Longitudinal Lipidomic Signature of Coronary Heart Disease in American Indian People.

BACKGROUND: Dyslipidemia is an independent risk factor for coronary heart disease (CHD). Standard lipid panel cannot capture the complexity of the blood lipidome (ie, all molecular lipids in the blood). To date, very few large-scale epidemiological studies have assessed the full spectrum of the blood lipidome on risk of CHD, especially in a longitudinal setting. METHODS AND RESULTS: Using an untargeted liquid chromatography-mass spectrometry, we repeatedly measured 1542 lipid species from 1835 unique American Indian participants who attended 2 clinical visits (≈5.5 years apart) and followed up to 17.8 years in the Strong Heart Family Study (SHFS). We first identified baseline lipid species associated with risk of CHD, followed by replication in a European population. The model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, low-density lipoprotein cholesterol, estimated glomerular filtration rate, education, and physical activity at baseline. We then examined the longitudinal association between changes in lipid species and changes in cardiovascular risk factors during follow-up. Multiple testing was controlled by the false discovery rate. We found that baseline levels of multiple lipid species (eg, phosphatidylcholines, phosphatidylethanolamines, and ceramides) were associated with the risk of CHD and improved the prediction accuracy over conventional risk factors in American Indian people. Some identified lipids in American Indian people were replicated in European people. Longitudinal changes in multiple lipid species (eg, acylcarnitines, phosphatidylcholines, and triacylglycerols) were associated with changes in cardiovascular risk factors. CONCLUSIONS: Baseline plasma lipids and their longitudinal changes over time are associated with risk of CHD. These findings provide novel insights into the role of dyslipidemia in CHD.

Determinants of Diet Quality in Adolescents: Results from the Prospective Population-Based EVA-Tyrol and EVA4YOU Cohorts.

(1) Background: Unhealthy dietary behaviors are estimated to be one of the leading causes of death globally and are often shaped at a young age. Here, we investigated adolescent diet quality and its predictors, including nutrition knowledge, in two large Central European cohorts. (2) Methods: In 3056 participants of the EVA-Tyrol and EVA4YOU prospective population-based cohort studies aged 14 to 19 years, diet quality was assessed using the AHEI-2010 and DASH scores, and nutrition knowledge was assessed using the questionnaire from Turconi et al. Associations were examined utilizing multivariable linear regression. (3) Results: The mean overall AHEI-2010 score was 42%, and the DASH score was 45%. Female participants (60.6%) had a significantly higher diet quality according to the AHEI-2010 and DASH score. AHEI-2010 and DASH scores were significantly associated (p < 0.001) with sex, school type, smoking, and total daily energy intake. The DASH score was additionally significantly associated (p < 0.001) with age, socioeconomic status, and physical activity. Participants with better nutrition knowledge were more likely to be older, to attend a general high school, to live in a high-income household, to be non-smokers, and to have a higher diet quality according to the AHEI-2010 and DASH score. (4) Conclusions: Predictors of better diet quality included female sex, physical activity, educational level, and nutrition knowledge. These results may aid focused interventions to improve diet quality in adolescents.

Mortality of Hemato-Oncologic Patients Admitted to a Pediatric Intensive Care Unit: A Single-Center Experience.

Introduction: Mortality in children with hemato-oncologic disease admitted to a pediatric intensive care unit (PICU) is higher compared to the general population. The reasons for this fact remain unexplored. The aim of this study was to assess outcomes and trends in hemato-oncologic patients admitted to a PICU, with analytical emphasis on emergency admissions. Methods: Patients with a hemato-oncologic diagnosis admitted to a tertiary care university hospital PICU between 1 January 2009 and 31 December 2019 were retrospectively analyzed. Additionally, patient mortality 6 months after PICU admission and follow-up mortality until 31 December 2020 were recorded. Measurements and Main Results: We reviewed a total of 701 PICU admissions of 338 children with hemato-oncologic disease, of which 28.5% were emergency admissions with 200 admissions of 122 patients. Of these, 22 patients died, representing a patient mortality of 18.0% and an admission mortality of 11.0% in this group. Follow-up patient mortality was 25.4% in emergency-admitted children. Multivariable analysis revealed severe neutropenia at admission and invasive mechanical ventilation (IMV) as independent risk factors for PICU death (p = 0.029 and p = 0.002). The total number of PICU admissions of hemato-oncologic patients rose notably over time, from 44 in 2009 to 125 in 2019. Conclusion: Although a high proportion of emergency PICU admissions of hemato-oncologic patients required intensive organ support, mortality seemed to be lower than previously reported. Moreover, in this study, total PICU admissions of the respective children rose notably over time.

Association of desphospho-uncarboxylated matrix gla protein with incident cardiovascular disease and all-cause mortality: Results from the prospective Bruneck Study.

BACKGROUND AND AIMS: Matrix Gla protein (MGP), a vitamin K-dependent protein, is a potent inhibitor of vascular calcification. Desphospho-uncarboxylated MGP (dp-ucMGP), a marker of vitamin K insufficiency, has been shown to predict cardiovascular disease (CVD) and all-cause mortality in high-risk populations. Whether the increased risk associated with dp-ucMGP also applies to the general, and especially, the elderly population has not yet been fully elucidated. METHODS AND RESULTS: Plasma dp-ucMGP was measured in 684 individuals aged 50-89 years of the prospective population-based Bruneck Study (baseline evaluation in 2000). Baseline median dp-ucMGP was 478.4 (IQR 335.0-635.2) pmol/L. Over a median follow-up of 15.5 years, 163 CVD events occurred and 235 participants died. Age-/sex-adjusted hazard ratios (HRs) per 1-SD higher level of loge transformed dp-ucMGP were 1.30 (95%CI: 1.09-1.55; p=0.004) for incident CVD and 1.36 (95%CI: 1.17-1.57; p<0.001) for all-cause mortality. After multivariable adjustment, the associations remained significant with HRs of 1.23 (95%CI: 1.02-1.47, p=0.029) for CVD and 1.40 (95%CI: 1.20-1.64; p<0.001) for all-cause mortality. The associations remained virtually unchanged after additional adjustment for dietary quality as measured with the Alternative Healthy Eating Index. We found no association of dp-ucMGP with myocardial infarction and sudden cardiac deaths, but a strong association with other vascular deaths and non-vascular/non-cancer deaths. CONCLUSIONS: This study shows a significant association of plasma dp-ucMGP with incident CVD and a significant and even stronger association with all-cause mortality. Clinical trials are needed to investigate whether vitamin K substitution results in improved health outcomes.

PCSK9 Activity Is Potentiated Through HDL Binding.

Rationale: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored. Objective: This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Methods and Results: Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation. Conclusions: This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.

Cardiovascular health behaviors and associations of sex, age, and education in adolescents - Results from the EVA Tyrol study.

BACKGROUND AND AIMS: Ideal cardiovascular health (CVH) behaviors in adolescents are defined by body mass index (BMI), diet, physical activity and smoking, and are directly associated with better health in later life. To further improve health prevention programs we investigated the prevalence of these behaviors in a cohort of healthy adolescents and focused on the associations with sex, age, and education. METHODS AND RESULTS: The Early Vascular Aging Tyrol study is a cross-sectional study assessing 14- to 19-year-old pupils and apprentices in Western Austria and South Tyrol. Between May 2015 and July 2018 2047 adolescents (43.6% males, mean age 16.4 years) with complete data for all 4 health behaviors were included. The prevalence of ideal body mass index (BMI) was 78.3%, of ideal physical activity 42.5%, of non-smoking 70.4% and of ideal diet 8.1%. Females showed a higher smoking prevalence and a lower physical activity, but better dietary habits than males. Older adolescents of both sexes had lower prevalence of ideal smoking and diet. Apprentices and pupils of vocational schools had a higher BMI and a less favorable diet compared to secondary academic school students. Smoking prevalence was highest in apprentices. Non-ideal BMI was independently associated with smoking. CONCLUSION: In our cohort, only a minority showed ideal CVH behaviors which were best in adolescents younger than 16 years. We observed significant differences between males and females and a clear impact of school education with apprentices being at risk for non-ideal CVH behaviors. CLINICAL TRIAL REGISTRATION NUMBER: NCT03929692, clinicaltrials.gov.

Impact of lifestyle and cardiovascular risk factors on early atherosclerosis in a large cohort of healthy adolescents: The Early Vascular Ageing (EVA)-Tyrol Study.

BACKGROUND AND AIMS: Atherosclerosis starts early in life. We aimed to assess the dimension and progression of the intima-media thickness, a surrogate marker for early vascular aging, and its association with a broad palette of cardiovascular risk and lifestyle factors in a large cohort of healthy adolescents. METHODS: The EVA-Tyrol cohort study enrolled 1573 adolescents with a mean age of 16.0 years (SD 0.9). 1000 participants had a prospective follow-up after 22.1 months on average (SD 3.4). Cardiovascular risk and lifestyle factors were evaluated by standardized interviews, physical examination, and fasting blood analyses. Carotid intima-media thickness (cIMT) was measured at baseline and follow-up by high-resolution ultrasound. Aortic intima-media thickness (aIMT) was assessed during follow-up only. RESULTS: Several vascular risk factors like elevated blood pressure (4.7% > 95th percentile), overweight (9.2% > 95th percentile) and smoking (29.7%) were already prevalent at this age. Maximum cIMT progressed by 2.78 µm (95% CI, 0.39-5.17) per year. In multivariable linear regression analysis, sex, body weight, systolic blood pressure, LDL-cholesterol and physical activity were independent predictors of cIMT both at baseline and follow-up. In addition, alanine-aminotransferase, a laboratory surrogate of non-alcoholic fatty liver disease, was independently associated with cIMT at follow-up and pack-years of smoking with aIMT. CONCLUSIONS: Unfavourable lifestyle and vascular risk factors were prevalent in adolescents and several of them were associated with vessel wall thickness, even though effect sizes were modest and cIMT variability was limited. These data suggest adolescence as a prime age range for early vascular prevention.

The dimension of preventable stroke in a large representative patient cohort.

OBJECTIVE: To analyze the frequency of inadequately treated risk factors in a large representative cohort of patients with acute ischemic stroke or TIA and to estimate the proportion of events potentially avertable by guideline-compliant preventive therapy compared to the status quo. METHODS: A total of 1,730 patients from the Poststroke Disease Management STROKE-CARD trial (NCT02156778) were recruited between 2014 and 2017. We focused on 8 risk conditions amenable to drug therapy and 3 lifestyle risk behaviors and assessed pre-event risk factor control in retrospect. RESULTS: The proportion of patients with at least 1 inadequately treated risk condition was 79.5% (95% confidence interval [CI] 77.6%-81.4%) and increased to 95.1% (95% CI 94.1%-96.1%) upon consideration of the lifestyle risk behaviors. Risk factor control was worse in patients with recurrent vs first-ever events (p < 0.001), men vs women (p = 0.003), and patients ≤75 vs >75 years of age (p < 0.001). The estimated degree of stroke preventability ranged from 0.4% (95% CI 0.2%-0.6%) to 13.7% (95% CI 12.2%-15.2%) for the individual risk factors. Adequate control of the 5 most relevant risk factors combined (hypertension, hypercholesterolemia, atrial fibrillation, smoking, and overweight) would have averted ≈1 of 2 events or 1 in 4 with a highly conservative computation approach. CONCLUSIONS: Our study confirms the existence of a considerable gap between risk factor control recommended by guidelines and real-world stroke prevention. Our study intends to increase awareness among physicians about stroke preventability and provides a quantitative basis for the emerging discussion on how to best tackle this challenge.

Association of MicroRNAs and YRNAs With Platelet Function.

RATIONALE: Platelets shed microRNAs (miRNAs). Plasma miRNAs change on platelet inhibition. It is unclear whether plasma miRNA levels correlate with platelet function. OBJECTIVE: To link small RNAs to platelet reactivity. METHODS AND RESULTS: Next-generation sequencing of small RNAs in plasma revealed 2 peaks at 22 to 23 and 32 to 33 nucleotides corresponding to miRNAs and YRNAs, respectively. Among YRNAs, predominantly, fragments of RNY4 and RNY5 were detected. Plasma miRNAs and YRNAs were measured in 125 patients with a history of acute coronary syndrome who had undergone detailed assessment of platelet function 30 days after the acute event. Using quantitative real-time polymerase chain reactions, 92 miRNAs were assessed in patients with acute coronary syndrome on different antiplatelet therapies. Key platelet-related miRNAs and YRNAs were correlated with platelet function tests. MiR-223 (rp=0.28; n=121; P=0.002), miR-126 (rp=0.22; n=121; P=0.016), and other abundant platelet miRNAs and YRNAs showed significant positive correlations with the vasodilator-stimulated phosphoprotein phosphorylation assay. YRNAs, miR-126, and miR-223 were also among the small RNAs showing the greatest dependency on platelets and strongly correlated with plasma levels of P-selectin, platelet factor 4, and platelet basic protein in the population-based Bruneck study (n=669). A single-nucleotide polymorphism that facilitates processing of pri-miR-126 to mature miR-126 accounted for a rise in circulating platelet activation markers. Inhibition of miR-126 in mice reduced platelet aggregation. MiR-126 directly and indirectly affects ADAM9 and P2Y12 receptor expression. CONCLUSIONS: Levels of platelet-related plasma miRNAs and YRNAs correlate with platelet function tests in patients with acute coronary syndrome and platelet activation markers in the general population. Alterations in miR-126 affect platelet reactivity.