Circulating levels of metabolic biomarkers of site-specific and sex-specific arterial calcification in the multi-cohort BBMRI setting

Abstract Background/Introduction Increasing evidence shows that greater arterial calcification leads to an elevated risk of atherosclerotic cardiovascular disease. Risk factors and prognosis of arterial calcification seems to vary per site and between women and men. However, the underlying biological mechanisms of site-specific calcification and the associated sex differences are largely unknown. Within the BBMRI framework, we performed a multi-cohort study on the associations of the circulating levels of metabolic biomarkers with arterial calcification at various sites among women and men. Purpose To examine the associations of the circulating levels of metabolic biomarkers with coronary artery (CAC), aortic arch (AAC) and the aortic valve (AVC) calcifications among women and men. Methods We included a total of 1,114 participants from the population-based Rotterdam Study and 390 from the Leiden Longevity Study. Study populations were comparable concerning study characteristics. Blood samples were used to determine a wide range of plasma metabolic biomarkers by proton nuclear magnetic resonance (NMR). Participants underwent non-contrast computed tomography to quantify the volume of CAC, AAC, and AVC. Linear regression modelling adjusted for relevant covariates was used to assess the associations of 166 metabolic biomarkers with CAC, AAC, and AVC. Correction for multiple testing was based on 33 independent metabolic biomarkers (p-value 0.05/33 = 1.5 x 10–3). Results Mean (standard deviation - SD) age was 69.5 (6.8) and 780 (52.0%) of the study population were women. One SD increase in concentration of a1-acid glycoprotein, was associated with a 0.10 SD (standard error (SE) = 0.03) increase in AAC (p-value = 9.5x10–4) in the overall population (Figure 1). When we stratified our analyses based on sex, this association was mainly driven by men [beta (SE) per SD: 0.12 (0.05), p-value = 0.007]. Moreover, an SD increase in acetate was associated with a 0.14 SD (SE = 0.04) decrease in CAC (p-value 1.7x10–4) in women but not in men [beta (SE) per SD: −0.04 (0.03), p-value = 0.22] (Figure 1). Conclusion(s) Higher levels of circulating glycoproteins were associated with increased AAC in men. Moreover, lower levels of circulating acetate were associated with increased CAC in women. These results provide evidence for location-specific differences and sex-specific effects in the underlying biological mechanisms of atherosclerosis. Our findings carry the potential to contribute to the early detection of individuals at increased risk for developing atherosclerotic cardiovascular disease and to a better understanding of disease etiology. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was performed within the framework of the BBMRI Metabolomics Consortium funded by BBMRI-NL, a research infrastructure financed by the Dutch government through Netherlands Organisation for Scientific Research (NWO) (Grant Nos. 184.021.007 and 184033111). MK was supported by VENI grant (91616079) from The Netherlands Organization for Health Research and Development (ZonMw).

Download Full-text

Arterial calcification in the prediction of atherosclerotic cardiovascular disease among women and men

European Heart Journal ◽

10.1093/ehjci/ehaa946.2946 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J.E Van Der Toorn ◽

D Bos ◽

B Arshi ◽

M.K Ikram ◽

M.W Vernooij ◽

...

Keyword(s):

Cardiovascular Disease ◽

High Risk ◽

The Netherlands ◽

Arterial Calcification ◽

Funding Source ◽

Atherosclerotic Cardiovascular Disease ◽

Intermediate Risk ◽

C Statistic ◽

Ascvd Risk ◽

Risk Categories

Abstract Background The Coronary Artery Calcium (CAC) Score has emerged as a valuable tool in atherosclerotic cardiovascular disease (ASCVD) risk stratification. However, data on the relevance of arterial calcification in different vascular territories for ASCVD risk prediction is lacking. Purpose First, to assess the sex-specific distribution of arterial calcification in different vessel beds across ASCVD risk categories. Second, to determine the added value of arterial calcification in different vascular territories for ASCVD risk prediction. Methods From a large population-based study, 2,139 participants (mean age 69 years, 55% women) underwent non-contrast computed tomography to quantify CAC, aortic arch calcification (AAC), extracranial- (ECAC) and intracranial carotid artery calcification (ICAC), and vertebrobasilar artery calcification (VBAC). The outcome measure, incident ASCVD, composed of fatal and nonfatal myocardial infarction (MI), other coronary heart disease (CHD) mortality, and stroke. We fitted sex-specific prediction models according to the Pooled Cohort Equations (PCE), and categorized participants into low- (<5%), borderline- (5% to 7.5%), intermediate- (7.5% to 20%), and high ASCVD risk (≥20%), based on the American College of Cardiology (ACC) and American Heart Association (AHA) guideline. Subsequently, we determined the distribution of calcifications in different vascular territories across the risk categories. Next, we extended the PCE prediction model with calcification volumes and calculated the c-statistic and the net reclassification improvement for events (NRIe) and non-events (NRIne). Results The median follow-up for ASCVD was 9.3 years. Among women, 38% was classified as low-risk, 19% as borderline risk, 31% as intermediate risk, and 12% as high risk. Among men, 2% was classified as low-risk, 10% as borderline risk, 60% as intermediate risk, and 28% as high risk. With increasing risk of ASCVD, a larger burden of calcification was observed. In women, simultaneously adding calcification volumes in all vessel beds led to the largest increase in c statistic (from 0.71 to 0.75) for the prediction of ASCVD and the most beneficial reclassification (NRIe: 11%, NRIne: 2%). Among men, the addition of CAC alone most substantially improved the prediction of ASCVD (c statistic improved from 0.65 to 0.68, NRIe and NRIne were 4% and 14%, respectively). Conclusions Our findings suggest a potential role for comprehensive assessment of calcification in different vessel beds for ASCVD risk stratification in particular among women. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The Rotterdam Study is supported by Erasmus MC and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture, and Science; the Ministry of Health, Welfare, and Sports; European Commission; and the Municipality of Rotterdam. Dr. Kavousi is supported by the VENI grant (91616079) from ZonMw. Dr. Bos was supported by a fellowship of the BrightFocus Foundation (A2017424F). Oscar L. Rueda-Ochoa receives a scholarship from COLCIENCIAS-Colombia and support from Universidad Industrial de Santander,UIS-Colombia. None of the funders had any role in study design; study conduct; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article.

Download Full-text

The association of artificial intelligence-enabled electrocardiogram-derived age (physiologic age) with atherosclerotic cardiovascular events in the community

European Heart Journal ◽

10.1093/ehjci/ehaa946.2905 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J Medina-Inojosa ◽

A Ladejobi ◽

Z Attia ◽

M Shelly-Cohen ◽

B Gersh ◽

...

Keyword(s):

Artificial Intelligence ◽

Bypass Graft ◽

P Value ◽

Funding Source ◽

Atherosclerotic Cardiovascular Disease ◽

Age Gap ◽

Predicted Risk ◽

Age And Sex

Abstract Background We have demonstrated that artificial intelligence interpretation of ECGs (AI-ECG) can estimate an individual's physiologic age and that the gap between AI-ECG and chronologic age (Age-Gap) is associated with increased mortality. We hypothesized that Age-Gap would predict long-term atherosclerotic cardiovascular disease (ASCVD) and that Age-Gap would refine the ACC/AHA Pooled Cohort Equations' (PCE) predictive abilities. Methods Using the Rochester Epidemiology Project (REP) we evaluated a community-based cohort of consecutive patients seeking primary care between 1998–2000 and followed through March 2016. Inclusion criteria were age 40–79 and complete data to calculate PCE. We excluded those with known ASCVD, AF, HF or an event within 30 days of baseline.A neural network, trained, validated, and tested in an independent cohort of ∼ 500,000 independent patients, using 10-second digital samples of raw, 12 lead ECGs. PCE was categorized as low<5%, intermediate 5–9.9%, high 10–19.9%, and very high≥20%. The primary endpoint was ASCVD and included fatal and non-fatal myocardial infarction and ischemic stroke; the secondary endpoint also included coronary revascularization [Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass Graft (CABG)], TIA and Cardiovascular mortality. Events were validated in duplicate. Follow-up was truncated at 10 years for PCE analysis. The association between Age-Gap with ASCVD and expanded ASCVD was assessed with cox proportional hazard models that adjusted for chronological age, sex and risk factors. Models were stratified by PCE risk categories to evaluate the effect of PCE predicted risk. Results We included 24,793 patients (54% women, 95% Caucasian) with mean follow up of 12.6±5.1 years. 2,366 (9.5%) developed ASCVD events and 3,401 (13.7%) the expanded ASCVD. Mean chronologic age was 53.6±11.6 years and the AI-ECG age was 54.5±10.9 years, R2=0.7865, p<0.0001. The mean Age-Gap was 0.87±7.38 years. After adjusting for age and sex, those considered older by ECG, compared to their chronologic age had a higher risk for ASCVD when compared to those with <−2 SD age gap (considered younger by ECG). (Figure 1A), with similar results when using the expanded definition of ASCVD (data not shown). Furthermore, Age-Gap enhanced predicted capabilities of the PCE among those with low 10-year predicted risk (<5%): Age and sex adjusted HR 4.73, 95% CI 1.42–15.74, p-value=0.01 and among those with high predicted risk (>20%) age and sex adjusted HR 6.90, 95% CI 1.98–24.08, p-value=0.0006, when comparing those older to younger by ECG respectively (Figure 1B). Conclusion The difference between physiologic AI-ECG age and chronologic age is associated with long-term ASCVD, and enhances current risk calculators (PCE) ability to identify high and low risk individuals. This may help identify individuals who should or should not be treated with newer, expensive risk-reducing therapies. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Mayo Clinic

Download Full-text

Low-density lipoprotein cholesterol goal attainment and treatment patterns in a cohort of >143,000 patients with atherosclerotic cardiovascular disease in Ontario, Canada

European Heart Journal ◽

10.1093/ehjci/ehaa946.1410 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Fairbairn ◽

P Oh ◽

R Goeree ◽

R.M Rogoza ◽

M Packalen ◽

...

Keyword(s):

Cardiovascular Disease ◽

Goal Attainment ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Data Repository ◽

Funding Source ◽

Atherosclerotic Cardiovascular Disease ◽

Low Density ◽

Low Density Lipoprotein Cholesterol

Abstract Background/Introduction Limited real-world data are available on attainment of low-density lipoprotein cholesterol (LDL-C) treatment goals in patients with atherosclerotic cardiovascular disease (ASCVD) in Canada. Purpose A retrospective observational study was conducted to describe types of ASCVD events/procedures, time between events and use of lipid lowering treatment (LLT) in patients who did not achieve LDL-C goal. Methods Patients in Ontario ≥65 years with a primary ASCVD event/procedure between 1 Apr 2005 and 31 Mar 2016, treated with an LLT and with index and follow up LDL-C values were identified from claims data at the Institute for Clinical Evaluative Sciences data repository. Patients were assessed over a 1-year follow up period for LDL-C goal attainment (<2.0 mmol/L or 50% reduction from index LDL-C) and analysed by LLT and by index event type. Results Overall, 28% of 143,302 patients ≥65 years on LLT failed to attain LDL-C goal at follow up (Figure). The proportion of patients failing to achieve LDL-C goal decreased from 35% to 22% over the 11-year study period. Mean time between index and follow up LDL-C (based on lowest score >2 weeks and up to 1 year after index LDL-C) was 203±97 days. When analysed by low-, moderate- or high-intensity statin, 57%, 30%, and 22% of patients failed to achieve LDL-C goal at follow up, respectively. Conclusions In this study, more than 1 in 4 patients with ASCVD in Ontario failed to achieve guideline recommended LDL-C goal despite treatment. In particular, ∼1 in 3 patients with cerebral and peripheral arterial disease were not at goal. An opportunity exists to better manage these high risk ASCVD patients with further statin intensification and additional LLTs This study made use of de-identified data from the ICES Data Repository, which is managed by the Institute for Clinical Evaluative Sciences with support from its funders and partners: Canada's Strategy for Patient-Oriented Research (SPOR), the Ontario SPOR Support Unit, the Canadian Institutes of Health Research and the Government of Ontario. The opinions, results and conclusions reported are those of the authors. No endorsement by ICES or any of its funders or partners is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen Canada Inc.

Download Full-text

IL-17 Pathway Members as Potential Biomarkers of Effective Systemic Treatment and Cardiovascular Disease in Patients with Moderate-to-Severe Psoriasis

International Journal of Molecular Sciences ◽

10.3390/ijms23010555 ◽

2022 ◽

Vol 23 (1) ◽

pp. 555

Author(s):

Xing Wang ◽

Hannah Kaiser ◽

Amanda Kvist-Hansen ◽

Benjamin D. McCauley ◽

Lone Skov ◽

...

Keyword(s):

Cardiovascular Disease ◽

Plasma Proteins ◽

Systemic Treatment ◽

Severe Psoriasis ◽

Atherosclerotic Cardiovascular Disease ◽

Strong Correlations ◽

Potential Marker ◽

Chronic Inflammatory Condition ◽

Circulating Levels ◽

Potential Biomarkers

Psoriasis is a chronic inflammatory condition associated with atherosclerotic cardiovascular disease (CVD). Systemic anti-psoriatic treatments mainly include methotrexate and biological therapies targeting TNF, IL-12/23 and IL-17A. We profiled plasma proteins from patients with moderate-to-severe psoriasis to explore potential biomarkers of effective systemic treatment and their relationship to CVD. We found that systemically well-treated patients (PASI < 3.0, n = 36) had lower circulating levels of IL-17 pathway proteins compared to untreated patients (PASI > 10, n = 23). Notably, IL-17C and PI3 were decreased with all four examined systemic treatment types. Furthermore, in patients without CVD, we observed strong correlations among IL-17C/PI3/PASI (r ≥ 0.82, p ≤ 1.5 × 10−12) pairs or between IL-17A/PASI (r = 0.72, p = 9.3 × 10−8). In patients with CVD, the IL-17A/PASI correlation was abolished (r = 0.2, p = 0.24) and the other correlations were decreased, e.g., IL-17C/PI3 (r = 0.61, p = 4.5 × 10−5). Patients with moderate-to-severe psoriasis and CVD had lower levels of IL-17A compared to those without CVD (normalized protein expression [NPX] 2.02 vs. 2.55, p = 0.013), and lower IL-17A levels (NPX < 2.3) were associated with higher incidence of CVD (OR = 24.5, p = 0.0028, 95% CI 2.1–1425.1). As a result, in patients with moderate-to-severe psoriasis, we propose circulating IL-17C and PI3 as potential biomarkers of effective systemic anti-psoriatic treatment, and IL-17A as potential marker of CVD.

Download Full-text

Evaluating the sensitivity of the ACC/AHA pooled cohort risk calculator to predict atherosclerotic cardiovascular events within 10 years: how many events are we failing to predict?

European Heart Journal ◽

10.1093/ehjci/ehaa946.2924 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J Medina-Inojosa ◽

V.K Somers ◽

S Hayes ◽

R Mankad ◽

F Lopez-Jimenez

Keyword(s):

Cardiovascular Risk ◽

Cardiovascular Health ◽

Fasting Blood Glucose ◽

Low Risk ◽

P Value ◽

Funding Source ◽

Atherosclerotic Cardiovascular Disease ◽

Ideal Cardiovascular Health ◽

Ascvd Risk

Abstract Background The ACC/AHA Pooled Cohort Equation (PCE) for atherosclerotic cardiovascular disease (ASCVD) has been recommended as the initial step in cardiovascular risk assessment. The sensitivity of this tool to detect those who will develop ASCVD within 10-years, while considering age and sex groups, has not been extensively studied. Methods Using the Rochester Epidemiology Project (REP) we evaluated a community-based cohort of consecutive patients that sought primary care in Olmsted County, MN, between the years 1998–2000 and were followed up through March 1st 2016. Inclusion criteria were ages 40–79 and complete data to calculate the PCE. We excluded those with known ASCVD, atrial fibrillation or heart failure. Criteria were similar to those used to derive the PCE. Events were validated in duplicate and included fatal and non-fatal myocardial infarction and ischemic stroke. Patient information was ascertained using the record linkage system of the REP. Follow-up was truncated at 10 years. We assessed the ASCVD predicted risk (categorized as low <5%, intermediate 5–9.9%, high 10–19.9%, and very high ≥20% risk) at baseline, in subjects having an ASCVD event within 10-years in the community across age (<65 years) and sex categories. We also categorized ideal cardiovascular health as ≥4 metrics [non-smoker, body mass index <25 kg/m2, and not having of elevated blood pressure (≥130/80 mmHg), LDL cholesterol (>100 mg/dL), or fasting blood glucose (>100 mg/dL), in the absence of a medical diagnosis or treatment]. Results We included 30,042 adults, mean ± SD age 48.5±12.2 years, 54% women, with a median follow-up of 16.5±5.3 years. There were 1,555 ASCVD events (5.2%) at 10 years of follow-up. The performance of the PCE was similar to what was described in the original report (0.78 vs 0.79). Overall, among those who suffered an ASCVD, 54% of women and 41% of men were not high risk as predicted by PCE (Figure 1A). Most women (73%) <65 years of age would had been considered low risk within 10-years before the event, and only 10% would have been considered to be high risks (Figure 1B). Nonetheless, women <65 years who had an ASCVD event and low 10-year predicted ASCVD risk by PCE were less likely to have ideal cardiovascular health [55 (0.40%) vs 3884 (28.39%), p-value<0.0001], when compared to women in the low risk category without an event. Conclusion The PCE fails to identify most women who will develop an ASCVD event, particularly women <65 years of age. These results underscore the importance of using additional information when estimating ASCVD risk among women and the need for better cardiovascular risk prediction tools. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Mayo Clinic

Download Full-text

Abstract 15793: Joint Prediction of Hard Ascvd by Pooled Cohorts Equations Risk and Presence of Breast Arterial Calcification: The Minerva Study

Circulation ◽

10.1161/circ.142.suppl_3.15793 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Carlos Iribarren ◽

Malini Chandra ◽

Gabriela Sanchez ◽

Danny Sam ◽

Fatemeh Azamian-Bidgoli ◽

...

Keyword(s):

Cardiovascular Disease ◽

Predictive Ability ◽

Mammographic Screening ◽

Arterial Calcification ◽

Atherosclerotic Cardiovascular Disease ◽

Kaiser Permanente ◽

Cox Models ◽

Continuous Mass ◽

Artery Disease ◽

Joint Prediction

Introduction: Prior studies have documented independent associations of breast arterial calcification (BAC) detected on mammographic screening with coronary artery disease or prospective cardiovascular disease outcomes. This study aims to ascertain the additional predictive ability for hard atherosclerotic cardiovascular disease (ASCVD) imparted by presence of BAC on top of the 10-year AHA/ACC Pooled Cohort Equations (PCE) Risk estimator. Hypothesis: BAC presence on mammograms will help further risk stratify women for risk of ASCVD. Methods: We used data from MINERVA, a multiethnic cohort of women aged 60 to 79 years at baseline (2012-15), free of symptomatic CVD, and recruited after mammography screening at Kaiser Permanente of Northern California. The sample available for analyses with complete data on BAC and PCE was 5,046. A BAC continuous mass score (mg) was obtained from digital mammograms using a validated densitometry method. BAC presence was BAC score > 0 mg. Follow-up for hospitalization and death was through 5/31/20 (mean, 6.2 years). We defined hard ASCVD as acute myocardial infarction or stroke or CVD death (n=122 events). Results: The mean (SD) age at baseline was 66 (4) years; 47 percent were non-white. Overall, 26.4 percent had a BAC score > 0 mg, 33 percent had low (< 5%), 36 percent intermediate (between 5 and 10%) and 31 percent high (> 10%) PCE risk. Using Cox models, there was a graded association by level of PCE risk and, within each level of PCE risk, women with BAC presence were at higher risk for ASCVD than women without BAC. In models adjusting for age, race/ethnicity, education level, BMI, statin use, menopausal hormone therapy, breast feeding and parity, being in the intermediate PCE risk group (relative to being at low PCE risk and having no BAC) was associated with 3.1 (95% CI, 1.5 - 6.5) increased hazard of ASCVD when no BAC was present and with 3.8 (95% CI, 1.7 - 8.7) increased hazard of ASCVD when BAC was present. Corresponding hazard ratios for women in the high PCE risks were 4.3 (95% CI, 1.9-9.6) and 7.5 (95% CI, 3.1-17.8), respectively. Conclusions: Our findings support additional predictive utility of BAC for ASCVD. In women at intermediate or high risk for ASCVD, BAC presence may help guide primary prevention.

Download Full-text

Long-term safety and efficacy of bempedoic acid in patients at high risk of atherosclerotic cardiovascular disease: results from the CLEAR Harmony open-label extension study

European Heart Journal ◽

10.1093/ehjci/ehaa946.3344 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

C.M Ballantyne ◽

M Banach ◽

H.E Bays ◽

A.L Catapano ◽

U Laufs ◽

...

Keyword(s):

Cardiovascular Disease ◽

Cumulative Exposure ◽

Lipid Lowering ◽

Funding Source ◽

Atherosclerotic Cardiovascular Disease ◽

Therapeutic Area ◽

Open Label ◽

Phase 3 ◽

Open Label Extension

Abstract Background Bempedoic acid (BA) is an oral first-in-class, ATP-citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) levels in adults with hypercholesterolemia. In the phase 3 CLEAR Harmony study (NCT02666664, n=2230), BA 180 mg for 52 weeks significantly lowered LDL-C at week 12 compared with placebo and was maintained for 52 weeks in hypercholesterolemic patients with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) on stable, maximally tolerated statins. Purpose To report long-term safety, tolerability, and efficacy of BA from the CLEAR Harmony open-label extension (OLE) study (NCT03067441). Methods After completing the 52-week placebo-controlled CLEAR Harmony study, patients immediately entered the OLE and received BA for 78 weeks, followed by a 4-week washout period; the potential cumulative exposure to BA was 2.5 years. The primary endpoint was long-term safety of BA in the OLE. Results A total of 1462 patients enrolled in the OLE (BA n=970; placebo n=492 from CLEAR Harmony). At OLE baseline, mean (SD) age was 66.9 (8.7) years, 73.9% were male, 96.3% had ASCVD, 3.7% had HeFH with or without ASCVD, and all were receiving statins (93.5% moderate or high intensity). At baseline of CLEAR Harmony, patients had mean (SD) LDL-C of 102.9 (29.9) mg/dL (BA) and 99.0 (24.2) mg/dL (placebo). The majority of OLE patients (86.2%, n=1260) completed 78 weeks of BA treatment. At week 12 and 78 of OLE treatment, respectively, mean LDL-C lowering from CLEAR Harmony baseline was –14.9% and –14.4%. A total of 1143 patients (78.2%) reported a treatment-emergent adverse event (TEAE), and 299 (20.5%) reported a serious TEAE. TEAEs of special interest, determined by the therapeutic area or prior observations in preclinical or early clinical studies, occurred at similar rates as CLEAR Harmony (creatine kinase elevations, 1.8%; gout, 2.6%; hepatic enzyme elevations, 2.0%; hypoglycemia, 1.2%; muscular disorders, 8.5%; neurocognitive disorders, 0.9%; new onset/worsening diabetes mellitus, 5.5%; renal disorders, 2.8%) with biochemical changes that were stable over the course of the study and approached baseline levels after treatment discontinuation. Overall, 114 patients (7.8%) reported a TEAE leading to discontinuation of BA (most common: myalgia [0.6%], muscle spasm [0.5%]). Conclusion Durable lipid lowering was observed through 78 weeks of BA treatment and patient adherence to BA therapy was high (86.2%). Overall safety during the OLE was similar to results reported in the 52-week-long CLEAR Harmony study and the overall BA phase 3 clinical program, with no new safety findings. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Esperion Therapeutics, Inc., funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, PhD, CMPP, of JB Ashtin.

Download Full-text

Plaque instability in acute coronary syndromes: a possible pathogenic role of gut microbial communities

European Heart Journal ◽

10.1093/ehjci/ehaa946.1254 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

E Pisano ◽

A Severino ◽

F Bugli ◽

D Pedicino ◽

F Paroni Sterbini ◽

...

Keyword(s):

Cardiovascular Disease ◽

Gut Microbiota ◽

Microbial Communities ◽

P Value ◽

Diversity Analysis ◽

Funding Source ◽

Unifrac Distance ◽

Plaque Instability ◽

Coronary Syndrome ◽

Β Diversity

Abstract Background The imbalance between protective and harmful bacteria in the microbial communities leads to a non-physiological condition, known as “dysbiosis”. In the last decade, several studies have suggested that gut microbiota can contribute to the development and progression of various disease including cardiovascular disease through metabolism-mediated pathways. The production and the release of bacterial metabolites, including Trimethylamine N-oxide (TMAO), can affect host health acting to distant organs. Purpose The aim of the present study was to explore the gut microbiota and the levels of TMAO in patients with stable angina (SA) and acute coronary syndrome (ACS) with or without elevation of the ST segment, respectively STEMI and NSTEMI, and in control subjects. Methods Feces were obtained from ACS (n=31) and SA (n=23) patients and controls (n=24). Genomic DNA was isolated using the QIamp DNA Stool Mini Kit. Samples were subjected to 16S rRNA gene V3–V4 region sequencing by an Illumina MiSeq TM platform. A combination of software packages QIIME and VSEARCH was used to generate a biological observation matrix (BIOM) at different taxonomic levels (from phylum to genus). The BIOM was analysed using the Web-based program MicrobiomeAnalyst. β-diversity between groups was obtained by weighted UniFrac distance metric analysis. Serum TMAO levels were measured with a UPLC-MS/MS mass spectrometry in SA and ACS patients. Results β-diversity analysis showed a different bacterial composition in SA and ACS patients and controls ([PERMANOVA] F-value: 1.9706; R-squared: 0.050567; p-value <0.018) (Figure 1A). In particular, analysis between the three groups revealed a significant enrichment of Streptococcus genus in ACS patients (Kruskas Wallis test; p=0.0085) (Figure 1B). Controls and ACS revealed a similar gut microbial composition ([PERMANOVA] F-value: 0.7591; R-squared: 0.014388; p-value <0.61) (Figure 2A); in contrast, controls and SA showed separate clusters according to relative differences in taxonomic composition ([PERMANOVA] F-value: 3.0498; R-squared: 0.064821 p-value <0.006) (Figure 2B). Finally, β-diversity analysis in SA and ACS revealed different microbial communities in the two groups [PERMANOVA] F-value: 2.5103; R-squared: 0.046051; p-value <0.025) (Figure 2C) that could partially explain the severity progression of cardiovascular disease. Serum TMAO levels were higher in STEMI (n=14) as compared to SA and to NSTEMI (n=16) (respectively p=0.016 and p=0.028) (Figure 3). Conclusion These results, taken together, suggest that gut microbiota and its derived metabolites might play an essential role in the progression of atherosclerosis and in coronary plaque instability. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Linea D1 Università Cattolica del Sacro Cuore

Download Full-text