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ABSTRACT: BACKGROUND: Cardiac resynchronization therapy (CRT) confers morbidity and mortality benefits to selected patients with heart failure. This systematic review examined effects of CRT in CKD patients (estimated GFR [eGFR] <60 ml/min per 1.73 m(2)). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: MEDLINE and Scopus (from 1990 to December 2012) and conference proceedings abstracts were searched for relevant observational studies and randomized controlled trials (RCTs). Studies comparing the following outcomes were included: (1) CKD patients with and without CRT and (2) CKD patients with CRT to non-CKD patients with CRT. Mortality, eGFR, and left ventricular ejection fraction data were extracted and pooled when appropriate using a random-effects model. RESULTS: Eighteen studies (14 observational studies and 4 RCTs) were included. There was a modest improvement in eGFR with CRT among CKD patients (mean difference 2.30 ml/min per 1.73m(2); 95% confidence interval, 0.33 to 4.27). Similarly, there was a significant improvement in left ventricular ejection with CRT in CKD patients (mean difference 6.24%; 95% confidence interval, 3.46 to 9.07). Subgroup analysis of three RCTs reported lower rates of death or hospitalization for heart failure with CRT (versus other therapy) in the CKD population. Survival outcomes of CKD patients (compared with the non-CKD population) with CRT differed among observational studies and RCTs. CONCLUSIONS: CRT improves left ventricular and renal function in the CKD population with heart failure. Given the increasing use of cardiac devices, further studies examining the effects of CRT on mortality in CKD patients, particularly those with advanced kidney disease, are warranted.
Clinical Journal of the American Society of Nephrology 05/2013; · 5.23 Impact Factor
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ABSTRACT: Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans.
We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography.
Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups.
The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.).
New England Journal of Medicine 04/2013; 368(17):1575-84. · 53.30 Impact Factor
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Robert A Koeth,
Zeneng Wang,
Bruce S Levison,
Jennifer A Buffa,
Elin Org,
Brendan T Sheehy,
Earl B Britt,
Xiaoming Fu,
Yuping Wu,
Lin Li, [......],
Hongzhe Li,
Gary D Wu,
James D Lewis,
Manya Warrier,
J Mark Brown,
Ronald M Krauss, W H Wilson Tang,
Frederic D Bushman,
Aldons J Lusis,
Stanley L Hazen
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ABSTRACT: Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary l-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of l-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma l-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary l-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.
Nature medicine 04/2013; · 27.14 Impact Factor
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ABSTRACT: Protein carbamylation, a posttranslational modification promoted during uremia and catalyzed by myeloperoxidase (MPO) at sites of inflammation, is linked to altered protein structure, vascular dysfunction, and poor prognosis. We examine the relationship between plasma protein-bound homocitrulline (PBHCit) levels, a marker of protein lysine residue carbamylation, with cardiorenal function and long-term outcomes in chronic systolic heart failure (HF).
In 115 patients with chronic systolic HF (left ventricular ejection fraction ≤35%), we measured plasma PBHCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. In our study cohort, the median PBHCit level was 87 (interquartile range 59-128) μmol/mol lysine. Higher plasma PBHcit levels were associated with poorer renal function (estimated glomerular filtration rate [eGFR]: Spearman r = -0.37; P < .001), cystatin C (r = 0.31; P = .001), and elevated plasma amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (r = 0.26; P = .006), but not with markers of systemic inflammation or oxidant stress (high-sensitivity C-reactive protein and myeloperoxidase [MPO]: P > .10 for each). Furthermore, elevated plasma PBHCit levels were not related to indices of cardiac structure or function (P > .10 for all examined) except modestly with increased right atrial volume index (r = 0.31; P = .002). PBHCit levels predicted adverse long-term events (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.3-2.6; P < .001), including after adjustment for age, eGFR, MPO, and NT-proBNP (HR 1.9, 95% CI 1.2-3.1; P = .006).
In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardiorenal indices of adverse prognosis.
Journal of cardiac failure 04/2013; 19(4):219-24. · 3.25 Impact Factor
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Xin-Min Li, W H Wilson Tang,
Marian K Mosior,
Ying Huang,
Yuping Wu,
William Matter,
Vivian Gao,
David Schmitt,
Joseph A Didonato,
Edward A Fisher,
Jonathan D Smith,
Stanley L Hazen
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ABSTRACT: OBJECTIVE: Diminished cholesterol efflux activity of apolipoprotein B (apoB)-depleted serum is associated with prevalent coronary artery disease, but its prognostic value for incident cardiovascular events is unclear. We investigated the relationship of cholesterol efflux activity with both prevalent coronary artery disease and incident development of major adverse cardiac events (death, myocardial infarction, or stroke).Approach and Results-Cholesterol efflux activity from free cholesterol-enriched macrophages was measured in 2 case-control cohorts: (1) an angiographic cohort (n=1150) comprising stable subjects undergoing elective diagnostic coronary angiography and (2) an outpatient cohort (n=577). Analysis of media from cholesterol efflux assays revealed that the high-density lipoprotein fraction (1.063<d<1.21) contained only a minority (≈40%) of [(14)C]cholesterol released, with the majority found within the lipoprotein particle-depleted fraction, where ≈60% was recovered after apolipoprotein A1 immunoprecipitation. Albumin immunoprecipitation recovered another ≈30% of radiolabel cholesterol within this fraction. Enhanced cholesterol efflux activity from ATP-binding cassette transporter A1-stimulated macrophages was associated with reduced risk of prevalent coronary artery disease in unadjusted models within both cohorts; however, the inverse risk relationship remained significant after adjustment for traditional coronary artery disease risk factors only within the outpatient cohort. Surprisingly, higher cholesterol efflux activity was associated with increase in prospective (3 years) risk of myocardial infarction/stroke (adjusted hazard ratio, 2.19; 95% confidence interval, 1.02-4.74) and major adverse cardiac events (adjusted hazard ratio, 1.85; 95% confidence interval, 1.11-3.06). CONCLUSIONS: Heightened cholesterol efflux to apoB-depleted serum was paradoxically associated with increased prospective risk for myocardial infarction, stroke, and death. The majority of released radiolabeled cholesterol from macrophages in cholesterol efflux activity assays does not reside within a high-density lipoprotein particle.
Arteriosclerosis Thrombosis and Vascular Biology 03/2013; · 6.37 Impact Factor
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ABSTRACT: Aspirin is rapidly hydrolyzed within erythrocytes by a heterodimer of PAFAH1b2/PAFAH1b3, but also in plasma by unidentified activity. Hydrolysis in both compartments is variable, with a 12-fold variation in plasma among 2,226 GeneBank patients. Platelet inhibition by aspirin was suppressed in plasma that rapidly hydrolyzed aspirin. Plasma aspirin hydrolysis was significantly higher in patients with coronary artery disease (CAD) compared to control subjects (16.5 ± 4.4 vs. 15.1 ± 3.7 nmol/ml/min; p=3.4×10-8). A genome-wide association study in 2,054 GeneBank subjects identified a single locus immediately adjacent to the butyrylcholinesterase gene (BCHE) associated with plasma aspirin hydrolytic activity (lead SNP rs6445035; p=9.1×10-17). However, its penetrance was low, and plasma from an individual with an inactivating mutation in BCHE still effectively hydrolyzed aspirin. A second aspirin hydrolase was identified in plasma, which purification showed to be homomeric PAF acetylhydrolase 1b2. This is distinct from the erythrocyte PAFAH1b2/PAFAH1b3 heterodimer. Inhibitors showed both BChE and PAFAH1b2 contribute to aspirin hydrolysis in plasma, with variation primarily reflecting non-genetic variation of butyrylcholinesterase activity. Therefore aspirin is hydrolyzed in plasma by two enzymes, butyrylcholinesterase and a new extracellular form of PAF acetylhydrolase, PAFAH1b2. Hydrolytic effectiveness varies widely primarily from non-genetic variation of butyrylcholinesterase activity that affect aspirin bioavailability in blood and the ability of aspirin to inhibit platelet aggregation.
Journal of Biological Chemistry 03/2013; · 4.77 Impact Factor
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Journal of the American College of Cardiology 03/2013; · 14.16 Impact Factor
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ABSTRACT: Adiponectin is an anti-inflammatory, antiatherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailability. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA), and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman's r = 0.41, P < 0.001) and NT-proBNP levels (r = 0.55, P < 0.001), inversely correlated with GABR (r = -0.39, P < 0.001), and were not associated with high-sensitivity C-reactive protein (P = 0.81) or myeloperoxidase (P = 0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r = 0.33, P = 0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sums P = 0.002), right ventricular (RV) systolic dysfunction (rank sums P = 0.002), and RV diastolic dysfunction (rank sums P = 0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (hazard ratio, 95% confidence interval 1.45 [1.02-2.07], P = 0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust in the setting of cardiac dysfunction or elevated natriuretic peptide levels.
Translational research : the journal of laboratory and clinical medicine. 03/2013;
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ABSTRACT: Traditional risk factors fail to explain the increased risk for cardiovascular morbidity and mortality in ESRD. Cyanate, a reactive electrophilic species in equilibrium with urea, posttranslationally modifies proteins through a process called carbamylation, which promotes atherosclerosis. The plasma level of protein-bound homocitrulline (PBHCit), which results from carbamylation, predicts major adverse cardiac events in patients with normal renal function, but whether this relationship is similar in ESRD is unknown. We quantified serum PBHCit in a cohort of 347 patients undergoing maintenance hemodialysis with 5 years of follow-up. Kaplan-Meier analyses revealed a significant association between elevated PBHCit and death (log-rank P<0.01). After adjustment for patient characteristics, laboratory values, and comorbid conditions, the risk for death among patients with PBHCit values in the highest tertile was more than double the risk among patients with values in the middle tertile (adjusted hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.5-3.9) or the lowest tertile (adjusted HR, 2.3; 95% CI, 1.5-3.7). Including PBHCit significantly improved the multivariable model, with a net reclassification index of 14% (P<0.01). In summary, seurm PBHCit, a footprint of protein carbamylation, predicts increased cardiovascular risk in patients with ESRD, supporting a mechanistic link among uremia, inflammation, and atherosclerosis.
Journal of the American Society of Nephrology 02/2013; · 9.66 Impact Factor
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ABSTRACT: OBJECTIVE
To investigate the relationship between different degrees of subclinical myocardial necrosis, glycemic control, and long-term adverse clinical outcomes within a stable patient population with diabetes mellitus.RESEARCH DESIGN AND METHODS
We examined 1,275 stable patients with diabetes mellitus undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (<0.03 ng/mL). The relationship of subclinical myocardial necrosis (cTnI 0.009-0.029 ng/mL) with incident major adverse cardiovascular events (MACE; defined as any death, myocardial infarction, or stroke) over 3 years of follow-up was examined.RESULTSSubclinical myocardial necrosis was observed in 22% of patients. A strong association was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident MACE (hazard ratio, 1.98; 95% confidence interval, 1.48-2.65; P < 0.001) and remained statistically significant even after adjustment for traditional risk factors, high-sensitivity C-reactive protein, and creatinine clearance. Only a weak correlation was observed between the presence of subclinical myocardial necrosis and either glycemic control (r = 0.06; P = 0.044 for hemoglobin A1C versus cTnI) or insulin resistance (r = 0.04; P = 0.094 for glucose-to-insulin ratio versus cTnI).CONCLUSION
The presence of detectable subclinical myocardial necrosis in stable patients with diabetes mellitus is associated with heightened long-term risk for MACE, independent of traditional risk factors and glycemic control.
Diabetes care 02/2013; · 8.09 Impact Factor
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Erika L Lundgrin,
Margaret M Park,
Jacqueline Sharp, W H Wilson Tang,
James D Thomas,
Kewal Asosingh,
Suzy A Comhair,
Frank P Difilippo,
Donald R Neumann,
Laura Davis,
Brian B Graham,
Rubin M Tuder,
Iva Dostanic,
Serpil C Erzurum
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ABSTRACT: Background: The development of tools to monitor the right ventricle in pulmonary arterial hypertension (PAH) is of clinical importance. PAH is associated with pathologic expression of the transcription factor hypoxia-inducible factor (HIF)-1α, which induces glycolytic metabolism and mobilization of proangiogenic progenitor (CD34(+)CD133(+)) cells. We hypothesized that PAH cardiac myocytes have a HIF-related switch to glycolytic metabolism that can be detected with fasting 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography (FDG-PET) and that glucose uptake is informative for cardiac function. Methods: Six healthy control subjects and 14 patients with PAH underwent fasting FDG-PET and echocardiogram. Blood CD34(+)CD133(+) cells and erythropoietin were measured as indicators of HIF activation. Twelve subjects in the PAH cohort underwent repeat studies 1 year later to determine if changes in FDG uptake were related to changes in echocardiographic parameters or to measures of HIF activation. Measurements and Results: FDG uptake in the right ventricle was higher in patients with PAH than in healthy control subjects and correlated with echocardiographic measures of cardiac dysfunction and circulating CD34(+)CD133(+) cells but not erythropoietin. Among patients with PAH, FDG uptake was lower in those receiving β-adrenergic receptor blockers. Changes in FDG uptake over time were related to changes in echocardiographic parameters and CD34(+)CD133(+) cell numbers. Immunohistochemistry of explanted PAH hearts of patients undergoing transplantation revealed that HIF-1α was present in myocyte nuclei but was weakly detectable in control hearts. Conclusions: PAH hearts have pathologic glycolytic metabolism that is quantitatively related to cardiac dysfunction over time, suggesting that metabolic imaging may be useful in therapeutic monitoring of patients.
Annals of the American Thoracic Society. 02/2013; 10(1):1-9.
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ABSTRACT: Systemic alterations in arginine bioavailability occur in heart failure (HF) patients with more advanced myocardial dysfunction and poorer clinical outcomes, and they improve with beta-blocker therapy.
We measured fasting plasma levels of L-arginine and related biogenic amine metabolites in 138 stable symptomatic HF patients with left ventricular ejection fraction ≤35% and comprehensive echocardiographic evaluation. Long-term adverse clinical outcomes (death and cardiac transplantation) were followed for 5 years. Lower global arginine bioavailability ratio (GABR; ratio of L-arginine to L-ornithine + L-citrulline) was associated with higher plasma natriuretic peptide levels, more advanced left ventricular diastolic dysfunction, and more severe right ventricular systolic dysfunction (all P < .001). Patients taking beta-blockers had significantly higher GABR than those not taking beta-blockers (0.86 [interquartile range (IQR) 0.68-1.17] vs 0.61 [0.44-0.89]; P < .001). Subjects with higher GABR experienced fewer long-term adverse clinical events (hazard ratio 0.61 [95% confidence interval 0.43-0.84]; P = .002). In an independent beta-blocker naïve patient cohort, GABR increased following long-term (6 month) beta-blocker therapy (0.89 [IQR 0.52-1.07] to 0.97 [0.81-1.20]; P = .019).
In patients with chronic systolic heart failure, diminished global L-arginine bioavailability is associated with more advanced myocardial dysfunction and poorer long-term adverse clinical outcomes. GABR levels improved with beta-blocker therapy.
Journal of cardiac failure 02/2013; 19(2):87-93. · 3.25 Impact Factor
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Kenneth Chan,
Riyaz S Patel,
Paul Newcombe,
Christopher P Nelson,
Atif Qasim,
Stephen E Epstein,
Susan Burnett,
Viola L Vaccarino,
A Maziar Zafari,
Svati H Shah, [......],
Akinori Kimura,
Wei-Feng Shen,
Iain A Simpson,
Stanley L Hazen,
Benjamin D Horne,
Elizabeth R Hauser,
Arshed A Quyyumi,
Muredach P Reilly,
Nilesh J Samani,
Shu Ye
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ABSTRACT: OBJECTIVES: The aim of this study was to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
Journal of the American College of Cardiology 01/2013; · 14.16 Impact Factor
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ABSTRACT: Worsening renal function (WRF) during treatment of acute decompensated heart failure (ADHF) is generally associated with adverse outcomes. An increase ≥0.3 mg/dL in creatinine level is widely used as the definition of WRF. The authors sought to determine the level of agreement between WRF based on changes in creatinine and changes in cystatin C (CysC) by analyzing data from 121 ADHF patients with available admission and day 3 creatinine and CysC levels. Admission creatinine and CysC levels were 1.39 (0.98-2.11) mg/dL and 1.95 (1.42-2.69) mg/L, respectively, and correlated well (r=0.81). On average, creatinine (-0.04±0.40 mg/dL) and CysC (0.001±0.34 mg/L) changed minimally from admission to day 3. Although the correlation between both markers on day 3 was still good (r=0.79), the correlation between changes therein was only modest (r=0.43). From the 14 and 15 patients who had WRF based on a ≥0.3 mg/dL increase in creatinine and ≥0.3 mg/L increase in CysC, respectively, only four (about 30%) met both definitions. These observations, together with recent insights in the inconsistencies of creatinine-defined concept of worsening renal function and outcomes, raises the need to research more reliable measures of renal function during treatment of ADHF.
Congestive Heart Failure 01/2013;
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ABSTRACT: AIMS: 'Worsening renal function' (WRF) and 'improvement in renal function' (IRF) monitored by changes in serum creatinine are frequently encountered during treatment of acute decompensated heart failure (ADHF). We sought to establish the important haemodynamic determinants of alterations in serum creatinine. METHODS AND RESULTS: We reviewed data from 443 patients treated for ADHF with haemodynamic guidance in a single centre. WRF and IRF were defined as a 25% increase or decrease in estimated glomerular filtration rate (eGFR) from time of admission to pulmonary artery catheter removal, respectively. Of the 443 patients, 46 (10%) experienced WRF and 127 (29%) had IRF. Baseline eGFR was lower in patients with IRF when compared with stable patients or those with WRF (45 ± 25 vs. 63 ± 30 vs. 68 ± 27 mL/min/m(2), respectively, P < 0.0001). In contrast, the relative decrease in mean blood pressure (BP) was more pronounced in patients with WRF when compared with stable patients or those with IRF (15 ± 15 vs. 9 ± 17 vs. 4 ± 15%, respectively, P = 0.003). With larger decreases in mean BP, there was greater likelihood of experiencing WRF (P = 0.04) but less likelihood of experiencing IRF (P = 0.01). In contrast, the degree of changes in right atrial pressure or cardiac index did not affect the propensity for developing WRF or IRF. There was no difference in adverse clinical outcomes (death, heart transplantation, LV assist device implantation, or readmission) between the three groups (P = 0.56). CONCLUSION: Blood pressure decrease, rather than alterations in cardiac output or central venous pressure, were associated with changes in serum creatinine during treatment of ADHF.
European Journal of Heart Failure 01/2013; · 4.90 Impact Factor
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ABSTRACT: Currently, fluid restriction recommendations in heart failure (HF) are based on expert opinion. After implementing a 1,000-mL/d fluid restriction for 60 days after discharge, outcomes were examined.
In a randomized controlled design, hyponatremic patients (serum sodium ≤137 mg/dL) received usual care (UC; n = 26) or 1,000 mL/d fluid restriction (n = 20) at discharge. Quality of life (QoL), thirst, difficulty following fluid recommendations, adherence to fluid restriction, HF emergency care, HF rehospitalization, and all-cause death were examined. Mean age was 62.8 ± 12.8 years; 46% were white. There were no differences by group in baseline demographics, comorbidities, and QoL, except that more UC patients had New York Heart Association (NYHA) functional class III/IV status (P = .019). Median [interquartile range] QoL scores were better in the 1,000 mL/d group for symptom burden (83.3 [68.8-91.7] vs 50 [29.2-79.2]; P = .018), total symptoms (77.1 [58.1-91.7] vs 54.2 [30.2-73.9]; P = .022), overall QoL summary (72.6 [52.2-86.3] vs 51.0 [37.7-68.5]; P = .038), and clinical QoL summary (75.5 [57.8-92.9] vs 59.1 [35.7-77.3]; P = .039). There were no group differences in thirst, difficulty adhering to fluid recommendations, adherence to fluid restriction, or health care consumption.
The 1,000 mL/d fluid restriction led to improved QoL at 60 days after discharge. Future research in a larger more heterogeneous sample is needed.
Journal of cardiac failure 01/2013; 19(1):1-9. · 3.25 Impact Factor
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ABSTRACT: Decreased serum arylesterase activity, catalyzed by the high-density lipoprotein-associated paraoxonase (PON)-1, is associated with increased oxidant stress and atherosclerosis risk. We sought to determine the prognostic value of serum PON-1 activity, as monitored by PON or arylesterase activities, in subjects with chronic kidney disease (CKD), particularly in relation to established cardiac biomarkers.
Serum arylesterase and PON activities were measured in sequential subjects with CKD (n=630; estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m(2)) and an age- and sex-matched control group of non-CKD subjects (n=315) presenting for cardiac evaluations and prospectively followed for incident (3-year) major adverse cardiac events (composite of death, nonfatal myocardial infarction, and stroke). Serum arylesterase activity in CKD subjects was lower compared with that in non-CKD control subjects [median (interquartile range) 94 (77 to 112) versus 103 (85 to 121) μmol(L·min) per mL, P<0.001]; similarly, PON activity in CKD subjects was lower compared with that in non-CKD control subjects [median (interquartile range) 474 (275 to 936) versus 586 (301 to 1118) nmol(L·min) per mL, P<0.001]. Lower serum arylesterase (hazard ratio 1.8, 95% CI 1.26 to 2.57, P<0.01) was a predictor of poorer outcomes. After adjusting for traditional risk factors and medication use, lower serum arylesterase (hazard ratio 1.55, 95% CI 1.08 to 2.23, P<0.05) still conferred an increased risk of major adverse cardiac events at 3 years.
In patients with CKD, decreased serum arylesterase activity, a measure of diminished antioxidant properties of PON-1, predicts higher risk of incident long-term adverse cardiovascular events (heart attack, stroke, or death) in multivariable models adjusting for established clinical and biochemical risk factors.
Journal of the American Heart Association. 01/2013; 2(2):e000104.
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ABSTRACT: Iron insufficiency has been associated with heart failure, but the impact of a reduction of hemoglobin content in the erythrocytes as estimated by mean corpuscular hemoglobin concentration (MCHC) to myocardial structure, performance, and long-term clinical outcomes has not been well-established. The authors examined hematologic data and long-term outcomes of 197 ambulatory patients with chronic systolic and symptomatic heart failure who underwent comprehensive echocardiographic evaluation. The authors observed that relative hypochromia (defined as low MCHC) was associated with higher natriuretic peptide levels (NT-proBNP, r =-0.40, P<.0001) and lower estimated glomerular filtration rate (eGFR; r = 0.45, P <. 0001) and correlated modestly with indices of left and right ventricular diastolic dysfunction (all P<.05), but were not related to left ventricular ejection fraction (LVEF, r=0.17, P=.079). After 5 years of follow-up, lower MCHC levels were associated with higher risk of death, transplant, or heart failure hospitalization after adjusting for age, LVEF, eGFR, and New York Heart Association class (hazard ratio, 1.34; 95% confidence interval, 1.04-1.72; P=.025), particularly in those with above-median hemoglobin (>13.8 g/dL; hazard ratio, 2.02; 95% confidence interval, 1.44-2.81, P<.0001). Taken together, the observations imply that physicians should take notice of the presence of relative hypochromia particularly in the absence of anemia in the setting of chronic systolic heart failure.
Congestive Heart Failure 12/2012;
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Pim van der Harst,
Weihua Zhang,
Irene Mateo Leach,
Augusto Rendon,
Niek Verweij,
Joban Sehmi,
Dirk S Paul,
Ulrich Elling,
Hooman Allayee,
Xinzhong Li, [......],
Manuel A Ferreira,
Serena Sanna,
Manuela Uda,
Andrew A Hicks,
Josef Martin Penninger,
Christian Gieger,
Jaspal S Kooner,
Willem H Ouwehand,
Nicole Soranzo,
John C Chambers
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ABSTRACT: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
Nature 12/2012; · 36.28 Impact Factor
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ABSTRACT: Several clinically available cardiac biomarkers have established their prognostic value in patients with acute coronary syndromes. However, their relative prognostic significance in stable subjects has not been prospectively validated, either individually or in combination. The aim of this study was to evaluate the extent to which B-type natriuretic peptide, myeloperoxidase, and high-sensitivity C-reactive protein alone or together could be prognostic biomarkers in 3,635 consecutive stable patients without acute coronary syndrome who underwent elective diagnostic coronary angiography. After adjusting for traditional risk factors and renal function, each of the markers monitored was a significant predictor of incident major adverse cardiovascular events (death, nonfatal myocardial infarction, and stroke) over 3 years. A cardiac biomarker score based on the sum total of "positive" biomarkers provided independent prediction of future risk for incident major adverse cardiovascular events at 3 years (hazard ratio [HR] 7.61, 95% confidence interval [CI] 4.98 to 11.65, p <0.001), even after adjusted for traditional risk factors (HR 6.11, 95% CI 3.98 to 9.38, p <0.001). A positive cardiac biomarker score remained a strong and independent predictor of 3-year risk for major adverse cardiovascular events among those with normal glycemic control (HR 4.24, 95% CI 1.96 to 9.18, p <0.001), those with prediabetes (HR 7.62, 95% CI 3.87 to 15.01, p <0.001), and those with diabetes (HR 5.61, 95% CI 2.55 to 12.33, p <0.001), as well as within subjects without significant angiographic evidence of coronary artery disease (HR 10.82, 95% CI 3.82 to 30.6, p <0.001). In conclusion, an integrated assessment of cardiac biomarkers may provide independent prognostic value for long-term adverse clinical events in stable cardiac patients.
The American journal of cardiology 12/2012; · 3.58 Impact Factor
