Coronary Sinus Metabolite 12,13-diHOME Is a Novel Biomarker for Left Atrial Remodeling in Patients With Atrial Fibrillation.

BACKGROUND: 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) has shown potential in protecting against heart disease, but its relationship with atrial fibrillation (AF) remains unknown. METHODS: Coronary sinus (CS) and femoral vein blood samplings were synchronously collected from AF and non-AF subjects (paroxysmal supraventricular tachycardia or idiopathic premature ventricular complexes) who underwent catheter ablation. First, untargeted metabolomic profiling was performed in a discovery cohort (including 12 AF and 12 non-AF subjects) to identify the most promising CS or femoral vein metabolite. Then, the selected metabolite was further measured in a validation cohort (including 119 AF and 103 non-AF subjects) to confirm its relationship with left atrium remodeling and 1-year postablation recurrence of AF. Finally, the biological function of the selected metabolite was validated in a rapid-paced cultured HL-1 atrial cardiomyocytes model. RESULTS: Metabolomic analysis identified CS 12,13-diHOME as the most pronounced change metabolite correlated with left atrium remodeling in the discovery cohort. In the validation cohort, CS 12,13-diHOME was significantly lower in patients with AF than non-AF controls (84.32±20.13 versus 96.24±23.56 pg/mL; P<0.01), and associated with worse structural, functional, and electrical remodeling of left atrium. Multivariable regression analyses further demonstrated that decreased CS 12,13-diHOME was an independent predictor of 1-year postablation recurrence of AF (odds ratio, 0.754 [95% CI, 0.648-0.920]; P=0.005). Biological function validations showed that 12,13-diHOME treatment significantly protect the cell viability, improved the expression of MHC (myosin heavy chain) and Cav1.2 (L-type calcium channel α1c), and attenuated mitochondrial damage in the rapid-paced cultured HL-1 cardiomyocytes model. CONCLUSIONS: CS metabolite 12,13-diHOME is decreased in patients with AF and can serve as a novel biomarker for left atrium remodeling.

A MicroRNA Signature in Acute Coronary Syndrome Patients and Modulation by Colchicine.

BACKGROUND: Circulating microRNAs (miRNAs) may play a pathogenic role in acute coronary syndromes (ACS). It is not yet known if miRNAs dysregulated in ACS are modulated by colchicine. We profiled miRNAs in plasma samples simultaneously collected from the aorta, coronary sinus, and right atrium in patients with ACS. METHODS: A total of 396 of 754 miRNAs were detected by TaqMan real-time polymerase chain reaction from EDTA-plasma in a discovery cohort of 15 patients (n = 3 controls, n = 6 ACS standard therapy, n = 6 ACS standard therapy plus colchicine). Fifty-one significantly different miRNAs were then measured in a verification cohort of 92 patients (n = 13 controls, n = 40 ACS standard therapy, n = 39 ACS standard therapy plus colchicine). Samples were simultaneously obtained from the coronary sinus, aortic root, and right atrium. RESULTS: Circulating levels of 30 of 51 measured miRNAs were higher in ACS standard therapy patients compared to controls. In patients with ACS, levels of 12 miRNAs (miR-17, -106b-3p, -191, -106a, -146a, -130a, -223, -484, -889, -425-3p, -629, -142-5p) were lower with colchicine treatment. Levels of 7 of these 12 miRNA were higher in ACS standard therapy patients compared to controls and returned to levels seen in control individuals after colchicine treatment. Three miRNAs suppressed by colchicine (miR-146a, miR-17, miR-130a) were identified as regulators of inflammatory pathways. MicroRNAs were comparable across sampling sites with select differences in the transcoronary gradient of 4 miRNA. CONCLUSION: The levels of specific miRNAs elevated in ACS returned to levels similar to control individuals following colchicine. These miRNAs may mediate ACS (via inflammatory pathways) or increase post-ACS risk, and could be potentially used as biomarkers of treatment efficacy.

Coronary Sinus Neuropeptide Y Levels and Adverse Outcomes in Patients With Stable Chronic Heart Failure.

Importance: Chronic heart failure (CHF) is associated with increased sympathetic drive and may increase expression of the cotransmitter neuropeptide Y (NPY) within sympathetic neurons. Objective: To determine whether myocardial NPY levels are associated with outcomes in patients with stable CHF. Design, Setting, and Participants: Prospective observational cohort study conducted at a single-center, tertiary care hospital. Stable patients with heart failure undergoing elective cardiac resynchronization therapy device implantation between 2013 and 2015. Main Outcomes and Measures: Chronic heart failure hospitalization, death, orthotopic heart transplantation, and ventricular assist device placement. Results: Coronary sinus (CS) blood samples were obtained during cardiac resynchronization therapy (CRT) device implantation in 105 patients (mean [SD] age 68 [12] years; 82 men [78%]; mean [SD] left ventricular ejection fraction [LVEF] 26% [7%]). Clinical, laboratory, and outcome data were collected prospectively. Stellate ganglia (SG) were collected from patients with CHF and control organ donors for molecular analysis. Mean (SD) CS NPY levels were 85.1 (31) pg/mL. On bivariate analyses, CS NPY levels were associated with estimated glomerular filtration rate (eGFR; rs = -0.36, P < .001); N-terminal-pro hormone brain natriuretic peptide (rs = 0.33; P = .004), and LV diastolic dimension (rs = -0.35; P < .001), but not age, LVEF, functional status, or CRT response. Adjusting for GFR, age, and LVEF, the hazard ratio for event-free (death, cardiac transplant, or left ventricular assist device) survival for CS NPY ≥ 130 pg/mL was 9.5 (95% CI, 2.92-30.5; P < .001). Immunohistochemistry demonstrated significantly reduced NPY protein (mean [SD], 13.7 [7.6] in the cardiomyopathy group vs 31.4 [3.7] in the control group; P < .001) in SG neurons from patients with CHF while quantitative polymerase chain reaction demonstrated similar mRNA levels compared with control individuals, suggesting increased release from SG neurons in patients with CHF. Conclusions and Relevance: The CS levels of NPY may be associated with outcomes in patients with stable CHF undergoing CRT irrespective of CRT response. Increased neuronal traffic and release may be the mechanism for elevated CS NPY levels in patients with CHF. Further studies are warranted to confirm these findings. Trial Registration: ClinicalTrials.gov identifier: NCT01949246.

Control of sinus venous valve and sinoatrial node development by endocardial NOTCH1.

AIMS: Sinus venous valve (SVV) and sinoatrial node (SAN) develop together at the sinoatrial junction during embryogenesis. SVV ensures unidirectional cardiac input and SAN generates sinus rhythmic contraction, respectively; both functions are essential for embryonic survival. We aim to reveal the potential role of endocardial NOTCH signalling in SVV and SAN formation. METHODS AND RESULTS: We specifically deleted Notch1 in the endocardium using an Nfatc1Cre line. This deletion resulted in underdeveloped SVV and SAN, associated with reduced expression of T-box transcription factors, Tbx5 andTbx18, which are essential for the formation of SVV and SAN. The deletion also led to decreased expression of Wnt2 in myocardium of SVV and SAN. WNT2 treatment was able to rescue the growth defect of SVV and SAN resulted from the Notch1 deletion in whole embryo cultures. Furthermore, the Notch1 deletion reduced the expression of Nrg1 in the SVV myocardium and supplement of NRG1 restored the growth of SVV in cultured Notch1 knockout embryos. CONCLUSION: Our findings support that endocardial NOTCH1 controls the development of SVV and SAN by coordinating myocardial WNT and NRG1 signalling functions.

Profiling of the plasma proteome across different stages of human heart failure.

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.

Association between Galectin-3 levels within central and peripheral venous blood, and adverse left ventricular remodelling after first acute myocardial infarction.

Our study investigates association between Galectin-3 levels and adverse left ventricular remodelling (LVR) at six months. Fifty-seven patients following first acute myocardial infarction (AMI) were enrolled in this study and blood samples collected on day 1 from the femoral vein and artery, the right atrium near the coronary sinus and the aortic root, and on day 30, from the cubital vein. Patients with LVESV ≥20% at six months, were included in the LVR group. On day 1, Galectin-3 plasma levels in the femoral vein (10.34 ng/ml ± 3.81 vs 8.22 ng/ml ± 2.34, p = 0.01), and near coronary sinus (10.7 ng/ml ± 3.97 vs 8.41 ng/ml ± 2.56, p = 0.007) were higher in the LVR group. Positive correlations between Galectin-3 levels from aortic root and coronary sinus, aortic root and femoral vein, and coronary sinus and femoral vein, were observed in both groups. On day 30, Galectin-3 concentration in the cubital vein was an independent risk factor of LVR six months post-AMI, demonstrating 1.5-fold increased risk. Day-30 Galectin-3 also showed positive correlations with echocardiography parameters indicative of diastolic and systolic dysfunction. Determining Galectin-3 plasma concentration on day 30 following AMI could have beneficial prognostic value in predicting LVR.

Neuropeptide-Y causes coronary microvascular constriction and is associated with reduced ejection fraction following ST-elevation myocardial infarction.

AIMS: The co-transmitter neuropeptide-Y (NPY) is released during high sympathetic drive, including ST-elevation myocardial infarction (STEMI), and can be a potent vasoconstrictor. We hypothesized that myocardial NPY levels correlate with reperfusion and subsequent recovery following primary percutaneous coronary intervention (PPCI), and sought to determine if and how NPY constricts the coronary microvasculature. METHODS AND RESULTS: Peripheral venous NPY levels were significantly higher in patients with STEMI (n = 45) compared to acute coronary syndromes/stable angina ( n = 48) or with normal coronary arteries (NC, n = 16). Overall coronary sinus (CS) and peripheral venous NPY levels were significantly positively correlated (r = 0.79). STEMI patients with the highest CS NPY levels had significantly lower coronary flow reserve, and higher index of microvascular resistance measured with a coronary flow wire. After 2 days they also had significantly higher levels of myocardial oedema and microvascular obstruction on cardiac magnetic resonance imaging, and significantly lower ejection fractions and ventricular dilatation 6 months later. NPY (100-250 nM) caused significant vasoconstriction of rat microvascular coronary arteries via increasing vascular smooth muscle calcium waves, and also significantly increased coronary vascular resistance and infarct size in Langendorff hearts. These effects were blocked by the Y1 receptor antagonist BIBO3304 (1 µM). Immunohistochemistry of the human coronary microvasculature demonstrated the presence of vascular smooth muscle Y1 receptors. CONCLUSION: High CS NPY levels immediately after reperfusion correlate with microvascular dysfunction, greater myocardial injury, and reduced ejection fraction 6 months after STEMI. NPY constricts the coronary microcirculation via the Y1 receptor, and antagonists may be a useful PPCI adjunct therapy.

NT-proBNP and CA 125 levels are associated with increased pro-inflammatory cytokines in coronary sinus serum of patients with chronic heart failure.

PURPOSE: Heart failure (HF) is considered to be a complex syndrome associated with neurohormonal and cytokine activation, that contribute to its progression. There are evidences which showed that, carbohydrate antigen 125 (CA 125), a tumor marker widely used for ovarian cancer therapy monitoring, was significantly elevated in HF patients. We hypothesized that inflammatory stimuli may be responsible for amino-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) and CA-125 production and release in chronic HF (CHF). We aimed to measure the levels of NT-proBNP, CA 125, pro-anti-inflammatory cytokines (IL-6, IL-1ß, IL-8, TNF-α and IL-4), from peripheral venous (PV) and coronary sinus (CS) blood samples, in patients with CHF and to assess their correlation with echocardiographic indices. METHODS: We enrolled 32 subjects (20M/12F) with CHF (III-IV NYHA functional class) who were to undergo cardiac resynchronization therapy (CRT) device implantation and 30 healthy controls (18M/12F). Two blood samples, from PV and CS, were collected at the time of CRT for each CHF patient. Serum levels of biomarkers were measured by ELISA. Cardiac function was assessed echocardiographically. RESULTS: All investigated biomarkers were significantly higher in CHF patients than in non-CHF controls (P < 0.001). There were positive correlations between biomarkers concentrations in PV and CS (r between 0.54 and 0.98, all P < 0.003). NT-proBNP, IL-6 and IL-1ß levels were 17%, 86% and 36% higher in CS than in PV, these increases being very well correlated each other, while CA 125 levels were 86% higher in PV than in CS. Moreover, CS NT-proBNP, CS IL-6 and CS IL-1ß serum concentrations were inversely related to the echocardiographically determined left ventricular ejection fraction (LVEF) (r = -0.61, P < 0.001; r = -0.71, P < 0.001 and r = -0.48, P = 0.005, respectively). A positive relationship was found between CA 125 and IL-1ß (r = 0.51, P = 0.003) in CS serum and between CA 125 and IL-6 (r = 0.43, P = 0.015), TNF-α (r = 0.46, P = 0.008) in PV serum. CA 125 concentrations were closely related to NT-proBNP both in CS (r = 0.46, P = 0.008) and PV (r = 0.52, P = 0.002). CONCLUSIONS: CS sampling of NT-proBNP, CA 125 and pro-anti-inflammatory cytokines provides an additional insight into the possible mechanisms by which these biomarkers lead to left ventricular remodeling. Our results clearly suggest that serum NT-proBNP and CA 125 levels not only in PV, but also in CS of patients with CHF, may be dependent on inflammation as a consequence of cytokine network activation.

Presence of cardiomyocytes exhibiting Purkinje-type morphology and prominent connexin45 immunoreactivity in the myocardial sleeves of cardiac veins.

BACKGROUND: Pulmonary vein (PV) myocardium is a known source of atrial fibrillation. A debated question is whether myocardial extensions into caval veins and coronary sinus (CS) have similar properties. No studies have documented specific pacemaker and/or conducting properties of human extracardiac myocardium. OBJECTIVE: The purpose of this study was to characterize the histology and immunohistochemical features of myocardial sleeves in the wall of cardiac veins. METHODS: Sections of 32 human hearts were investigated. Specimens of PVs, superior caval vein (SVC), CS, sinoatrial and atrioventricular nodes, and left ventricle were stained with Best's Carmine for selective staining of intracellular glycogen. Anti-connexin45 (Cx45)- and Cx43-specific antibodies were used to determine the conduction properties of extracardiac myocardium. RESULTS: Myocardial sleeve was found in the wall of PVs of 15 of 16 hearts, 21 of 22 SVCs, and 8 of 8 CSs. Bundles of glycogen-positive cardiomyocytes exhibiting pale cytoplasm and peripheral myofibrils were observed in the venous sleeves. Strong Cx45 and weak Cx43 labeling was detected in the extracardiac myocardium. Similar staining pattern was observed for the pacemaker and conduction system, whereas ventricular myocardium exhibited prominent Cx43 and no Cx45 immunoreactivity. CONCLUSION: Myocardial fibers of PVs, SVC, and CS exhibit morphology similar to that of Purkinje fibers and are enriched in glycogen. We provide data for the first time on prominent positive staining for Cx45 in the extracardiac myocardium, indicating its potential pacemaker and/or conducting nature.

Coronary Sinus Isoflurane Concentration in Cardiac Surgery.

OBJECTIVE: Volatile anesthetic agents such as isoflurane may be associated with fewer adverse myocardial events compared with total intravenous anesthesia in cardiac surgery. The authors aimed to determine whether reasonable isoflurane concentrations at tissue level were being achieved to protect the myocardium using this agent. The isoflurane concentration in myocardium has never been measured. The primary aim was to sample coronary sinus (CS) blood and measure its isoflurane concentration. Secondary aims were to determine whether the CS blood concentration would equilibrate with the arterial blood concentration and the relationship of CS blood concentration with oxygenator exhaust isoflurane concentrations during cardiopulmonary bypass (CPB). DESIGN: Prospective, observational study. SETTING: Single-center university hospital. PARTICIPANTS: The study comprised 23 patients undergoing cardiac surgery using CPB and isoflurane. MEASUREMENTS AND MAIN RESULTS: Shortly after initiation of CPB and insertion of a CS retrograde cardioplegia catheter but before aortic cross-clamping, CS blood was aspirated, followed by radial artery blood, which then were analyzed for isoflurane with gas chromatography and mass spectrometry. The oxygenator exhaust isoflurane level was measured with an anesthetic gas analyzer. The mean arterial and CS isoflurane concentrations were 87.7 ± 50.1 and 73.0 ± 42.9 µg/mL, respectively. There was a significant mean difference of 14.7 µg/mL (95% confidence interval 6.7-22.8) between CS and arterial isoflurane concentrations. Oxygenator exhaust isoflurane levels were correlated positively with those in the CS blood (r = 0.68, p < 0.001) and arterial blood (r = 0.72, p < 0.001). CONCLUSIONS: This was the first study in which CS blood was sampled and measured for isoflurane concentration. The CS isoflurane concentration could be estimated from the isoflurane concentration in the oxygenator exhaust gas. However, the value of this relationship is limited because the CS isoflurane concentration does not accurately represent its myocardial levels during CPB.

Sfrp5 identifies murine cardiac progenitors for all myocardial structures except for the right ventricle.

Upon acquirement of pulmonary circulation, the ancestral heart may have been remodelled coincidently with, or accompanied by, the production and rearrangement of progenitor cells. However, the progenitor populations that give rise to the left ventricle (LV) and sinus venosus (SV) are still ambiguous. Here we show that the expression of Secreted frizzled-related protein Sfrp5 in the mouse identifies common progenitors for the outflow tract (OFT), LV, atrium and SV but not the right ventricle (RV). Sfrp5 expression begins at the lateral sides of the cardiac crescent, excluding early differentiating regions, and continues in the venous pole, which gives rise to the SV. Lineage-tracing analysis revealed that descendants of Sfrp5-expressing cells at E7.5 contribute not only to the SV but also to the LV, atria and OFT and are found also in the dorsal splanchnic mesoderm accompanied by the expression of the secondary heart field marker, Islet1. These findings provide insight into the arrangement of cardiac progenitors for systemic circulation.

The Values of Coronary Circulating miRNAs in Patients with Atrial Fibrillation.

The mechanism of miRNA regulation in atrial fibrillation (AF) occurrence and development is still unclear, especially, the regulating values of coronary circulating miRNAs has not been reported. Based on our AF radiofrequency ablation clinical practice and previous miRNA study, we proposed a hypothesis that the coronary circulating miRNA might much better reflect the regulating state and metabolic level of myocardial miRNA in AF patient. To investigate the regulating values of coronary circulation miRNA, 90 AF patients were selected and compared with 90 healthy subjects, the changes of coronary circulating miRNA differential expression profile in the whole genome were observed in this study. We found out that compared with autologous peripheral blood (PB), 6 miRNAs were upregulated and 8 miRNA downregulated in AF patients' coronary sinus blood (CSB) significantly, especially, the expression of miR-1266, miR-4279 and miR-4666a-3p were obviously increased. Compared with normal donors' peripheral blood, 16 miRNAs were upregulated and 24 miRNAs downregulated dramatically in patients' peripheral blood, among them, the miR-3171 decreased, but miR-892a and miR-3149 increased significantly from the early to end stages of AF. Our results indicated that the coronary circulating miRNA can really reflect the regulating values of miRNA in AF patient; the level of miRNA change in 3 types of AF may reflect the severity of AF clinical and pathophysiological advance; The miR-892a, miR-3171 and miR-3149 may be used as biomarkers for earlier diagnosis, while miR-1266, miR-4279 and miR-4666a-3p may serve as potential intervening targets for AF patient in future.

Short-term prognostic value of perioperative coronary sinus-derived-serum cardiac troponin-I, creatine kinase-MB, lactate, pyruvate, and lactate-pyruvate ratio in adult patients undergoing open heart surgery.

OBJECTIVES: To investigate the release pattern of different cardiac metabolites and biomarkers directly from the coronary sinus (CS) and to establish the diagnostic discrimination limits of each marker protein and metabolites to evaluate perioperative myocardial injury in patients undergoing cardiac surgery under cardiopulmonary bypass (CPB). PATIENTS AND METHODS: Sixty-eight patients undergoing first mitral and/or aortic valve replacements with/without coronary artery bypass grafting and Bentall procedure under CPB and blood cardioplegic arrest were studied. All cardiac metabolites and biomarkers were measured in serial CS-derived blood samples at pre-CPB, immediate post aortic declamping, 10 minutes post-CPB and 12 hrs post-CPB. RESULTS: Receiver operating characteristic curve analysis of cardiac biomarkers indicated lactate-pyruvate ratio as the superior diagnostic discriminator of myocardial injury with an optimal "cut-off" value >10.8 immediately after aortic declamping (AUC, 0.92; 95% CI: 0.85-0.98). Lactate was the second best diagnostic discriminator of myocardial injury with an optimal "cut-off" value >2mmol/l at immediately after aortic declamping (AUC, 0.89; 95% CI: 0.80-0.96). Cardiac troponin-I was the third best diagnostic discriminator of myocardial injury with an optimal "cut-off" value >2.1ng/ml at immediately after aortic declamping (AUC, 0.88; 95% CI: 0.80-0.95). Creatine kinase-MB was the fourth best diagnostic discriminator of myocardial injury with an optimal "cut-off" value >58 log units/ml prior to decanulation (AUC, 0.85; 95% CI: 0.78-0.94). CONCLUSIONS: Measurable cardiac damage exists in all patients undergoing cardiac surgery under cardioplegic arrest. The degree of myocardial injury is more in patients with poor ventricular function and those requiring longer aortic clamp time. CS-derived lactate-pyruvate ratio, lactate, cTn-I served as superior diagnostic discriminators of peri-operative myocardial damage.

Correlation between C-reactive protein in peripheral vein and coronary sinus in stable and unstable angina.

BACKGROUND: High sensitivity C-reactive protein (hs-CRP) is commonly used in clinical practice to assess cardiovascular risk. However, a correlation has not yet been established between the absolute levels of peripheral and central hs-CRP. OBJECTIVE: To assess the correlation between serum hs-CRP levels (mg/L) in a peripheral vein in the left forearm (LFPV) with those in the coronary sinus (CS) of patients with coronary artery disease (CAD) and a diagnosis of stable angina (SA) or unstable angina (UA). METHODS: This observational, descriptive, and cross-sectional study was conducted at the Instituto do Coração, Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, and at the Hospital Beneficência Portuguesa de Sao Paulo, where CAD patients referred to the hospital for coronary angiography were evaluated. RESULTS: Forty patients with CAD (20 with SA and 20 with UA) were included in the study. Blood samples from LFPV and CS were collected before coronary angiography. Furthermore, analysis of the correlation between serum levels of hs-CRP in LFPV versus CS showed a strong linear correlation for both SA (r = 0.993, p < 0.001) and UA (r = 0.976, p < 0.001) and for the entire sample (r = 0.985, p < 0.001). CONCLUSION: Our data suggest a strong linear correlation between hs-CRP levels in LFPV versus CS in patients with SA and UA.

Coronary sinus biomarker sampling compared to peripheral venous blood for predicting outcomes in patients with severe heart failure undergoing cardiac resynchronization therapy: the BIOCRT study.

BACKGROUND: A significant minority of patients receiving cardiac resynchronization therapy (CRT) remain nonresponsive to this intervention. OBJECTIVE: This study aimed to determine whether coronary sinus (CS) or baseline peripheral venous (PV) levels of established and emerging heart failure (HF) biomarkers are predictive of CRT outcomes. METHODS: In 73 patients (aged 68 ± 12 years; 83% men; ejection fraction 27% ± 7%) with CS and PV blood samples drawn simultaneously at the time of CRT device implantation, we measured amino-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3 (gal-3), and soluble ST2 (sST2) levels. NT-proBNP concentrations >2000 pg/mL, gal-3 concentrations >25.9 ng/mL, and sST2 concentrations >35 ng/mL were considered positive on the basis of established PV cut points for identifying "high-risk" individuals with HF. CRT response was adjudicated by the HF Clinical Composite Score. A major adverse cardiovascular event (MACE) was defined as the composite end point of death, cardiac transplant, left ventricular assist device, and HF hospitalization at 2 years. RESULTS: NT-proBNP concentrations were 20% higher in the CS than in the periphery, while gal-3 and sST2 concentrations were 10% higher in the periphery than in the CS (all P < .001). There were 45% CRT nonresponders at 6 months and 16 (22%) patients with MACE. Triple-positive CS values yielded the highest specificity of 95% for predicting CRT nonresponse. Consistently, CS strategies identified patients at higher risk of developing MACE, with >11-fold adjusted increase for triple-positive CS patients compared to triple-negative patients (all P ≤ .04). PV strategies were not predictive of MACE. CONCLUSION: Our findings suggest that CS sampling of HF biomarkers may be better than PV sampling for predicting CRT outcomes. Larger studies are needed to confirm our findings.

Significance of soluble lectin-like oxidized LDL receptor-1 levels in systemic and coronary circulation in acute coronary syndrome.

BACKGROUND: Soluble lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) level is a novel biomarker for diagnosis of acute coronary syndrome (ACS); however, this level in the coronary circulation has yet to be examined. METHODS: Twenty-seven consecutive patients with ACS and 40 patients with effort angina pectoris (EAP) undergoing percutaneous coronary intervention (PCI) had levels of soluble LOX-1 and LOX-1 index measured in paired blood samples from aorta (Ao) and coronary sinus (CS) just prior to the PCI. RESULTS: We found positive correlations between soluble LOX-1 levels in the Ao and CS in both ACS and EAP patients (P < 0.01, for both). The soluble LOX-1 levels in the Ao and CS were higher in ACS than in EAP patients (P < 0.01, for both). The levels of soluble LOX-1 and LOX-1 index of the CS were significantly greater than those of the Ao in both ACS and EAP patients (P < 0.01, for both). Receiver operating characteristic curves for ACS detection demonstrated high sensitivity and specificity for the soluble LOX-1 and LOX-1 index with no differences between the Ao and CS. CONCLUSIONS: The present study showed that circulating soluble LOX-1 originates from coronary circulation and soluble LOX-1 and LOX-1 index are useful biomarkers for ACS.

Osteoprotegerin is secreted into the coronary circulation: a possible association with the renin-angiotensin system and cardiac hypertrophy.

The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67±10 years old, male 57%, hypertension 73%, coronary artery disease 50%) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7±4.1 vs. 6.7±3.6 pmol/l, p<0.001). The trans-cardiac OPG concentration was significantly (p=0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients subgroup who did not take an ACEI/ARB (n=27), the trans-cardiac OPG level was positively correlated with age (r=0.396, p=0.041) and relative wall thickness of left ventricle (r=0.534, p=0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p=0.004). Moreover, trans-cardiac OPG was significantly (p=0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased (≥116 for males, or ≥ 104 for females, g/m(2)) or not (p=0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system.

B-type natriuretic peptide forms within the heart, coronary sinus, and peripheral circulation in humans: evidence for degradation before secretion.

BACKGROUND: The B-type natriuretic peptides (BNP and N-terminal pro-BNP) are secreted by the heart and, in the case of BNP, serve to maintain circulatory homeostasis through renal and vascular actions and oppose many effects of the renin-angiotensin system. Recent evidence suggests that in patients with severe heart failure, circulating immunoreactive BNP is made up mainly of metabolites that may have reduced bioactivity. We hypothesized that BNP may be degraded before it even leaves the heart. METHODS: Peripheral venous plasma plus atrial and ventricular tissue, obtained from explanted hearts at the time of transplantation, were collected from 3 patients with end-stage heart failure. In a separate study, plasma was collected from the coronary sinus and femoral artery of 3 separate patients undergoing cardiac catheterization. Plasma C18 reverse-phase extracts were separated on reverse-phase HPLC, and the collected fractions were subjected to RIAs with highly specific antisera directed to the amino- and carboxy-terminal ends of BNP(1-32). RESULTS: ProBNP, BNP(1-32), and 2 major BNP metabolites were present in atrial and ventricular tissue, where BNP(1-32) represented 45% and 70% of total processed BNP, respectively. Neither BNP(1-32) nor the 2 metabolites were detected in peripheral venous plasma. Nor was BNP(1-32) detected in matching coronary sinus and femoral artery plasma from the 3 patients undergoing cardiac catheterization. CONCLUSIONS: BNP(1-32) is partly degraded within the hearts of patients with end-stage heart failure, and even in patients with relatively well-preserved left ventricular systolic function, only BNP metabolites enter the systemic circulation.

Incremental diagnostic value of circulating pentraxin in patients with intermediate risk of coronary artery disease.

OBJECTIVES: Pentraxins are a superfamily of multifunctional conserved proteins, some of which are components of the humoral arm of innate immunity and behave as functional ancestors of antibodies. They are divided into short (C reactive protein) and long pentraxins (pentraxin 3; PTX3). We investigated the diagnostic values of systematic arterial and coronary sinus (PTX3) in developing prediction models for estimating pretest probability of coronary artery disease (CAD) among an intermediate-risk population of patients with chronic stable angina. DESIGN: Cross-sectional analysis. SETTING: Referral cardiology hospital. PARTICIPANTS: Patients with chronic stable angina, without evidence of previous CAD if they were referred for angiography. MAIN OUTCOME MEASURES: All participants underwent diagnostic angiography. Prevalence rate ratio (PRR) of angiographically-determined coronary artery stenosis was separately examined in association with coronary sinus and femoral artery PTX3 concentrations using a general linear model. Duke treadmill score (DTS) was derived from the results of treadmill exercise cardiac stress testing. PTX3 data were collected in 100 patients with DTS-determined intermediate-risk chronic stable angina (aged 56.1 (1.1) years, 51 female). RESULTS: Both coronary sinus (PRR: 2.33, 95% CIs 1.64 to 3.31) and femoral artery PTX3 (PRR: 2.09, 95% CIs 1.46 to 2.97) independently predicted the prevalence rate of coronary artery involved with stenosis independent of the established CAD risk factors. Femoral artery PTX3 was highly correlated with coronary sinus PTX3 (ß=0.8, 95% CIs 0.66 to 0.94; p value<0.001). When we added femoral artery PTX3 to the predictive models incorporating traditional CAD risk factors, net reclassification improvement indices were 40% (cutpoint-free) and 15% (cutpoint-based). In the presence of PTX3, high-density lipoprotein cholesterol (HDL-C) was no longer protective against CAD. CONCLUSIONS: Gathering information on systemic arterial PTX3 may help more accurately reclassify DTS-determined patients with intermediate-risk chronic stable angina into more appropriate risk categories. PTX3 possibly, at least in part, mediates the protective effect on CAD of HDL-C.