Genetic Regulation of Atherosclerosis-Relevant Phenotypes in Human Vascular Smooth Muscle Cells.

RATIONALE: Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent genome-wide association studies revealed 163 loci associated with CAD. However, the precise molecular mechanisms by which the majority of these loci increase CAD risk are not known. Vascular smooth muscle cells (VSMCs) are critical in the development of CAD. They can play either beneficial or detrimental roles in lesion pathogenesis, depending on the nature of their phenotypic changes. OBJECTIVE: To identify genetic variants associated with atherosclerosis-relevant phenotypes in VSMCs. METHODS AND RESULTS: We quantified 12 atherosclerosis-relevant phenotypes related to calcification, proliferation, and migration in VSMCs isolated from 151 multiethnic heart transplant donors. After genotyping and imputation, we performed association mapping using 6.3 million genetic variants. We demonstrated significant variations in calcification, proliferation, and migration. These phenotypes were not correlated with each other. We performed genome-wide association studies for 12 atherosclerosis-relevant phenotypes and identified 4 genome-wide significant loci associated with at least one VSMC phenotype. We overlapped the previously identified CAD loci with our data set and found nominally significant associations at 79 loci. One of them was the chromosome 1q41 locus, which harbors MIA3. The G allele of the lead risk single nucleotide polymorphism (SNP) rs67180937 was associated with lower VSMC MIA3 expression and lower proliferation. Lentivirus-mediated silencing of MIA3 (melanoma inhibitory activity protein 3) in VSMCs resulted in lower proliferation, consistent with human genetics findings. Furthermore, we observed a significant reduction of MIA3 protein in VSMCs in thin fibrous caps of late-stage atherosclerotic plaques compared to early fibroatheroma with thick and protective fibrous caps in mice and humans. CONCLUSIONS: Our data demonstrate that genetic variants have significant influences on VSMC function relevant to the development of atherosclerosis. Furthermore, high MIA3 expression may promote atheroprotective VSMC phenotypic transitions, including increased proliferation, which is essential in the formation or maintenance of a protective fibrous cap.

Central Apnea of Prematurity: Does Sex Matter?

OBJECTIVE: Apnea is common among infants in the neonatal intensive care unit (NICU). Our group previously developed an automated algorithm to quantitate central apneas with associated bradycardia and desaturation (ABDs). Sex differences in lung disease are well described in preterm infants, but the influence of sex on apnea has not been established. STUDY DESIGN: This study includes infants < 34 weeks' gestation admitted to the University of Virginia NICU from 2009 to 2014 with at least 1 day of bedside monitor data available when not on mechanical ventilation. Waveform and vital sign data were analyzed using a validated algorithm to detect ABD events of low variance in chest impedance signal lasting at least 10 seconds with associated drop in heart rate to < 100 beats/minute and drop in oxygen saturation to < 80%. Male and female infants were compared for prevalence of at least one ABD event during the NICU stay, treatment with caffeine, occurrence of ABDs at each week of postmenstrual age, and number of events per day. RESULTS: Of 926 infants studied (median gestational age 30 weeks, 53% male), median days of data analyzed were 19 and 22 for males and females, respectively. There was no sex difference in prevalence of at least one ABD event during the NICU stay (males 62%, females 64%, p = 0.47) or in the percentage of infants treated with caffeine (males 64%, females 67%, p = 0.40). Cumulative prevalence of ABDs from postmenstrual ages 24 to 36 weeks was comparable between sexes. Males had 18% more ABDs per day of data, but this difference was not statistically significant (p = 0.16). CONCLUSION: In this large cohort of infants < 34 weeks' gestation, we did not detect a sex difference in prevalence of central ABD events. There was a nonsignificant trend toward a greater number of ABDs per day in male infants. KEY POINTS: · Central apnea is pervasive among preterm infants in the NICU, but potential disparities between males and females have not been thoroughly studied.. · Identification of risk factors for central apnea can lead to improved treatment protocols.. · The rate and prevalence of central apnea events accompanied by bradycardia and desaturation does not significantly differ between male and female preterm infants..

Evidence From a Multistate Cohort: Enrollment in Affordable Care Act Qualified Health Plans' Association With Viral Suppression.

BACKGROUND: Healthcare delivery changes associated with viral suppression (VS) could contribute to the United States' "Ending the HIV Epidemic" (EtHE) initiative. This study aims to determine whether Qualified Health Plans (QHPs) purchased by AIDS Drug Assistance Programs (ADAPs) are associated with VS for low-income people living with HIV (PLWH) across 3 states. METHODS: A multistate cohort of ADAP clients eligible for ADAP-funded QHPs were studied (2014-2015). A log-binomial model was used to estimate the association of demographics and healthcare delivery factors with QHP enrollment prevalence and 1-year risk of VS. A number needed to treat/enroll (NNT) for 1 additional person to achieve viral suppression was calculated. RESULTS: Of the cohort (n = 7776), 52% enrolled in QHPs. QHP enrollment in 2015 was associated with QHP coverage in 2014 (adjusted PR [aPR], 3.28; 95% confidence intervals [CIs], 3.06-3.53) and engagement in care in 2014 (aPR, 1.16; 1.04-1.28). PLWH who were engaged in care (n = 4597) and had QHPs had a higher VS rate than those who received medications from Direct ADAP (86.0% vs 80.2%). QHPs' NNT for an additional person to achieve VS is 20 (14.1-34.5). Starting undetectable (adjusted risk ratio [aRR], 1.39; 1.28-1.52) and enrolling in QHPs in 2015 (aRR, 1.06; 0.99-1.14) was associated with VS. CONCLUSIONS: Once enrolled in ADAP-funded QHPs, ADAP clients stay enrolled. Enrollment is associated with VS across states/demographic groups. ADAPs, especially in the South and in Medicaid nonexpansion states, should consider investing in QHPs because increased enrollment could improve VS rates. This evidence-based intervention could be part of EtHE.

Correction: Oxygen desaturations in the early neonatal period predict development of bronchopulmonary dysplasia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction: Recovery from bradycardia and desaturation events at 32 weeks corrected age and NICU length of stay: an indicator of physiologic resilience?

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Oxygen desaturations in the early neonatal period predict development of bronchopulmonary dysplasia.

BACKGROUND: Bradycardia and oxygen desaturation episodes are common among preterm very low birth weight (VLBW) infants in the Neonatal Intensive Care Unit (NICU), and their association with adverse outcomes such as bronchopulmonary dysplasia (BPD) is unclear. METHODS: For 502 VLBW infants we quantified bradycardias (HR < 100 for ≥ 4 s) and desaturations (SpO2 < 80% for ≥ 10 s), combined bradycardia and desaturation (BD) events, and percent time in events in the first 4 weeks after birth (32 infant-years of data). We tested logistic regression models of clinical risks (including a respiratory acuity score incorporating FiO2 and level of respiratory support) to estimate the risks of BPD or death and secondary outcomes. We then tested the additive value of the bradycardia and desaturation metrics for outcomes prediction. RESULTS: BPD occurred in 187 infants (37%). The clinical risk model had ROC area for BPD of 0.874. Measures of desaturation, but not bradycardia, significantly added to the predictive model. Desaturation metrics also added to clinical risks for prediction of severe intraventricular hemorrhage, retinopathy of prematurity and prolonged length of stay in the NICU. CONCLUSIONS: Oxygen desaturations in the first month of the NICU course are associated with risk of BPD and other morbidities in VLBW infants.

Recovery from bradycardia and desaturation events at 32 weeks corrected age and NICU length of stay: an indicator of physiologic resilience?

BACKGROUND: Preterm very low birth weight (VLBW) infants experience physiologic maturation and transitions off therapies from 32 to 35 weeks postmenstrual age (PMA), which may impact episodic bradycardia and oxygen desaturation. We sought to characterize bradycardias and desaturations from 32 to 35 weeks PMA and test whether events at 32 weeks PMA are associated with NICU length of stay. METHODS: For 265 VLBW infants from 32 to 35 weeks PMA, we quantified the number and duration of bradycardias (HR <100 for ≥4 s) and desaturations (SpO2 <80% for ≥10 s) and compared events around discontinuation of CPAP, caffeine, and supplemental oxygen. We modeled associations between clinical variables, bradycardias and desaturations at 32 weeks PMA, and discharge PMA. RESULTS: Desaturations decreased from 60 to 41 per day at 32 and 35 weeks, respectively (p < 0.01). Duration of desaturations and number and duration of bradycardias decreased to a smaller extent (p < 0.05), and there was a non-significant trend toward increased desaturations after stopping CPAP and caffeine. Controlling for clinical variables, longer duration of bradycardias and desaturations at 32 weeks PMA was associated with later discharge PMA. CONCLUSION: Delayed recovery from bradycardias and desaturations at 32 weeks PMA, perhaps reflecting less physiologic resilience, is associated with prolonged NICU stay for VLBW infants.

Major cardiorespiratory events do not increase after immunizations, eye exams, and other stressors in most very low birth weight infants.

BACKGROUND: Increased cardiorespiratory events with bradycardia and oxygen desaturation have been reported in very low birthweight (VLBW) infants following stressors such as immunizations. These events are difficult to quantify and may be mild. Our group developed an automated algorithm to analyze bedside monitor data from NICU patients for events with bradycardia and prolonged oxygen desaturation (BDs) and used this to compare BDs 24 hours before and after potentially stressful interventions. METHODS: We included VLBW infants from 2012-2017 with data available around at least one of four interventions: two-month immunizations, retinopathy of prematurity (ROP) examinations, ROP therapy, and inguinal hernia surgery. We used a validated algorithm to analyze electrocardiogram heart rate and pulse oximeter saturation data (HR, SpO2) to quantify BD events of HR < 100 beats/minute for≥4 seconds with oxygen desaturation < 80%SpO2 for≥10 seconds. BDs were analyzed 24 hours before and after interventions using Wilcoxon rank-sum tests. RESULTS: In 354 of 493 (72%) interventions, BD frequency stayed the same or decreased in the 24 hours after the event. An increase of at least five BD's occurred in 17/146 (12%) after immunizations, 85/290 (29%) after ROP examinations, 4/33 (12%) after ROP therapy, and 3/25 (12%) after hernia surgery. Infants with an increase in BDs after interventions had similar demographics compared to those without. More infants with an increase in BDs following immunizations were on CPAP or caffeine than those without. CONCLUSIONS: Most VLBW infants in our cohort had no increase in significant cardiorespiratory events in the 24 hours following potentially stressful interventions.

Hypoxemia in infants with trisomy 21 in the neonatal intensive care unit.

OBJECTIVE: Newborns with trisomy 21 (T21) often require NICU hospitalization. Oxygen desaturations are frequently observed in these infants, even in the absence of congenital heart defects (CHD). We hypothesized that NICU patients with T21 have more hypoxemia than those without T21. DESIGN: All infants with T21 without significant CHD discharged home from the NICU between 2009 and 2018 were included (n = 23). Controls were matched 20:1 for gestational age and length of stay. We compared daily severe hypoxemia events (SpO2 < 80% for ≥10 s) for the whole NICU stay and the pre-discharge week. RESULTS: Infants with T21 showed significantly more daily hypoxemia events during their entire NICU stay (median 10 versus 7, p = 0.0064), and more so in their final week (13 versus 7, p = 0.0008). CONCLUSION: NICU patients with T21 without CHD experience more severe hypoxemia events than controls, particularly in the week before discharge. Whether this hypoxemia predicts or contributes to adverse outcomes is unknown.

Temperature instability in infants with trisomy 21 in the neonatal intensive care unit.

BACKGROUND: Temperature instability has been observed in infants with trisomy 21 (T21) in the neonatal intensive care unit (NICU) but has not been described in the literature. METHODS: All infants with T21 in the NICU 2011-2017 with at least 2 days of temperatures when ≥36 weeks PMA and not receiving external thermoregulation, and 2:1 matched controls were included. Prevalence and number of temperatures < 36 and >38 °C and infection workups were compared. RESULTS: Hypothermia and hyperthermia were more common among T21 infants (n = 61) vs. controls: hypothermia 30% vs. 11% (p < 0.01); hyperthermia 16% vs. 8% (p = 0.13). Infants with T21 were more likely to have infection workups at the time of temperature instability (16% vs. 6%) but only one of ten workups was diagnostic of infection. CONCLUSIONS: Temperature instability without infection is common among infants with T21 in the NICU.