel ECG correlates of arrhythmic risk. ECG-based CNNs may help select those MVP patients requiring closer follow-up and/or a CMR.

The Association of QRS Duration with Risk of Adverse Outcomes in Sex- and Race- Based Subgroups: The Dallas Heart Study.

Introduction: We explored sex and race differences in the prognostic implications of QRS prolongation among healthy adults. Methods: Participants from the Dallas Heart Study (DHS) free of cardiovascular (CV) disease who underwent ECG testing and cMRI evaluation were included. Multivariable linear regression was used to examine the cross-sectional association of QRS duration with left ventricular (LV) mass, LV ejection fraction (LVEF), and LV end diastolic volume (LVEDV). Association of QRS duration with risk of MACE was evaluated using Cox models. Interaction testing was performed between QRS duration and sex/race respectively for each outcome of interest. QRS duration was log transformed. Results: The study included 2,785 participants. Longer QRS duration was associated with higher LV mass, lower LVEF, and higher LVEDV, independent of CV risk factors ([ß: 0.21, P<0.001], [ß: - 0.13, P<0.001], [ß: 0.22, P<0.001] respectively). Men with longer QRS duration were more likely to have higher LV mass and higher LVEDV compared to women (P-int=0.012, P-int=0.01, respectively). Black participants with longer QRS duration were more likely to have higher LV mass as compared to White participants (P-int<0.001). In Cox analysis, QRS prolongation was associated with higher risk of MACE in women (HR = 6.66 [95% CI: 2.32, 19.1]) but not men. This association was attenuated after adjustment for CV risk factors, with a trend toward significance (HR = 2.45 [95% CI: 0.94, 6.39]). Longer QRS duration was not associated with risk of MACE in Black or White participants in the adjusted models. No interaction between sex/race and QRS duration for risk of MACE was observed. Discussion: In healthy adults, QRS duration is differentially associated with abnormalities in LV structure and function. These findings inform the use of QRS duration in identifying subgroups at risk for CV disease, and caution against using QRS duration cut offs uniformly for clinical decision making. What is known?: QRS prolongation in healthy adults is associated with higher risk of death, cardiovascular disease, and left ventricular hypertrophy. What the study adds?: QRS prolongation may reflect a higher degree of underlying LV hypertrophy in Blacks compared to Whites. Longer QRS interval may reflect higher risk of adverse cardiac events, driven by prevalent cardiovascular risk factors. Graphic Abstract: Risk of underlying left ventricular hypertrophy in demographic groups based on QRS prolongation.

Significant Reduction of Pulmonary Embolism in Orthopaedic Trauma Patients.

OBJECTIVES: To report results of a protocol to lessen incidence of pulmonary embolism (PE) among orthopaedic trauma patients. DESIGN: Retrospective review. SETTING: Level 1 trauma center. PATIENT/PARTICIPANTS: Orthopaedic trauma inpatients were included in the study. INTERVENTION: On arrival, an orthopaedic trauma patient's PE risk is calculated using a previously developed tool. If possible, patients at high risk are given their first dose of enoxaparin before leaving the emergency room. If other injuries preclude enoxaparin, then chemoprophylaxis is held for 24 hours. Twenty-four hours after arrival, the patient's ability to receive enoxaparin is reassessed. If possible, enoxaparin is started, with dosing twice a day. If enoxaparin is still contraindicated, a removable inferior vena cava filter is placed. Adequacy of enoxaparin dosing is tested using anti-factor Xa assay, drawn 4 hours after the third dose of enoxaparin. If the anti-factor Xa result is less than 0.2 IU/mL, a removable inferior vena cava filter is placed. If the result is 0.2-0.5 IU/mL, enoxaparin dosing is continued. If greater than 0.5 IU/mL, the dose of enoxaparin is reduced. OUTCOME MEASURE: The main outcome measure was rate of PE. RESULTS: From September 1, 2015 to December 31, 2015, our hospital admitted 420 orthopaedic trauma patients. Fifty-one patients were classed as high risk for PE. In September through December 2015, 9 sustained PE, 1 of which was fatal. From September 1, 2016 to December 31, 2016, our hospital admitted 368 orthopaedic trauma patients with comparable age and Injury Severity Score to 2015. Forty patients were at high risk for PE, 1 sustained a nonfatal PE. PE incidence from September to December 2016 was significantly lower than in 2015 (P = 0.02). Overall, 26 patients managed under the new protocol had IVCFs placed, 21 had their filters removed, and 3 died with filters in place. There were no complications during filter placement or removal. One patient had hemorrhage felt to be attributable to enoxaparin. CONCLUSIONS: Our protocol emphasizes more robust enoxaparin dosing, and more frequent use of IVCF, but only among those at high risk. We lessened the incidence of PE, with a low complication rate. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Sleep Disturbance in Orthopaedic Trauma Patients.

OBJECTIVE: To evaluate the prevalence and severity of sleep disturbance experienced by patients who have sustained a traumatic orthopaedic injury, how sleep disturbance affects the patient's perceived health quality, and identify factors associated with sleep disturbance. DESIGN: Cross-sectional cohort study. SETTING: Urban Level I trauma center. PATIENTS/PARTICIPANTS: Three hundred thirty-five nonconsecutive patients who presented to clinic at various stages of treatment for their traumatic orthopaedic injuries. MAIN OUTCOME MEASUREMENTS: Pittsburgh sleep quality index (PSQI) and 36-item short form-36 (SF-36) survey questionnaires; injury severity score (ISS). RESULTS: The average PSQI score was 10.3 (±4.8). Two hundred eighty-eight (86.0%) patients had a PSQI score ≥5, indicating the presence of sleep disturbance. The PSQI score was ≥10 in 183 (54.6%) patients, which is sleep disturbance similar to the level seen in clinical depression. Patients reported an average sleep latency of 38.9 (±37.5) minutes, with a total nightly sleep time of 6.3 (±1.9) hours. Univariate statistical analysis demonstrated that age, time since injury, and all components of the SF-36 were significantly associated with increased PSQI scores. When these variables were assessed with multivariate analysis to control for confounding variables, the bodily pain, vitality, and mental health components of the SF-36 remained independently associated with PSQI (P ≤ 0.001, 0.002, and 0.001, respectively). ISS measurements at the time of presentation were not associated with PSQI scores. CONCLUSIONS: Our findings suggest that sleep disturbance is both highly prevalent (86% PSQI ≥5) and severe (54.6% PSQI ≥10) in patients recovering from a traumatic orthopaedic injury. The bodily pain, vitality, and mental health components of the SF-36 were independently associated with worse sleep quality. The average orthopaedic trauma patient presents with a sleep score similar to that seen in clinical sleep disorders and clinical depression. Interestingly, in our study, the severity of the overall injury burden as measured by ISS and time since injury were not independently associated with the severity of sleep disturbance, as one might expect. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Substoichiometric hydroxynonenylation of a single protein recapitulates whole-cell-stimulated antioxidant response.

Lipid-derived electrophiles (LDEs) that can directly modify proteins have emerged as important small-molecule cues in cellular decision-making. However, because these diffusible LDEs can modify many targets [e.g., >700 cysteines are modified by the well-known LDE 4-hydroxynonenal (HNE)], establishing the functional consequences of LDE modification on individual targets remains devilishly difficult. Whether LDE modifications on a single protein are biologically sufficient to activate discrete redox signaling response downstream also remains untested. Herein, using T-REX (targetable reactive electrophiles and oxidants), an approach aimed at selectively flipping a single redox switch in cells at a precise time, we show that a modest level (∼34%) of HNEylation on a single target is sufficient to elicit the pharmaceutically important antioxidant response element (ARE) activation, and the resultant strength of ARE induction recapitulates that observed from whole-cell electrophilic perturbation. These data provide the first evidence that single-target LDE modifications are important individual events in mammalian physiology.