Converting PROMIS®-29 v2.0 profile data to SF-36 physical and mental component summary scores in patients with cardiovascular disorders.

BACKGROUND: Health-related quality of life (HRQL) has become an important outcome parameter in cardiology. The MOS 36-ltem Short-Form Health Survey (SF-36) and the PROMIS-29 are two widely used generic measures providing composite HRQL scores. The domains of the SF-36, a well-established instrument utilized for several decades, can be aggregated to physical (PCS) and mental (MCS) component summary scores. Alternative scoring algorithms for correlated component scores (PCSc and MCSc) have also been suggested. The PROMIS-29 is a newer but increasingly used HRQL measure. Analogous to the SF-36, physical and mental health summary scores can be derived from PROMIS-29 domain scores, based on a correlated factor solution. So far, scores from the PROMIS-29 are not directly comparable to SF-36 results, complicating the aggregation of research findings. Thus, our aim was to provide algorithms to convert PROMIS-29 data to well-established SF-36 component summary scores. METHODS: Data from n = 662 participants of the Berlin Long-term Observation of Vascular Events (BeLOVE) study were used to estimate linear regression models with either PROMIS-29 domain scores or aggregated PROMIS-29 physical/mental health summary scores as predictors and SF-36 physical/mental component summary scores as outcomes. Data from a subsequent assessment point (n = 259) were used to evaluate the agreement between empirical and predicted SF-36 scores. RESULTS: PROMIS-29 domain scores as well as PROMIS-29 health summary scores showed high predictive value for PCS, PCSc, and MCSc (R2 ≥ 70%), and moderate predictive value for MCS (R2 = 57% and R2 = 40%, respectively). After applying the regression coefficients to new data, empirical and predicted SF-36 component summary scores were highly correlated (r > 0.8) for most models. Mean differences between empirical and predicted scores were negligible (|SMD|<0.1). CONCLUSIONS: This study provides easy-to-apply algorithms to convert PROMIS-29 data to well-established SF-36 physical and mental component summary scores in a cardiovascular population. Applied to new data, the agreement between empirical and predicted SF-36 scores was high. However, for SF-36 mental component summary scores, considerably better predictions were found under the correlated (MCSc) than under the original factor model (MCS). Additionally, as a pertinent byproduct, our study confirmed construct validity of the relatively new PROMIS-29 health summary scores in cardiology patients.

Early clinical outcomes of Portico and Edwards Sapien 3 valve prosthesis in transcatheter aortic valve replacement: propensity-matched analysis.

Introduction: There is a lack of real-world data directly comparing different valve prostheses for transaortic valve replacement (TAVR). We aimed to compare early clinical outcomes at 30-days between the self-expandable Portico valve (Abbott) with the balloon-expandable Edwards Sapien 3 valve (Edwards Lifesciences) (ES3). Methods: Out of 1,901 patients undergoing TAVR between January 2018 and December 2021, all patients who received either Portico valve or ES3 valve via transfemoral TAVR were matched using nearest-neighbor (1:1) propensity scoring. Primary endpoints were single safety endpoints and early safety composite endpoints defined by Valve Academic Research Consortium-2 (VARC-2) criteria. The secondary endpoint was to analyze risk predictors for new permanent pacemaker (PPM) implantation in TAVR. Results: Out of 661 complete cases, a total of 434 patients were successfully matched based on age, sex, Euro Score II and STS-score. In the matched cohort, 217 received either a Portico or valve and 217 received an ES3 valve. The VARC-2 early safety composite scores indicated a significantly greater overall 30-day safety risk in the Portico group at 9.2% (n = 20) compared to 3.7% (n = 8) in the ES3 group (p = 0.032). The requirement for new permanent pacemaker (PPM) implantation was also higher in the Portico group, at 21.2% (n = 46) vs. 13.4% (n = 29) in the ES3 group (p = 0.042). 30-day mortality was higher was 3.7% (n = 8) in Portico group compared to 0.9% in ES3 group (p = 0.11). Furthermore, implantation of the Portico valve was identified as a significant risk predictor for new PPM implantation, alongside higher age, preprocedural atrioventricular block (AVB) and longer total procedure duration. Conclusion: This study shows significantly higher rates of early clinical complications for Portico valve prostheses compared to ES3. These findings should be especially taken into consideration when selecting valve prosthesis for high-risk patients.

Modulation of the Serum Metabolome by the Short-Chain Fatty Acid Propionate: Potential Implications for Its Cholesterol-Lowering Effect.

(1) Background: Dyslipidemia represents a major risk factor for atherosclerosis-driven cardiovascular disease. Emerging evidence suggests a close relationship between cholesterol metabolism and gut microbiota. Recently, we demonstrated that the short-chain fatty acid (SCFA) propionate (PA) reduces serum cholesterol levels through an immunomodulatory mechanism. Here, we investigated the effects of oral PA supplementation on the human serum metabolome and analyzed changes in the serum metabolome in relation to the cholesterol-lowering properties of PA. (2) Methods: The serum metabolome of patients supplemented with either placebo or propionate orally for 8 weeks was assessed using a combination of flow injection analysis-tandem (FIA-MS/MS) as well as liquid chromatography (LC-MS/MS) and mass spectrometry using a targeted metabolomics kit (MxP®Quant 500 kit: BIOCRATES Life Sciences AG, Innsbruck, Austria). A total of 431 metabolites were employed for further investigation in this study. (3) Results: We observed a significant increase in distinct bile acids (GCDCA: fold change = 1.41, DCA: fold change = 1.39, GUDCA: fold change = 1.51) following PA supplementation over the study period, with the secondary bile acid DCA displaying a significant negative correlation with the serum cholesterol levels. (4) Conclusions: Oral supplementation with PA modulates the serum metabolome with a particular impact on the circulatory bile acid profile. Since cholesterol and bile acid metabolism are interconnected, the elevation of the secondary bile acid DCA may contribute to the cholesterol-lowering effect of PA.

Prognostic impact of quantitative flow ratio (QFR)-consistent complete revascularization in patients with myocardial infarction and multivessel coronary artery disease.

BACKGROUND: Complete revascularization is associated with improved outcomes in patients with myocardial infarction and multivessel coronary artery disease. Quantitative flow ratio (QFR) represents an emerging angiography-based tool for functional lesion assessment. The present study investigated the prognostic impact of QFR-consistent complete revascularization in patients with myocardial infarction and multivessel disease. METHODS: A total of 792 patients with myocardial infarction and multivessel disease were enrolled in the analysis. Post-hoc QFR analyses of 1,320 nonculprit vessels were performed by investigators blinded to clinical outcomes. The primary endpoint was a composite of all-cause death, nonculprit vessel related nonfatal myocardial infarction, and ischemia-driven revascularization at 2 years after index myocardial infarction. Patients were stratified into a QFR-consistent PCI group (n = 646) and a QFR-inconsistent PCI group (n = 146), based on whether the intervention was congruent with the QFR-determined functional significance of the nonculprit lesions. RESULTS: The primary endpoint occurred in a total of 22 patients (3.4%) in the QFR-consistent PCI group and in 27 patients (18.5%) in the QFR-inconsistent group (HR 0.17, 95% CI 0.10-0.30, P < .001).The difference in the primary endpoint was driven by reduced rates of nonfatal myocardial infarction (2.0% vs. 15.1%; HR 0.13, 95% CI 0.06-0.25; P < .001) and ischemia-driven revascularization (1.2% vs. 5.5%; HR 0.21, 95% CI 0.08-0.57; P = .001) in the QFR-consistent PCI group. CONCLUSIONS: Among patients with myocardial infarction and multivessel disease, a QFR-consistent complete revascularization was associated with a reduced risk of all-cause mortality, nonfatal myocardial infarction, and ischemia-driven revascularization. These findings underline the value of angiography-based functional lesion assessment for personalized revascularization strategies.

Effects of Oral Butyrate on Blood Pressure in Patients With Hypertension: A Randomized, Placebo-Controlled Trial.

BACKGROUND: The microbiota-derived short chain fatty acid butyrate has been shown to lower blood pressure (BP) in rodent studies. Nonetheless, the net effect of butyrate on hypertension in humans remains uncovered. In this study, for the first time, we aimed to determine the effect of oral butyrate on BP in patients with hypertension. METHODS: We performed a double-blind randomized placebo-controlled trial including 23 patients with hypertension. Antihypertensive medication was discontinued for the duration of the study with a washout period of 4 weeks before starting the intervention. Participants received daily oral capsules containing either sodium butyrate or placebo with an equivalent dosage of sodium chloride for 4 weeks. The primary outcome was daytime 24-hour systolic BP. Differences between groups over time were assessed using linear mixed models (group-by-time interaction). RESULTS: Study participants (59.0±3.7 years; 56.5% female) had an average baseline office systolic BP of 143.5±14.6 mm Hg and diastolic BP of 93.0±8.3 mm Hg. Daytime 24-hour systolic and diastolic BP significantly increased over the intervention period in the butyrate compared with the placebo group, with an increase of +9.63 (95% CI, 2.02-17.20) mm Hg in daytime 24-hour systolic BP and +5.08 (95% CI, 1.34-8.78) mm Hg in diastolic BP over 4 weeks. Butyrate levels significantly increased in plasma, but not in feces, upon butyrate intake, underscoring its absorption. CONCLUSIONS: Four-week treatment with oral butyrate increased daytime systolic and diastolic BP in subjects with hypertension. Our findings implicate that butyrate does not have beneficial effects on human hypertension, which warrants caution in future butyrate intervention studies. REGISTRATION: URL: https://clinicaltrialregister.nl/nl/trial/22936; Unique identifier: NL8924.

Full-Moon Coronary Calcification as Detected With Computed Tomography Angiography in Chronic Total Occlusion Percutaneous Coronary Intervention.

"Full moon" is a central calcification that occludes the entire vessel on coronary computed tomography angiography (CCTA). We examined the association of full moon calcification as identified by CCTA, on clinical and procedural outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We studied patients who underwent elective CTO-PCI in 2 European centers and had preprocedural CCTA. The primary end point was the inability to cross the lesion and/or the need for extensive debulking techniques. Secondary end points were procedural success, in-hospital cardiac mortality, the need for extensive debulking techniques, myocardial infarction, major adverse cardiac events (defined as in-hospital death, myocardial infarction, and clinically driven target vessel revascularization), and stent thrombosis. Secondary procedural end points included procedural time, fluoroscopy time, number of guidewires and balloons, stent length, number and diameter, and contrast volume. Multivariable logistic regression analysis was performed, identifying potential covariates related to the primary outcome according to knowledge and previous studies. Subsequently, a stepwise selection approach was performed to select factors with the greatest predictive value. Of 140 patients included, 28 (20%) had a full moon calcified CTO plaque. Patients in the full moon group were older and had more cardiovascular risk factors. There was not significant difference in the need for retrograde approach and anterograde dissection and reentry techniques between the full moon group and the other groups (32.1% vs 37.5%, p = 0.59 and 0% vs 1.7%, p = 0.47, respectively). Patients in the full moon group had greater incidence of the primary outcome than did those who did not have full moon morphology (53.5% vs 12.5%, p <0.001). On multivariable analysis that included chronic kidney failure and previous coronary artery bypass surgery, full moon calcification was associated with greater incidence of the primary end point (odds ratio 6.5, 95% confidence interval 2.1 to 20.5, p = 0.001). Moreover, less procedural success (71.4% vs 87.5%, p = 0.03), greater incidence of coronary perforations (14.2% vs 3.5%, p <0.02), and greater procedural (172.5 [118.0 to 237.5] vs 144.0 [108.50 to 174.75], p = 0.02) and fluoroscopic time (62.6 [38.1 to 83.0] vs 42.8 [29.5 to 65.7], p = 0.03) were observed in the full moon group. Overall major adverse cardiac events did not differ between the 2 groups (1 patient in the full moon group vs 1 patient in the non-full moon group; 3.5% vs 0.8%, p = 0.29). In conclusion, full moon calcification on CCTA was independently associated with procedural complexity and adverse outcomes in CTO-PCI.

Predictors of atrial fibrillation after embolic stroke of undetermined source in patients with implantable loop recorders.

BACKGROUND: In patients with embolic stroke of undetermined source (ESUS), underlying subclinical atrial fibrillation (AF) is often suspected. Previous studies identifying predictors of AF have been limited in their ability to diagnose episodes of AF. Implantable loop recorders enable prolonged, continuous, and therefore more reliable detection of AF. The aim of this study was to identify clinical and ECG parameters as predictors of AF in ESUS patients with implantable loop recorders. METHODS: 101 ESUS patients who received an implantable loop recorder between 2012 and 2020 were included in this study. Patients were followed up regularly on a three-monthly outpatient interval. RESULTS: During a mean follow-up of 647 ± 385 days, AF was detected in 26 patients (26%). Independent risk factors of AF were age ≥ 60 years (HR 2.753, CI 1.129-6.713, p = 0.026), P-wave amplitude in lead II ≤ 0.075 mV (HR 3.751, CI 1.606-8.761, p = 0.002), and P-wave duration ≥ 125 ms (HR 4.299, CI 1.844-10.021, p < 0.001). In patients without risk factors, the risk of developing AF was 16%. In the presence of one risk factor, the probability increased only slightly to 18%. With two or three risk factors, the risk of AF increased to 70%. CONCLUSION: AF was detected in about one in four patients after ESUS in this study. A comprehensive evaluation involving multiple parameters and the existence of multiple risk factors yields the highest predictive accuracy for detecting AF in patients with ESUS.

Impact of elevated lipoprotein(a) on coronary artery disease phenotype and severity.

AIMS: A thorough characterization of the relationship between elevated lipoprotein(a) [Lp(a)] and coronary artery disease (CAD) is lacking. This study aimed to quantitatively assess the association of increasing Lp(a) levels and CAD severity in a real-world population. METHODS AND RESULTS: This non-interventional, cross-sectional, LipidCardio study included patients aged ≥21 years undergoing angiography (October 2016-March 2018) at a tertiary cardiology centre, who have at least one Lp(a) measurement. The association between Lp(a) and CAD severity was determined by synergy between PCI with taxus and cardiac surgery (SYNTAX)-I and Gensini scores and angiographic characteristics. Overall, 975 patients (mean age: 69.5 years) were included; 70.1% were male, 97.5% had Caucasian ancestry, and 33.2% had a family history of premature atherosclerotic cardiovascular disease. Median baseline Lp(a) level was 19.3 nmol/L. Patients were stratified by baseline Lp(a): 72.9% had < 65 nmol/L, 21.0% had ≥100 nmol/L, 17.2% had ≥125 nmol/L, and 12.9% had ≥150 nmol/L. Compared with the normal (Lp(a) < 65 nmol/L) group, elevated Lp(a) groups (e.g. ≥ 150 nmol/L) had a higher proportion of patients with prior CAD (48.4% vs. 62.7%; P < 0.01), prior coronary revascularization (39.1% vs. 51.6%; P = 0.01), prior coronary artery bypass graft (6.0% vs. 15.1%; P < 0.01), vessel(s) with lesions (68.5% vs. 81.3%; P = 0.03), diffusely narrowed vessels (10.9% vs. 16.5%; P = 0.01) or chronic total occlusion lesions (14.3% vs. 25.2%; P < 0.01), and higher median SYNTAX-I (3.0 vs. 5.5; P = 0.01) and Gensini (10.0 vs. 16.0; P < 0.01) scores. CONCLUSION: Elevated Lp(a) was associated with a more severe presentation of CAD. Awareness of Lp(a) levels in patients with CAD may have implications in their clinical management.

Patients with coronary artery disease (CAD) suffer with progressive plaque buildup in the walls of coronary blood vessels, which restricts blood flow and may result in serious cardiovascular outcomes such as chest pain (angina) and heart attacks (myocardial infarction). In this study, we assessed whether elevated levels of lipoprotein(a) [Lp(a)­a lipoprotein found in blood] are associated with more severe illness. We observed that elevated Lp(a) was associated with a higher proportion of patients with prior CAD, prior interventions on coronary blood vessels, and more diseased blood vessels. These collectively form what is considered a 'severe' clinical presentation of CAD, meaning a greater likelihood of adverse clinical outcomes.

A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk.

Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10-2.42) and 2.02 (1.29-3.18), respectively; for 4PY: 1.89 (1.26-2.84) and 1.99 (1.26-3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both 2PY and 4PY levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10-18). Moreover, sVCAM-1 levels were significantly correlated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10-5; 4PY: rho = 0.18, P = 1.1 × 10-8). Lastly, treatment with physiological levels of 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.

Lipoprotein(a) and cardiovascular disease: sifting the evidence to guide future research.

Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease including coronary heart disease, peripheral arterial disease, ischaemic stroke, and calcific aortic valve stenosis. Clinical trials of specific and potent Lp(a)-lowering drugs are currently underway. However, in clinical practice, widespread assessment of Lp(a) is still lacking despite several guideline recommendations to measure Lp(a) at least once in a lifetime in all adults to identify those at high or very high risk due to elevated levels. The present review provides an overview of key findings from observational and genetic Lp(a) studies, highlights the main challenges in observational Lp(a) studies, and proposes a minimum set of requirements to enhance the quality and harmonize the collection of Lp(a)-related data. Adherence to the recommendations set forth in the present manuscript is intended to enhance the quality of future observational Lp(a) studies, to better define thresholds for increased risk, and to better inform clinical trial design. The recommendations can also potentially assist in the interpretation and generalization of clinical trial findings, to improve care of patients with elevated Lp(a) and optimize treatment and prevention of cardiovascular disease.

Coronary microevaginations characterize culprit plaques and their inflammatory microenvironment in a subtype of acute coronary syndrome with intact fibrous cap: results from the prospective translational OPTICO-ACS study.

AIMS: Coronary microevaginations (CMEs) represent an outward bulge of coronary plaques and have been introduced as a sign of adverse vascular remodelling following coronary device implantation. However, their role in atherosclerosis and plaque destabilization in the absence of coronary intervention is unknown. This study aimed to investigate CME as a novel feature of plaque vulnerability and to characterize its associated inflammatory cell-vessel-wall interactions. METHODS AND RESULTS: A total of 557 patients from the translational OPTICO-ACS study programme underwent optical coherence tomography imaging of the culprit vessel and simultaneous immunophenotyping of the culprit lesion (CL). Two hundred and fifty-eight CLs had a ruptured fibrous cap (RFC) and one hundred had intact fibrous cap (IFC) acute coronary syndrome (ACS) as an underlying pathophysiology. CMEs were significantly more frequent in CL when compared with non-CL (25 vs. 4%, P < 0.001) and were more frequently observed in lesions with IFC-ACS when compared with RFC-ACS (55.0 vs. 12.7%, P < 0.001). CMEs were particularly prevalent in IFC-ACS-causing CLs independent of a coronary bifurcation (IFC-ICB) when compared with IFC-ACS with an association to a coronary bifurcation (IFC-ACB, 65.4 vs. 43.7%, P = 0.030). CME emerged as the strongest independent predictor of IFC-ICB (relative risk 3.36, 95% confidence interval 1.67-6.76, P = 0.001) by multivariable regression analysis. IFC-ICB demonstrated an enrichment of monocytes in both culprit blood analysis (culprit ratio: 1.1 ± 0.2 vs. 0.9 ± 0.2, P = 0.048) and aspirated culprit thrombi (326 ± 162 vs. 96 ± 87 cells/mm2, P = 0.017), while IFC-ACB confirmed the accumulation of CD4+ T cells, as recently described. CONCLUSION: This study provides novel evidence for a pathophysiological involvement of CME in the development of IFC-ACS and provides first evidence for a distinct pathophysiological pathway for IFC-ICB, driven by CME-derived flow disturbances and inflammatory activation involving the innate immune system. TRIAL REGISTRATION: Registration of the study at clinicalTrials.gov (NCT03129503).

Cholesterol crystals at the culprit lesion in patients with acute coronary syndrome are associated with worse cardiovascular outcomes at two years follow up - results from the translational OPTICO-ACS study program.

BACKGROUND: Cholesterol crystals (CCs) represent a feature of advanced atherosclerotic plaque and may be assessed by optical coherence tomography (OCT). Their impact on cardiovascular outcomes in patients presenting with acute coronary syndromes (ACS) is yet unknown. METHODS: The culprit lesion (CL) of 346 ACS-patients undergoing preintervention OCT imaging were screened for the presence of CCs and divided into two groups accordingly. The primary end-point was the rate of major adverse cardiac events plus (MACE+) consisting of cardiac death, myocardial infarction, target vessel revascularization and re-hospitalization due to unstable or progressive angina at two years. RESULTS: Among 346 patients, 57.2% presented with CCs at the CL. Patients with CCs exhibited a higher prevalence of ruptured fibrous caps (RFC-ACS) (79.8% vs. 56.8%; p < 0.001) and other high-risk features such as thin cap fibroatheroma (80.8% vs. 64.9%; p = 0.001), presence of macrophages (99.0% vs. 85.1%; p < 0.001) as well as a greater maximum lipid arc (294.0° vs. 259.3°; p < 0.001) at the CL as compared to patients without CCs. MACE+ at two years follow-up occurred more often in CC-patients (29.2% vs. 16.1%; p = 0.006) as compared to patients without CCs at the culprit site. Multivariable cox regression analysis identified CCs as independent predictor of MACE+ (HR 1.705; 1.025-2.838 CI, p = 0.040). CONCLUSIONS: CCs were associated with conventional high-risk plaque features and associated with increased MACE+-rates at two years follow up. The identification of CCs might be useful as prognostic marker in patients with ACS and assist "precision prevention" in the future.

Prognostic value of gut microbe-generated metabolite phenylacetylglutamine in patients with heart failure.

AIM: Phenylacetylglutamine (PAGln) is a phenylalanine-derived metabolite produced by gut microbiota with mechanistic links to heart failure (HF)-relevant phenotypes. We sought to investigate the prognostic value of PAGln in patients with stable HF. METHODS AND RESULTS: Fasting plasma PAGln levels were measured by stable-isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) in patients with stable HF from two large cohorts. All-cause mortality was assessed at 5-year follow-up in the Cleveland cohort, and HF, hospitalization, or mortality were assessed at 3-year follow-up in the Berlin cohort. Within the Cleveland cohort, median PAGln levels were 4.2 (interquartile range [IQR] 2.4-6.9) µM. Highest quartile of PAGln was associated with 3.09-fold increased mortality risk compared to lowest quartile. Following adjustments for traditional risk factors, as well as race, estimated glomerular filtration rate, amino-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, left ventricular ejection fraction, ischaemic aetiology, and HF drug treatment, elevated PAGln levels remained predictive of 5-year mortality in quartile comparisons (adjusted hazard ratio [HR] [95% confidence interval, CI] for Q4 vs Q1: 1.64 [1.07-2.53]). In the Berlin cohort, a similar distribution of PAGln levels was observed (median 3.2 [IQR 2.0-4.8] µM), and PAGln levels were associated with a 1.92-fold increase in 3-year HF hospitalization or all-cause mortality risk (adjusted HR [95% CI] for Q4 vs Q1: 1.92 [1.02-3.61]). Prognostic value of PAGln appears to be independent of trimethylamine N-oxide levels. CONCLUSION: High levels of PAGln are associated with adverse outcomes independent of traditional cardiac risk factors and cardio-renal risk markers.

Spotty calcium deposits within acute coronary syndrome (ACS)-causing culprit lesions impact inflammatory vessel-wall interactions and are associated with higher cardiovascular event rates at one year follow-up: Results from the prospective translational OPTICO-ACS study program.

BACKGROUND AND AIMS: Spotty calcium deposits (SCD) represent a vulnerable plaque feature which seems to result - as based on recent invitro studies - from inflammatory vessel-wall interactions. SCD can be reliably assessed by optical coherence tomography (OCT). Their prognostic impact is yet unknown. Therefore, the aims of this translational study were to comprehensively characterize different plaque calcification patterns, to analyze the associated inflammatory mechanisms in the microenvironment of acute coronary syndrome (ACS)-causing culprit lesions (CL) and to investigate the prognostic significance of SCD in a large cohort of ACS-patients. METHODS: CL of the first 155 consecutive ACS-patients from the translational OPTICO-ACS-study program were investigated by OCT-characterization of the calcium phenotype at ACS-causing culprit lesions. Simultaneous immunophenotyping by flow-cytometric analysis and cytokine bead array technique across the CL gradient (ratio local/systemic levels) was performed and incidental major adverse cardiovascular events plus (MACE+) at 12 months after ACS were assessed. RESULTS: SCD were observed within 45.2% of all analyzed ACS-causing culprit lesions (CL). Culprits containing spotty calcium were characterized by an increased culprit ratio of innate effector cytokines interleukin (IL)-8 [2.04 (1.24) vs. 1.37 (1.10) p < 0.05], as well as TNF (tumor necrosis factor)-α [1.17 (0.93) vs. 1.06 (0.89); p < 0.05)] and an increased ratio of circulating neutrophils [0.96 (0.85) vs. 0.91 (0.77); p < 0.05] as compared to culprit plaques without SCD. Total monocyte levels did not differ between the two groups (p = n.s.). However, SCD-containing CLs were characterized by an increased culprit ratio of intermediate monocytes [(1.15 (0.81) vs. 0.96 (0.84); p < 0.05)] with an enhanced surface expression of the integrin receptor CD49d as compared to intermediate monocytes derived from SCD-free CLs [(1.06 (0.94) vs. 0.97 (0.91)] p < 0.05. Finally, 12 months rates of MACE+ were higher in patients with, as compared to patients without SCD at CL (16.4% vs. 5.3%; p < 0.05). CONCLUSIONS: This study for the first time identified a specific inflammatory profile of CL with SCD, with a predominance of neutrophils, intermediate monocytes and their corresponding effector molecules. Hence, this study advances our understanding of ACS-causing CL and provides the basis for future personalized anti-inflammatory, therapeutic approaches to ACS.

Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation.

Acute coronary syndrome (ACS) remains a major cause of worldwide mortality. The syndrome occurs when blood flow to the heart muscle is decreased or blocked, causing muscle tissues to die or malfunction. There are three main types of ACS: Non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and unstable angina. The treatment depends on the type of ACS, and this is decided by a combination of clinical findings, such as electrocardiogram and plasma biomarkers. Circulating cell-free DNA (ccfDNA) is proposed as an additional marker for ACS since the damaged tissues can release DNA to the bloodstream. We used ccfDNA methylation profiles for differentiating between the ACS types and provided computational tools to repeat similar analysis for other diseases. We leveraged cell type specificity of DNA methylation to deconvolute the ccfDNA cell types of origin and to find methylation-based biomarkers that stratify patients. We identified hundreds of methylation markers associated with ACS types and validated them in an independent cohort. Many such markers were associated with genes involved in cardiovascular conditions and inflammation. ccfDNA methylation showed promise as a non-invasive diagnostic for acute coronary events. These methods are not limited to acute events, and may be used for chronic cardiovascular diseases as well.

Toll-like receptor 2, hyaluronan, and neutrophils play a key role in plaque erosion: the OPTICO-ACS study.

BACKGROUND AND AIMS: In one-third of patients with acute coronary syndrome (ACS), thrombosis occurs despite an intact fibrous cap (IFC) (IFC-ACS, 'plaque erosion'). Recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets. METHODS AND RESULTS: Thirty-two patients with IFC-ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC-ACS) from the OPTICO-ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)-embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC-ACS than RFC-ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC-ACS-derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC-ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of the TLR2 ligand: hyaluronic acid. CONCLUSION: The current study provides first in-human evidence for distinct TLR2-mediated neutrophil activation in IFC-ACS, presumably triggered by elevated soluble hyaluronic acid. Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss-triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC-ACS.

Culprit plaque morphology determines inflammatory risk and clinical outcomes in acute coronary syndrome.

AIMS: Rupture of the fibrous cap (RFC) and erosion of an intact fibrous cap (IFC) are the two predominant mechanisms causing acute coronary syndromes (ACS). It is uncertain whether clinical outcomes are different following RFC-ACS vs. IFC-ACS and whether this is affected by a specific inflammatory response. The prospective, translational OPTIcal-COherence Tomography in Acute Coronary Syndrome study programme investigates the impact of the culprit lesion phenotype on inflammatory profiles and prognosis in ACS patients. METHODS AND RESULTS: This analysis included 398 consecutive ACS patients, of which 62% had RFC-ACS and 25% had IFC-ACS. The primary endpoint was a composite of cardiac death, recurrent ACS, hospitalization for unstable angina, and target vessel revascularization at 2 years [major adverse cardiovascular events (MACE+)]. Inflammatory profiling was performed at baseline and after 90 days. Patients with IFC-ACS had lower rates of MACE+ than those with RFC-ACS (14.3% vs. 26.7%, P = 0.02). In 368-plex proteomic analyses, patients with IFC-ACS showed lower inflammatory proteome expression compared with those with RFC-ACS, including interleukin-6 and proteins associated with the response to interleukin-1ß. Circulating plasma levels of interleukin-1ß decreased from baseline to 3 months following IFC-ACS (P < 0.001) but remained stable following RFC-ACS (P = 0.25). Interleukin-6 levels decreased in patients with RFC-ACS free of MACE+ (P = 0.01) but persisted high in those with MACE+. CONCLUSION: This study demonstrates a distinct inflammatory response and a lower risk of MACE+ following IFC-ACS. These findings advance our understanding of inflammatory cascades associated with different mechanisms of plaque disruption and provide hypothesis generating data for personalized anti-inflammatory therapeutic allocation to ACS patients, a strategy that merits evaluation in future clinical trials.

Atlas of gut microbe-derived products from aromatic amino acids and risk of cardiovascular morbidity and mortality.

AIMS: Precision microbiome modulation as a novel treatment strategy is a rapidly evolving and sought goal. The aim of this study is to determine relationships among systemic gut microbial metabolite levels and incident cardiovascular disease risks to identify gut microbial pathways as possible targets for personalized therapeutic interventions. METHODS AND RESULTS: Stable isotope dilution mass spectrometry methods to quantitatively measure aromatic amino acids and their metabolites were used to examine sequential subjects undergoing elective diagnostic cardiac evaluation in two independent cohorts with longitudinal outcome data [US (n = 4000) and EU (n = 833) cohorts]. It was also used in plasma from humans and mice before vs. after a cocktail of poorly absorbed antibiotics to suppress gut microbiota. Multiple aromatic amino acid-derived metabolites that originate, at least in part, from gut bacteria are associated with incident (3-year) major adverse cardiovascular event (MACE) risks (myocardial infarction, stroke, or death) and all-cause mortality independent of traditional risk factors. Key gut microbiota-derived metabolites associated with incident MACE and poorer survival risks include: (i) phenylacetyl glutamine and phenylacetyl glycine (from phenylalanine); (ii) p-cresol (from tyrosine) yielding p-cresol sulfate and p-cresol glucuronide; (iii) 4-OH-phenyllactic acid (from tyrosine) yielding 4-OH-benzoic acid and 4-OH-hippuric acid; (iv) indole (from tryptophan) yielding indole glucuronide and indoxyl sulfate; (v) indole-3-pyruvic acid (from tryptophan) yielding indole-3-lactic acid and indole-3-acetyl-glutamine, and (vi) 5-OH-indole-3-acetic acid (from tryptophan). CONCLUSION: Key gut microbiota-generated metabolites derived from aromatic amino acids independently associated with incident adverse cardiovascular outcomes are identified, and thus will help focus future studies on gut-microbial metabolic outputs relevant to host cardiovascular health.