Metabolomics is the systematic study of the unique chemical fingerprints of small-molecules, or metabolite profiles, that are related to a variety of cellular metabolic processes in a cell, organ, or organism. While mRNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling provides direct and indirect physiologic insights that can potentially be detectable in a wide range of biospecimens. Although not specific to cardiac conditions, translating metabolomics to cardiovascular biomarkers has followed the traditional path of biomarker discovery from identification and confirmation to clinical validation and bedside testing. With technological advances in metabolomic tools (such as nuclear magnetic resonance spectroscopy and mass spectrometry) and more sophisticated bioinformatics and analytical techniques, the ability to measure low-molecular-weight metabolites in biospecimens provides a unique insight into established and novel metabolic pathways. Systemic metabolomics may provide physiologic understanding of cardiovascular disease states beyond traditional profiling, and may involve descriptions of metabolic responses of an individual or population to therapeutic interventions or environmental exposures.
Approximately 20% of patients with idiopathic dilated cardiomyopathy (iDCM) have autoantibodies (AAbs) specific to cardiac troponin-I (cTnI). However, there has been no work evaluating active cellular autoimmunity. We aimed to identify a cTnI-stimulated cellular autoimmune response and to correlate our findings with cTnI AAb production.
Samples were obtained from stable ambulatory iDCM patients and healthy controls. Peripheral blood monocytes were incubated with cTnI, and cellular proliferation was measured using flow cytometry. AAbs against cTnI were detected by ELISA.
A positive cellular proliferative response to cTnI was identified in 20.5% (9/44) patients with iDCM and 5.7% (2/35) of healthy controls (p < 0.05). Positive cTnI AAbs were identified in 20% (7/35) of healthy controls and 13.6% (6/44) of patients with iDCM (p = NS). The presence of cTnI AAbs did not correlate with a positive cellular proliferative response. However, patients with iDCM who had an AAb response to cTnI were less likely to be taking a statin (p < 0.05).
A cellular autoimmune response to cTnI is demonstrated in a subset of patients with iDCM. However, the presence of a cellular response did not correlate with the presence of AAbs to the same antigen.
Galectin-3 plays an important role in fibroblast activation and fibrosis in animal models. Elevated galectin-3 levels are associated with poor long-term survival in heart failure (HF). We examined the relation between plasma galectin-3 levels and myocardial indices of systolic HF. We measured plasma galectin-3 in 133 chronic HF and 45 advanced decompensated HF subjects with echocardiographic and hemodynamic evaluation. In our chronic HF cohort, median plasma galectin-3 level was 13.9ng/mL [interquartile range: 12.1–16.9ng/mL]. Higher galectin-3 was associated with more advanced age (r=0.22, p=0.010) and poor renal function (estimated glomerular filtration rate [eGFR]: r= −0.24, p=0.007; cystatin C: r= 0.38, p<0.0001), and predicted all-cause mortality (Hazard ratio [HR] 1.86 [95% confidence interval: 1.36–2.54], p<0.001). In multivariate analysis, galectin-3 remained an independent predictor of all-cause mortality after adjusting for age, eGFR, left ventricular (LV) ejection fraction (EF), and mitral E/septal Ea (HR 1.94 [1.30–2.91], p=0.001). However, galectin-3 did not predict the combined endpoint of all-cause mortality, cardiac transplantation, or HF hospitalization (p>0.05). Furthermore, there were no relations between galectin-3 and LV end-diastolic volume index (r= −0.05, p=0.61), LVEF (r= 0.10, p=0.25), or LV diastolic function (mitral E/septal Ea: r= 0.06, p=0.52; left atrial volume index: r= 0.08, p=0.41). In our advanced decompensated HF cohort, we did not observe any relation between galectin-3 and echocardiographic or hemodynamic indices. In conclusion, high plasma galectin-3 levels were associated with renal insufficiency and poorer survival in patients with chronic systolic HF. However, we did not observe a relation between galectin-3 and echocardiographic or hemodynamic indices.
Heart failure; galectin-3; renal function; prognosis
Neutrophil gelatinase-associated lipocalin (NGAL) is released by renal tubular cells in response to inflammation and injury. Recent studies have demonstrated that NGAL is upregulated in cardiomyocytes within the failing myocardium. However, the overall relationship between systemic NGAL levels and myocardial structure and performance has not been established.
Methods and Results
We measured systemic NGAL levels in 130 subjects with chronic systolic heart failure (HF) and comprehensive echocardiographic evaluation, as well as 69 subjects with acute decompensated systolic HF and hemodynamic evaluation. In the chronic HF cohort, higher plasma NGAL levels were modestly associated with increasing age (r= 0.18, p=0.035), higher NYHA class (rank sums, p=0.022) and impaired renal function (eGFR: r= −0.53, p<0.0001; cystatin C: r= 0.60, p<0.0001). Plasma NGAL levels were modestly associated with indices of diastolic dysfunction (mitral E/Ea: r= 0.27, p=0.002; LAVi, r= 0.25, p=0.011; tricuspid E/Ea: r= 0.20, p=0.029), but not after adjustment for renal function (p>0.10 for all). In Cox proportional hazards analysis, plasma NGAL predicted cardiac death or transplantation after adjustment for age, gender, LVEF, and mitral E/Ea (Hazard ratio 1.68, 95% confidence interval 1.08 – 2.57, p=0.022), but not after adjustment for renal function (p=0.83). In the acute HF cohort, we did not observe any relationship between NGAL and hemodynamic indices, but NGAL strongly correlated with renal function.
Systemic NGAL levels are largely determined by underlying impairment of renal rather than myocardial function. Our findings did not support any relationship or prognostic significance between systemic NGAL levels and indices of cardiac structure and function after adjustment for underlying renal function.
Congestive heart failure; NGAL; renal insufficiency; cardio-renal
n-3 PUFAs; heart failure; nonischemic cardiomyopathy; functional capacity; NYHA class
Early transmitral velocity / tissue Doppler mitral annular early diastolic velocity (E/Ea) has been correlated with pulmonary capillary wedge pressure (PCWP) in a wide variety of cardiac conditions. The objective of this study was to determine the reliability of mitral E/Ea for predicting PCWP in patients admitted for advanced decompensated heart failure (ADHF).
Methods and Results
Prospective consecutive patients with ADHF (ejection fraction [EF] ≤30%, NYHA class III-IV symptoms) underwent simultaneous echocardiographic and hemodynamic evaluation on admission and after 48 hours of intensive medical therapy. A total of 106 patients were included (mean age 57 ±12 years, EF 24 ±8%, PCWP 21 ±7 mmHg, mitral E/Ea 20 ±12). There was a lack of correlation between mitral E/Ea and PCWP, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy. Overall, mitral E/Ea was similar among patients with PCWP > and ≤ 18 mmHg, and sensitivity and specificity for mitral E/Ea > 15 to identify a PCWP > 18 mmHg was 66% and 50%, respectively. Contrary to prior reports, we did not observe any direct association between changes in PCWP and changes in mitral E/Ea.
In decompensated patients with advanced systolic heart failure, tissue Doppler derived mitral E/Ea may not be as reliable in predicting intracardiac filling pressures, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy.
heart failure; hemodynamics; diastole; remodeling; echocardiography
Right ventricular (RV) systolic dysfunction is a strong predictor of adverse outcomes in heart failure, yet quantitatively assessing the impact of therapy on this condition is difficult. Our objective was to compare the clinical significance of changes in RV echocardiographic indices in response to intensive medical treatment in patients admitted to the hospital with acute decompensated heart failure (ADHF).
Methods and Results
Serial comprehensive echocardiography was performed in 62 consecutive patients with ADHF, and adverse events (death, cardiac transplantation, assist device, heart failure rehospitalization) were prospectively documented. RV peak systolic strain was assessed using speckle-tracking longitudinal strain analysis as the average of the basal, mid-, and apical segment of the RV free wall. Other conventional parameters of RV function (RV fractional area change, RV myocardial performance index, tricuspid annular peak systolic excursion, and tissue Doppler peak tricuspid annular systolic velocity) were measured for comparison. In our study cohort [left ventricular ejection fraction, 26±10%; cardiac index, 2.0±0.6 L/(min · m2)], overall mean RV peak systolic strain was –14±4% at baseline and –15±4% at 48 to 72 hours (P=0.27). Among all the RV functional indices measured, only RV peak systolic strain at 48 to 72 hours was associated with adverse events (P=0.02). In particular, improvement in RV peak systolic strain after intensive medical treatment was associated with lower adverse events in this patient population (26% versus 78%; hazard ratio, 0.13; 95% CI, 0.02 to 0.84; P=0.02).
Dynamic improvement in RV mechanics in response to intensive medical therapy was associated with lower long-term adverse events in patients with ADHF than in patients not showing improvement.
echocardiography; heart failure; hemodynamics; prognosis; right ventricle
Measurement of impedance is becoming increasingly available in the clinical setting as a tool for assessing hemodynamics and volume status in patients with heart failure. The 2 major categories of impedance assessment are the band electrode method and the implanted device lead method. The exact sources of the impedance signal are complex and can be influenced by physiologic effects such as blood volume, fluid, and positioning. This article provides a critical review of our current understanding and promises of impedance measurements, the techniques that have evolved, as well as the evidence and limitations regarding their clinical applications in the setting of heart failure management.
Dilated cardiomyopathy is a devastating disease associated with poor outcomes. Although the etiology of this disease remains largely unknown, so-called “idiopathic” dilated cardiomyopathy (iDCM) is associated with evidence of an autoimmune process that may be contributing to the pathophysiology of this disease. Indeed, iDCM shares many characteristics with other autoimmune diseases, including an association with systemic and organ-specific inflammation, an association with viral infections, a genetic predisposition, and a correlation with specific human leukocyte antigen subtypes.
Additionally, numerous pathologic cardiac-specific autoantibodies have been associated with iDCM, including those against α-myosin, the β1-adrenoceptor, and cardiac troponin I.
This review highlights the emerging evidence regarding autoimmune characteristics of iDCM, and summarizes the data of specific immunomodulatory therapies used to target autoimmune mechanisms in the treatment of patients with this devastating disease.
Autoimmune; heart failure; immunoadsorption; intravenous immunoglobulin; inflammation
Reduced cardiac output is traditionally believed to be the main determinant of worsening renal function (WRF) in advanced decompensated heart failure (ADHF).
To determine if venous congestion, rather than impairment of cardiac output, is primarily associated with the development of WRF in ADHF.
A total of 145 consecutive patients admitted with ADHF treated with intensive medical therapy guided by pulmonary artery catheter were studied. WRF was defined as an increase of serum creatinine ≥0.3 mg/dl during hospitalization.
In the study cohort (age 57 ±14 years, cardiac index 1.9 ±0.6 l/kg.m2, LVEF 20 ±8%, serum creatinine 1.7 ±0.9 mg/dl), 58 patients (40%) developed WRF. Patients who developed WRF had a higher central venous pressure on admission (CVP, 18 ±7 versus 12 ±6 mmHg, p<0.001) and after intensive medical therapy (11 ±8 versus 8 ±5 mmHg, p=0.04). The development of WRF occurred less frequently in patients that achieved a CVP <8 mmHg (p=0.01). Furthermore, the ability of CVP to stratify risk for development of WRF was apparent across the spectrum of systemic blood pressure, pulmonary capillary wedge pressure, cardiac index, and estimated glomerular filtration rates.
Venous congestion is the most important hemodynamic factor driving WRF in decompensated patients with advanced heart failure.
worsening renal function; venous congestion; cardiac index; decompensated heart failure
Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein–associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr71), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other’s function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function.
Acute kidney injury (AKI) is a strong predictor of adverse events with an incompletely understood pathophysiology. Neutrophil gelatinase-associated lipocalin (NGAL) is proposed as an early marker of renal tubular injury. Our aim is to determine whether AKI during treatment of acute decompensated heart failure (ADHF) is accompanied by renal tubular injury.
Methods and results
Urinary NGAL (uNGAL) and urinary creatinine (uCreat) levels were measured in 141 consecutive patients hospitalized for ADHF and followed for 180 days for death or re-hospitalization. AKI was defined as a rise in serum creatinine ≥0.3 mg/dl in a 48 h period. Median uNGAL/uCreat levels on Day 1 (baseline) were similar between patients who did and did not develop AKI [22.8 (12.5–106.8) μg/g vs. 20.6 (12.4–52.0) μg/g, P = 0.55]. On Day 2 and beyond, the difference between the AKI and no AKI cohorts increased, but was only significant on Day 3 [36.2 (21.7–131.8) μg/g vs. 29.4 (11.4–54.6) μg/g, P = 0.02]. The area under the receiver operating characteristic curve for Day 2 uNGAL/uCreat (≥ or <32 µg/g) to predict AKI was 0.61. There was no difference in diuretic response between ‘uNGAL/uCreat + ’ (≥ 27 µg/g) and ‘uNGAL/uCreat–’ (<27 µg/g) patients. However ‘uNGAL/uCreat + ’ patients had more adverse events after 180 days (66% vs. 52%, P = 0.02).
In patients with ADHF who develop AKI following diuretic therapy, a minor rise in uNGAL precedes AKI. However, the degree of renal tubular insult was much lower than that observed in other forms of AKI.
Acute decompensated heart failure; Cardio-renal syndrome; Diuretics; NGAL; Tubular injury
Early diastolic myocardial tissue Doppler (TD) velocities have reported to be reduced in mutation-positive patients with HCM in some studies even in the absence of left ventricular hypertrophy (LVH). Strain is a sensitive tool in detecting early systolic abnormalities in patients with hypertrophic cardiomyopathy (HCM). Our goal is to examine novel echocardiographic characteristics of phenotype-negative carriers for a known sarcomeric gene mutation for HCM.
We evaluated 41 consecutive subjects with a known myosin binding protein C3 (MYBPC3) mutation (c.3330+2T>G). Subjects who were mutation-positive without LVH (G+/LVH−, n=35) were compared to healthy controls (n=30) regarding tissue Doppler and segmental longitudinal strain measures.
The G+/LVH− group was similar to the normal controls with respect to chamber size, LV mass index, and most diastolic filling parameters, including tissue Doppler derived Ea. Global longitudinal strain was similar for both groups (20.3 ± 2.1 vs. 19.8 ± 1.8; p=0.36) although regional segment analysis showed a notable reduction in the basal septum (16.8 ± 3.1 vs. 19.0 ± 4.0%, p=0.02) and increase in the basal posterior (22.5 ± 5.2 vs. 17.9 ± 5.2, p=0.001) as well as mid posterior (21.8 ± 4.7 vs. 18.2 ± 3.0, p=0.001) walls.
In our cohort of phenotype-negative carriers of a specific MYBPC3 mutation, there were minimal differences in conventional 2-dimensional, Doppler, and speckle-tracking derived parameters of systolic and diastolic function compared to that of normal subjects. The presence of regional alterations in strain indicative of the presence of underlying subclinical disease requires further validation.
hypertrophic cardiomyopathy; genetic heart disease; echocardiography; longitudinal strain
Although myeloperoxidase (MPO) monitoring is predictive for cardiovascular outcomes in suspected acute coronary syndromes, the value of serial testing is unknown.
We investigated the relationship between serial MPO concentrations in 490 individuals with acute chest pain and incident major adverse cardiac events (MACE) during 6 months of follow-up. We measured MPO with the CardioMPO assay, and cardiac troponin I (cTnI), with the Abbott Architect assay.
Plasma MPO concentrations during the first 16 h were higher in individuals who experienced MACE. Higher MPO quartiles predicted a greater likelihood of 6-month MACE at baseline [OR (95% CI), 2.4 (1.4 – 4.1), P = 0.001 for highest vs lowest quartile] and all subsequent time points, with strongest predictive ability found in 16-h postbaseline samples [9.9 (4.7–20.9), P < 0.001 for highest vs lowest quartile]. MPO was predictive for MACE among individuals whose cTnI remained within reference intervals (<0.028 μg/L). The lowest rate of missed cases was found when MPO was <640 pmol/L at baseline and all other time points. Serial MPO monitoring predicted MACE risk better than baseline MPO measurements alone (c statistic 0.813 vs 0.602; P = 0.002), including in individuals whose cTnI remained within reference intervals (c statistic 0.903; P = 0.009). Combined serial cTnI and MPO testing improved accuracy for predicting 6-month MACE, reduced the number of missed MACE events from cTnI testing alone, and improved risk classification in 26.1% of patients.
MPO concentrations are predictive of outcome up to 16 h after presentation with chest pain and predict events missed by cTnI testing, supporting a potential role in rapid patient triage.
Soluble ST2 reflects activity of an IL-33 dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches.
Methods and Results
We determined the association between ST2 level and risk of death or transplantation in a multi-center prospective cohort of 1,141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic (ROC) analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2>36.3ng/ml) had a markedly increased risk of adverse outcomes compared to the lowest tertile (ST2≤22.3ng/ml), with an unadjusted hazard ratio (HR) of 3.2 (95%CI:2.2-4.7;p<0.0001) that remained significant after multivariable adjustment (adjusted HR 1.9[95%CI:1.3-2.9];p=0.002). In ROC analyses, the area under the curve (AUC) for ST2 was 0.75 (95%CI:0.69-0.79), which was similar to NT-proBNP (AUC 0.77 [95%CI:0.72-0.81];p=0.24 versus ST2), but lower than the Seattle Heart Failure Model (SHFM; AUC 0.81 ([95%CI:0.77-0.85];p=0.014 versus ST2). Addition of ST2 and NT-proBNP to the SHFM reclassified 14.9% of patients into more appropriate risk categories (p=0.017).
ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.
ST2; chronic heart failure; cardiomyopathy
Metabolomics studies hold promise for discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. A metabolomics approach was used to generate unbiased small molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine, namely choline, trimethylamine N-oxide (TMAO), and betaine, were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted up-regulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases (FMOs), an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidemic mice. Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for atherosclerotic heart disease.
metabolomics; atherosclerosis; intestinal microbiota; diet; phospholipid; choline
Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) at multiple loci that are significantly associated with coronary artery disease (CAD) risk. In this study, we sought to determine and compare the predictive capabilities of 9p21.3 alone and a panel of SNPs identified and replicated through GWAS for CAD.
Methods and Results
We used the Ottawa Heart Genomics Study (OHGS) (3323 cases, 2319 control subjects) and the Wellcome Trust Case Control Consortium (WTCCC) (1926 cases, 2938 control subjects) data sets. We compared the ability of allele counting, logistic regression, and support vector machines. Two sets of SNPs, 9p21.3 alone and a set of 12 SNPs identified by GWAS and through a model-fitting procedure, were considered. Performance was assessed by measuring area under the curve (AUC) for OHGS using 10-fold cross-validation and WTCCC as a replication set. AUC for logistic regression using OHGS increased significantly from 0.555 to 0.608 (P=3.59×10–14) for 9p21.3 versus the 12 SNPs, respectively. This difference remained when traditional risk factors were considered in a subgroup of OHGS (1388 cases, 2038 control subjects), with AUC increasing from 0.804 to 0.809 (P=0.037). The added predictive value over and above the traditional risk factors was not significant for 9p21.3 (AUC 0.801 versus 0.804, P=0.097) but was for the 12 SNPs (AUC 0.801 versus 0.809, P=0.0073). Performance was similar between OHGS and WTCCC. Logistic regression outperformed both support vector machines and allele counting.
Using the collective of 12 SNPs confers significantly greater predictive capabilities for CAD than 9p21.3, whether traditional risks are or are not considered. More accurate models probably will evolve as additional CAD-associated SNPs are identified.
coronary disease; genetics; risk factors
Angiotensin converting enzyme 2 (ACE2) is an endogenous counter-regulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established.
We measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF] ≤ 35%, NYHA class II-IV). Comprehensive echocardiography was performed at the time of blood sampling. We prospectively examined adverse clinical events (death, cardiac transplant, and heart failure hospitalizations) over 34 ± 17 months.
Patients who had higher sACE2 plasma activity were more likely to have a lower LVEF (Spearman’s r= −0.36, p <0.001), greater RV systolic dysfunction (r=0.33, p<0.001), higher estimated pulmonary artery systolic pressure (r=0.35, p=0.002), larger LV end diastolic diameter (r=0.23, p=0.02), and higher plasma NT-proBNP levels (r=0.35, p<0.001). sACE2 was less associated with diastolic dysfunction (r=0.19, p=0.05), and was similar between patients with ischemic and non-ischemic cardiomyopathies. There was no relationship between sACE2 activity and markers of systemic inflammation. After adjusting for NT-proBNP and LVEF, sACE2 activity remained an independent predictor of adverse clinical events (HR=1.7 [95% CI: 1.1 – 2.6], p=0.018).
Elevated plasma sACE2 activity was associated with greater severity of myocardial dysfunction and was an independent predictor of adverse clinical events.
Heart failure; ACE2; remodeling; angiotensin
Myeloperoxidase (MPO) concentrations predict adverse clinical outcomes in the setting of acute coronary syndromes and heart failure, but the prognostic role of MPO in stable patients with known atherosclerotic burden is unclear.
We examined plasma MPO concentrations and their relationship with prevalent significant coronary artery disease (defined as >50% stenosis in any coronary vessel) and incident major adverse cardiovascular events (MACEs), including death, myocardial infarction, and stroke, in a 3-year prospective follow-up study of 1895 patients undergoing elective coronary angiography.
The median plasma MPO concentration was 101 pmol/L (interquartile range 68–187 pmol/L). Patients with plasma MPO concentrations >322 pmol/L (14.6% of population) had increased risk of developing future MACEs [hazard ratio (HR) 1.78, 95% CI 1.33–2.37, P < 0.001], and MPO as a single variable predictor of MACE showed an area under the ROC curve of 0.67. After adjusting for traditional cardiac risk factors, creatinine clearance, B-type natriuretic peptide, and high-sensitivity C-reactive protein (hsCRP), increased MPO concentrations remained significantly associated with incident MACEs over the ensuing 3-year period (HR 1.71; 95% CI 1.27–2.30, P < 0.001). In patients with increased hsCRP, MPO ≤322 pmol/L was associated with lower event rates than observed with MPO >322 pmol/L.
Plasma MPO concentrations provide independent prognostic value for the prediction of long-term incident MACEs in a stable, medically managed patient population with coronary artery disease. In individuals with increased hsCRP concentrations, we observed lower risk of incident MACEs when concomitant MPO concentrations were low vs when MPO concentrations were high.
The presence of subclinical myocardial necrosis as a prodrome to longer term adverse cardiac event risk has been debated. The debate has focused predominantly within patients with acute coronary syndrome, and on issues of troponin assay variability and accuracy of detection, rather than the clinical significance of the presence of subclinical myocardial necrosis (i.e. “troponin leak”) within stable cardiac patients. Herein we examine the relationship between different degrees of subclinical myocardial necrosis and long-term adverse clinical outcomes within a stable cardiac patient population with essentially normal renal function.
Methods and Results
Sequential consenting patients (N=3,828; median creatinine clearance 100 ml/min/1.73m2) undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cutoff for defining myocardial infarction (<0.03 ng/mL) were evaluated. The relationship of subclinical myocardial necrosis with incident major adverse cardiovascular events (MACE, defined as any death, myocardial infarction, or stroke) over 3-year follow-up was examined. “Probable” (cTnI 0.001–0.008 ng/mL) and “definite” (cTnI 0.009 –0.029 ng/mL) subclinical myocardial necrosis were observed frequently within the cohort (34% and 18%, respectively). A linear relationship was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident MACE, particularly in those with cTnI 0.009 ng/mL or higher (Hazard Ratio 3.00, 95% confidence interval 2.4–3.8), even following adjustment for traditional risk factors, C-reactive protein (CRP), and creatinine clearance. The presence of subclinical myocardial necrosis was associated with elevations in acute phase proteins (CRP, ceruloplasmin, p<0.01 each) and reduction in systemic anti-oxidant enzyme activities (arylesterase, p<0.01), but showed no significant associations with multiple specific measures of oxidant stress, and borderline associations with myeloperoxidase, a marker of leukocyte activation.
In stable cardiology patients, prodromal subclinical myocardial necrosis is associated with substantially higher long-term risk for MACE. The underlying mechanisms contributing to this minimal troponin leak phenomenon warrants further investigation.
Coronary artery disease; myocardium; ischemia; troponin; atherosclerosis
We tested the hypothesis that right ventricular (RV) pressure overload affects RV function, and further influences left ventricular (LV) geometry that adversely affects LV twist mechanics and segmental function.
Methods and Results
Echocardiographic images were prospectively acquired in 44 (46±12 years; 82%F) patients with evidence of pulmonary hypertension (PH) (estimated pulmonary systolic pressure [PASP] =71±23 mmHg) and in 44 age and gender-matched healthy subjects. Patients with intrinsic LV diseases were excluded. RV lateral wall (RVLAT) longitudinal strain (LS) and interventricular septal (IVS) LS were reduced in PH group compared with controls (-15.9±7.6% vs.-25.5±6.1%, p<0.001 and -17.3±4.4% vs.-20.2±3.9%, p=0.002, respectively), while LV lateral wall (LVLAT) LS was preserved. RVLAT and IVS LS, but not LVLAT LS, correlated with PASP(r=0.56, p<0.01; r=0.32, p<0.01) and LV eccentricity index (LVEI) (r=0.57, p<0.01; r=0.57, p<0.01). IVS and LVLAT circumferential strains (CS) were both reduced in the PH group. Although IVS CS and LVLAT CS correlated with PASP and LVEI, after adjusting CS for LVEI, differences between groups persisted for IVS CS (p<0.01) but not LVLAT CS (p=0.09). LV torsion was decreased in patients with PH compared with controls (9.6±4.9° vs. 14.7±4.9°, p<0.001). LV torsion inversely correlated with PASP (r=-0.39, p<0.01) and LVEI (r=-0.3, p<0.01). LV untwisting rates were similar in both groups (p=0.7).
Chronic RV pressure overload directly affects RV longitudinal systolic deformation. RV pressure overload further influences IVS and LV geometry, which impairs LV torsion and segmental LS and CS, more for the IVS than the free wall of the LV.
Torsion; pulmonary hypertension; strain; echocardiography
Recognition of biological patterns holds promise for improved identification of patients at risk for myocardial infarction (MI) and death. We hypothesized that identifying high- and low-risk patterns from a broad spectrum of hematologic phenotypic data related to leukocyte peroxidase-, erythrocyte- and platelet-related parameters may better predict future cardiovascular risk in stable cardiac patients than traditional risk factors alone.
Methods and Results
Stable patients (n=7369) undergoing elective cardiac evaluation at a tertiary care center were enrolled. A model (PEROX) that predicts incident 1-year death and MI was derived from standard clinical data combined with information captured by a high-throughput peroxidase-based hematology analyzer during performance of a complete blood count with differential. The PEROX model was developed using a random sampling of subjects in a derivation cohort (n=5895) and then independently validated in a nonoverlapping validation cohort (n=1474). Twenty-three high-risk (observed in ≥10% of subjects with events) and 24 low-risk (observed in ≥10% of subjects without events) patterns were identified in the derivation cohort. Erythrocyte- and leukocyte (peroxidase)-derived parameters dominated the variables predicting risk of death, whereas variables in MI risk patterns included traditional cardiac risk factors and elements from all blood cell lineages. Within the validation cohort, the PEROX model demonstrated superior prognostic accuracy (78%) for 1-year risk of death or MI compared with traditional risk factors alone (67%). Furthermore, the PEROX model reclassified 23.5% (P<0.001) of patients to different risk categories for death/MI when added to traditional risk factors.
Comprehensive pattern recognition of high- and low-risk clusters of clinical, biochemical, and hematologic parameters provided incremental prognostic value in stable patients having elective diagnostic cardiac catheterization for 1-year risks of death and MI.
atherosclerosis; biological markers; cardiovascular diseases; hematology; myocardial infarction
We examine the relationship of related post-translational modification products of arginine methylation and coronary artery disease (CAD) phenotypes.
Methods and Results
Plasma was isolated from 1,011 consecutive consenting subjects undergoing elective diagnostic cardiac catheterization, and future major adverse cardiac events (MACE, including myocardial infarction, stroke, and death) at 3 years were investigated. Plasma levels of asymmetric dimethylarginine (ADMA, endogenous nitric oxide synthase [NOS] inhibitor), symmetric dimethylarginine (SDMA, which lacks NOS inhibitory activity), N-mono-methylarginine (MMA, a potent NOS inhibitor), methyl-lysine (Methyl-Lys, an unrelated methylated amino acid), arginine and its major catabolites (citrulline and ornithine) were quantified simultaneously by stable isotope dilution HPLC with on-line electrospray ionization tandem mass spectrometry and adjusted for traditional risk factors, C-reactive protein, and estimated creatinine clearance. High SDMA levels (adjusted odds ratio [OR] 1.6, 95%CI, 1.1-2.6, p<0.001), low MMA (adjusted OR 0.5, 95%CI 0.4-0.8, p=0.007), but not ADMA (adjusted OR 1.3, 95%CI 0.88-2.0, p=0.177) were associated with increased prevalence of significantly obstructive CAD. Elevated levels of SDMA (adjusted Hazard Ratio [HR] 2.4, 95%CI 1.2-4.6, p=0.009), ADMA (adjusted HR 2.2, 95%CI 1.2-4.0, p=0.015), as well as an integrated index of arginine methylation [ArgMI = (ADMA+SDMA)/MMA] (adjusted HR 2.4, 95%CI 1.3-4.5, p=0.006) were significant independent predictors of incident MACE. ArgMI was predictive of incident MACE even following adjustments for global arginine bioavailability, particularly within secondary prevention patients.
ADMA, SDMA and the integrated quantification of arginine methylation (in the form of a methylation index) provided independent risk prediction for both significantly obstructive CAD and incident MACE in stable patients undergoing cardiac evaluation. These results suggest that factors beyond direct NOS inhibition contribute to the clinical associations between methylarginines and CAD outcomes.
Nitric oxide; coronary artery disease; prognosis
We hypothesized that an integrated assessment of arginine with its catabolic products may better predict cardiovascular risks than arginine levels alone.
Arginine is the sole nitrogen source for nitric oxide (NO) synthesis. The major catabolic products of arginine are ornithine and citrulline.
Plasma levels of free arginine, ornithine, citrulline and the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) were measured using LC/MS/MS. We examined the relationship of global arginine bioavailability ratio (GABR, defined as arginine/[ornithine+citrulline]) vs. arginine and its catabolic metabolites to prevalence of coronary artery disease (CAD) and incidence of major adverse cardiovascular events (MACE = death, myocardial infarction, stroke) over a 3-year follow-up in 1,010 subjects undergoing elective cardiac catheterization.
Patients with CAD had significantly lower GABR [median(IQR); 1.06(0.75, 1.31) versus 1.27(0.96, 1.73), p<0.001] and arginine levels [mean: 68 ±20 μM versus 74 ±24 μM, p<0.001) than those without CAD. After adjusting for Framingham risk score, C-reactive protein, and renal function, lower GABR (but not arginine levels) and higher citrulline levels remained significantly associated with both prevalence of CAD [adjusted odds-ratio (OR) 3.93, p<0.001 and 5.98, p<0.001, respectively] and 3-year risk for incidence of MACE [adjusted Hazard ratio (HR) 1.98, p=0.025 and 2.40, p=0.01, respectively], and remained significant after adjusting for ADMA.
GABR may serve as a more comprehensive concept of reduced NO synthetic capacity compared to systemic arginine levels. Diminished GABR and high citrulline levels are associated with both development of atherosclerotic CAD and heightened long-term risk for major adverse cardiac events.
Arginine; nitric oxide; coronary artery disease; prognosis