Quantifying Hemodynamic Cardiac Stress and Cardiomyocyte Injury in Normotensive and Hypertensive Acute Heart Failure.

BACKGROUND: The characterization of the different pathophysiological mechanisms involved in normotensive versus hypertensive acute heart failure (AHF) might help to develop individualized treatments. METHODS: The extent of hemodynamic cardiac stress and cardiomyocyte injury was quantified by measuring the B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP), and high-sensitivity cardiac troponin T (hs-cTnT) concentrations in 1152 patients presenting with centrally adjudicated AHF to the emergency department (ED) (derivation cohort). AHF was classified as normotensive with a systolic blood pressure (SBP) of 90-140 mmHg and hypertensive with SBP > 140 mmHg at presentation to the ED. Findings were externally validated in an independent AHF cohort (n = 324). RESULTS: In the derivation cohort, with a median age of 79 years, 43% being women, 667 (58%) patients had normotensive and 485 (42%) patients hypertensive AHF. Hemodynamic cardiac stress, as quantified by the BNP and NT-proBNP, was significantly higher in normotensive as compared to hypertensive AHF [1105 (611-1956) versus 827 (448-1419) pg/mL, and 5890 (2959-12,162) versus 4068 (1986-8118) pg/mL, both p < 0.001, respectively]. Similarly, the extent of cardiomyocyte injury, as quantified by hs-cTnT, was significantly higher in normotensive AHF as compared to hypertensive AHF [41 (24-71) versus 33 (19-59) ng/L, p < 0.001]. A total of 313 (28%) patients died during 360 days of follow-up. All-cause mortality was higher in patients with normotensive AHF vs. patients with hypertensive AHF (hazard ratio 1.66, 95%CI 1.31-2.10; p < 0.001). Normotensive patients with a high BNP, NT-proBNP, or hs-cTnT had the highest mortality. The findings were confirmed in the validation cohort. CONCLUSION: Biomarker profiling revealed a higher extent of hemodynamic stress and cardiomyocyte injury in patients with normotensive versus hypertensive AHF.

Focal and diffuse myocardial fibrosis both contribute to regional hypoperfusion assessed by post-processing quantitative-perfusion MRI techniques.

Introduction: Indications for stress-cardiovascular magnetic resonance imaging (CMR) to assess myocardial ischemia and viability are growing. First pass perfusion and late gadolinium enhancement (LGE) have limited value in balanced ischemia and diffuse fibrosis. Quantitative perfusion (QP) to assess absolute pixelwise myocardial blood flow (MBF) and extracellular volume (ECV) as a measure of diffuse fibrosis can overcome these limitations. We investigated the use of post-processing techniques for quantifying both pixelwise MBF and diffuse fibrosis in patients with clinically indicated CMR stress exams. We then assessed if focal and diffuse myocardial fibrosis and other features quantified during the CMR exam explain individual MBF findings. Methods: This prospective observational study enrolled 125 patients undergoing a clinically indicated stress-CMR scan. In addition to the clinical report, MBF during regadenoson-stress was quantified using a post-processing QP method and T1 maps were used to calculate ECV. Factors that were associated with poor MBF were investigated. Results: Of the 109 patients included (66 ± 11 years, 32% female), global and regional perfusion was quantified by QP analysis in both the presence and absence of visual first pass perfusion deficits. Similarly, ECV analysis identified diffuse fibrosis in myocardium beyond segments with LGE. Multivariable analysis showed both LGE (ß = -0.191, p = 0.001) and ECV (ß = -0.011, p < 0.001) were independent predictors of reduced MBF. In patients without clinically defined first pass perfusion deficits, the microvascular risk-factors of age and wall thickness further contributed to poor MBF (p < 0.001). Discussion: Quantitative analysis of MBF and diffuse fibrosis detected regional tissue abnormalities not identified by traditional visual assessment. Multi-parametric quantitative analysis may refine the work-up of the etiology of myocardial ischemia in patients referred for clinical CMR stress testing in the future and provide a deeper insight into ischemic heart disease.

The impact of functional vs degenerative mitral regurgitation on clinical outcomes among patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Among patients undergoing transcatheter aortic valve implantation (TAVI), concomitant mitral regurgitation (MR) has been associated with adverse prognosis. We aimed to assess long-term clinical outcomes according to MR etiology. METHODS: In a single-center registry of consecutive patients undergoing TAVI, we investigated the impact of functional (FMR) vs degenerative (DMR) MR on cardiovascular (CV) mortality throughout 2years of follow-up. RESULTS: Among 603 patients (mean age 82.4±5.7years, 55% female) undergoing TAVI, 149 patients had moderate or severe MR (24.7%). Functional MR and DMR were documented in 53 (36%) and 96 (64%) patients, respectively. At 2years, patients with FMR and DMR had higher rates of CV mortality (30.2% vs 32.4%) as compared with patients with no MR (14.6%; FMR vs no MR: hazard ratio [HR] 2.32, 95% CI 1.34-4.02, P=.003; DMR vs no MR: HR 2.56, 95% CI 1.66-3.96, P<.001). In adjusted analyses, DMR was associated with an increased risk of CV mortality throughout the 2-year follow-up (adjusted HR 2.21, 95% CI 1.4-3.49, P=.001) as compared with FMR (adjusted HR 1.13, 95% CI 0.59-2.18, P=.707). Relevant MR was postprocedurally significantly reduced in both the DMR and FMR groups, whereas improvement of a decreased left ventricular ejection fraction was predominantly seen in the FMR group as compared with baseline. CONCLUSION: Patients with severe, symptomatic aortic stenosis undergoing TAVI complicated by moderate or severe MR portend impaired prognosis. Particularly, patients with DMR are at increased risk for CV mortality during long-term follow-up.

Percutaneous closure of the patent foramen ovale using the HELEX® Septal Occluder: acute and long-term results in 405 patients.

AIMS: Although routinely used, limited data are available regarding the long-term outcome after patent foramen ovale (PFO) closure using the HELEX® Occluder system. The aim of this study was therefore the examination of the acute and long-term outcome after transcatheter PFO closure using this system. METHODS AND RESULTS: All (n=407) patients included had undergone PFO closure with the HELEX® Occluder system for secondary prevention of stroke, transient ischaemic attack (TIA) or peripheral embolism at a single centre. Primary endpoints were residual shunts at six or 12 months (assessed by transoesophageal echocardiography) and the number of neurological and other adverse events during follow-up. Device implantation was successful in 99% of patients. Complete closure at six months was achieved in 81%. During follow-up of 1,695 patient-years, 10 neurologic events occurred (four TIA, six strokes). The annual incidence of stroke was 1.2%. Other adverse events were wire frame fractures requiring no further intervention in five (1%), device-associated thrombus formation in one (0.25%), and paroxysmal atrial fibrillation in nine patients (2%). CONCLUSIONS: PFO closure using the HELEX® Occluder system is feasible and safe. Complications and adverse events during long-term follow-up are rare. The safety profile and efficacy in prevention of recurrent events compare well to that reported with other closure devices.

Pathophysiology of lower extremity edema in acute heart failure revisited.

BACKGROUND: The pathophysiology and key determinants of lower extremity edema in patients with acute heart failure are poorly investigated. METHODS: We prospectively enrolled 279 unselected patients presenting to the Emergency Department with acute heart failure. Lower extremity edema was quantified at predefined locations. Left ventricular ejection fraction, central venous pressure quantifying right ventricular failure, biomarkers to quantify hemodynamic cardiac stress (B-type natriuretic peptide), and the activity of the arginine-vasopressin system (copeptin) also were recorded. RESULTS: Lower extremity edema was present in 218 (78%) patients and limited to the ankle in 22%, reaching the lower leg in 40%, reaching the upper leg in 11%, and was generalized (anasarca) in 3% of patients. Patients in the 4 strata according to the presence and extent of lower leg edema had comparable systolic blood pressure, left ventricular ejection fraction, central venous pressure, and B-type natriuretic peptide levels, as well as copeptin and glomerular filtration rate (P=NS for all). The duration of dyspnea preceding the presentation was longer in patients with more extensive edema (P=.006), while serum sodium (P=.02) and serum albumin (P=.03) was lower. CONCLUSION: Central venous pressure, hemodynamic cardiac stress, left ventricular ejection fraction, and the activity of the arginine-vasopressin system do not seem to be key determinants of the presence or extent of lower extremity edema in acute heart failure.

Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure.

INTRODUCTION: The accurate prediction of acute kidney injury (AKI) in patients with acute heart failure (AHF) is an unmet clinical need. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel sensitive and specific marker of AKI. METHODS: A total of 207 consecutive patients presenting to the emergency department with AHF were enrolled. Plasma NGAL was measured in a blinded fashion at presentation and serially thereafter. The potential of plasma NGAL levels to predict AKI was assessed as the primary endpoint. We defined AKI according to the AKI Network classification. RESULTS: Overall 60 patients (29%) experienced AKI. These patients were more likely to suffer from pre-existing chronic cardiac or kidney disease. At presentation, creatinine (median 140 (interquartile range (IQR), 91 to 203) umol/L versus 97 (76 to 132) umol/L, P<0.01) and NGAL (114.5 (IQR, 67.1 to 201.5) ng/ml versus 74.5 (60 to 113.9) ng/ml, P<0.01) levels were significantly higher in AKI compared to non-AKI patients. The prognostic accuracy for measurements obtained at presentation, as quantified by the area under the receiver operating characteristic curve was mediocre and comparable for the two markers (creatinine 0.69; 95%CI 0.59 to 0.79 versus NGAL 0.67; 95%CI 0.57 to 0.77). Serial measurements of NGAL did not further increase the prognostic accuracy for AKI. Creatinine, but not NGAL, remained an independent predictor of AKI (hazard ratio (HR) 1.12; 95%CI 1.00 to 1.25; P=0.04) in multivariable regression analysis. CONCLUSIONS: Plasma NGAL levels do not adequately predict AKI in patients with AHF.

Quantifying cardiac hemodynamic stress and cardiomyocyte damage in ischemic and nonischemic acute heart failure.

BACKGROUND: The early and noninvasive differentiation of ischemic and nonischemic acute heart failure (AHF) in the emergency department (ED) is an unmet clinical need. METHODS AND RESULTS: We quantified cardiac hemodynamic stress using B-type natriuretic peptide (BNP) and cardiomyocyte damage using 2 different cardiac troponin assays in 718 consecutive patients presenting to the ED with AHF (derivation cohort). The diagnosis of ischemic AHF was adjudicated using all information, including coronary angiography. Findings were validated in a second independent multicenter cohort (326 AHF patients). Among the 718 patients, 400 (56%) were adjudicated to have ischemic AHF. BNP levels were significantly higher in ischemic compared with nonischemic AHF (1097 [604-1525] pg/mL versus 800 [427-1317] pg/mL; P<0.001). Cardiac troponin T (cTnT) and sensitive cardiac troponin I (s-cTnI) were also significantly higher in ischemic compared with nonischemic AHF patients (0.040 [0.010-0.306] µg/L versus 0.018 [0.010-0.060] µg/L [P<0.001]; 0.024 [0.008-0.106] µg/L versus 0.016 [0.004-0.044 ] µg/L [P=0.002]). The diagnostic accuracy of BNP, cTnT, and s-cTnI for the diagnosis of ischemic AHF, as quantified by the area under the receiver-operating characteristic curve, was low (0.58 [95% CI, 0.54-0.63], 0.61 [95% CI, 0.57-0.66], and 0.59 [95% CI,0.54-0.65], respectively). These findings were confirmed in the validation cohort. CONCLUSIONS: At presentation to the ED, patients with ischemic AHF exhibit more extensive hemodynamic cardiac stress and cardiomyocyte damage than patients with nonischemic AHF. However, the overlap is substantial, resulting in poor diagnostic accuracy.

Early diagnosis of acute myocardial infarction in patients with pre-existing coronary artery disease using more sensitive cardiac troponin assays.

AIMS: We sought to examine the diagnostic and prognostic utility of sensitive cardiac troponin (cTn) assays in patients with pre-existing coronary artery disease (CAD). METHODS AND RESULTS: We conducted a multicentre study to examine the diagnostic accuracy of one high-sensitive and two sensitive cTn assays in 1098 consecutive patients presenting with symptoms suggestive of acute myocardial infarction (AMI), of whom 401 (37%) had pre-existing CAD. Measurements of Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, Abbott-Architect cTnI and the standard assay (Roche cTnT) were performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the final diagnosis in 19% of CAD patients. Among patients with diagnoses other than AMI, baseline cTn levels were elevated above the 99th percentile with Roche hs-cTnT in 40%, with Siemens TnI-Ultra in 15%, and Abbott-Architect cTnI in 13% of them. In patients with pre-existing CAD, the diagnostic accuracy at presentation, quantified by the area under the receiver operator characteristic curve (AUC), was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.92; Siemens cTnI-Ultra, 0.94; and Abbott-Architect cTnI, 0.93 vs. AUC for the standard assay, 0.87; P < 0.01 for all comparisons). Elevated levels of cTn measured with the sensitive assays predicted mortality irrespective of pre-existing CAD, age, sex, and cardiovascular risk factors. CONCLUSION: Sensitive cTn assays have high-diagnostic accuracy also in CAD patients. Mild elevations are common in non-AMI patients and test-specific optimal cut-off levels tend to be higher in CAD patients than in patients without history of CAD. Sensitive cTn assays also retain prognostic value. (ClinicalTrials.gov number, NCT00470587).

Direct comparison of three natriuretic peptides for prediction of short- and long-term mortality in patients with community-acquired pneumonia.

BACKGROUND: Early and accurate risk stratification for patients with community-acquired pneumonia (CAP) is an unmet clinical need. METHODS: We enrolled 341 unselected patients presenting to the ED with CAP in whom blinded measurements of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional pro-atrial natriuretic peptide (MR-proANP), and B-type natriuretic peptide (BNP) were performed. The potential of these natriuretic peptides to predict short- (30-day) and long-term mortality was compared with the pneumonia severity index (PSI) and CURB-65 (confusion, urea plasma level, respiratory rate, BP, age over 65 years). The median follow-up was 942 days. RESULTS: NT-proBNP, MR-proANP, and BNP levels at presentation were higher in short-term (median 4,882 pg/mL vs 1,133 pg/mL; 426 pmol/L vs 178 pmol/L; 436 pg/mL vs 155 pg/mL, all P < .001) and long-term nonsurvivors (3,515 pg/mL vs 548 pg/mL; 283 pmol/L vs 136 pmol/L; 318 pg/mL vs 103 pg/mL, all P < .001) as compared with survivors. Receiver operating characteristics analysis to quantify the prognostic accuracy showed comparable areas under the curve for the three natriuretic peptides to PSI for short-term (PSI 0.76, 95% CI, 0.71-0.81; NT-proBNP 0.73, 95% CI, 0.67-0.77; MR-proANP 0.72, 95% CI, 0.67-0.77; BNP 0.68, 95% CI, 0.63-0.73) and long-term (PSI 0.72, 95% CI, 0.66-0.77; NT-proBNP 0.75, 95% CI, 0.70-0.80; MR-proANP 0.73, 95% CI, 0.67-0.77, BNP 0.70, 95% CI, 0.65-0.75) mortality. In multivariable Cox-regression analysis, NT-proBNP remained an independent mortality predictor (hazard ratio 1.004, 95% CI, 1.00-1.01, P = .02 for short-term; hazard ratio 1.004, 95% CI, 1.00-1.01, P = .001 for long-term, increase of 300 pg/mL). A categorical approach combining PSI point values and NT-pro-BNP levels adequately identified patients at low, medium, and high short- and long-term mortality risk. CONCLUSIONS: Natriuretic peptides are simple and powerful predictors of short- and long-term mortality for patients with CAP. Their prognostic accuracy is comparable to PSI.

Risk stratification for 1-year mortality in acute heart failure: classification and regression tree analysis.

BACKGROUND: Simple tools for risk stratification of patients with acute heart failure (AHF) are an unmet clinical need, particularly regarding long-term mortality. METHODS: We prospectively enrolled 610 consecutive patients presenting to the emergency department with AHF. The diagnosis of AHF was adjudicated by two independent cardiologists. The classification and regression tree (CART) analysis was used to develop a simple risk algorithm. This was internally validated by cross-validation. RESULTS: One-year follow-up was complete in all patients (100%). A total of 201 patients (33%) died within 360 days. The CART analysis identified blood urea nitrogen (BUN) and age as the best single predictors of 1-year mortality and patients were categorised to three risk groups: high risk group (BUN >27.5 mg/dl and age >86 years), intermediate risk group (BUN >27.5 mg/dl and age ≤ 86 years) and low risk group (BUN ≤ 27.5 mg/dl). The Kaplan-Meier curves showed a significant increase in mortality in the high risk group compared with the lower risk groups (log-rank test p <0.001). The hazard ratio regarding 1-year mortality between patients identified as low and high risk was 2.0 (95% confidence interval, 1.7-2.4), with statistically significant differences between all risk groups (p <0.001). The likelihood-based 95%-confidence set for the age- and the urea-threshold is contained in the rectangular set defined by 25 mg/dl ≤ urea threshold ≤30.6 mg/dl and 76 years ≤ age threshold ≤96 years. CONCLUSION: These results suggest that AHF patients at low, intermediate and high risk for death within 360 days can be easily identified using patient's demographics and laboratory data obtained at presentation. Application of this simple risk stratification algorithm may help to improve the management of these patients.

Systolic blood pressure at Emergency Department presentation and 1-year mortality in acute chest pain patients.

BACKGROUND: High blood pressure at rest has been an established risk factor for cardiovascular disease. However the relationship between Systolic Blood Pressure (SBP) and 1-year-mortality among acute chest pain patients presenting to Emergency Department (ED); and effects of preexisting renal insufficiency, hemodynamic stress - as quantified by Brain Natriuretic Peptide (BNP) and chest pain duration, on this relationship is unknown. METHODS: Data was used from APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation), a prospective observational multicenter study of 1240 ED chest pain patients. SBP at presentation was categorized into quartiles: Q1≤127mmHg; Q2 128-142mmHg; Q3 143-160mmHg; Q4≥161mmHg. RESULTS: 60 deaths occurred during 1-year. One-year-mortality-rate showed lower Hazard Ratios for Q2, Q3 and Q4 vs Q1 (HR [95% CI]; 0.39 (0.19-0.78), 0.34 (0.17-0.70), 0.35 (0.17-0.72); p<0.01 respectively). Cox model adjusted for various demographic and treatment variables showed that participants in Q3 and Q4 had better prognoses than Q1. Patients showed progressively better prognosis from Q2 through Q4 vs Q1 only in patients who presented to ED with for more than 12h of chest pain duration. Patients with renal insufficiency had lower SBP at presentation than others (p=0.001). There was no association between the outcome and interaction variable of SBP quartiles and BNP (p=0.27). CONCLUSION: Acute chest pain patients presenting to ED exhibit an inverse association between SBP at presentation and 1-year-mortality; a relationship which appears stronger in those who present with chest pain of greater than 12h duration.

Value of arterial blood gas analysis in patients with acute dyspnea: an observational study.

INTRODUCTION: The diagnostic and prognostic value of arterial blood gas analysis (ABGA) parameters in unselected patients presenting with acute dyspnea to the Emergency Department (ED) is largely unknown. METHODS: We performed a post-hoc analysis of two different prospective studies to investigate the diagnostic and prognostic value of ABGA parameters in patients presenting to the ED with acute dyspnea. RESULTS: We enrolled 530 patients (median age 74 years). ABGA parameters were neither useful to distinguish between patients with pulmonary disorders and other causes of dyspnea nor to identify specific disorders responsible for dyspnea. Only in patients with hyperventilation from anxiety disorder, the diagnostic accuracy of pH and hypoxemia rendered valuable with an area under the receiver operating characteristics curve (AUC) of 0.86. Patients in the lowest pH tertile more often required admission to intensive care unit (28% vs 12% in the first tertile, P < 0.001) and had higher in-hospital (14% vs 5%, P = 0.003) and 30-day mortality (17% vs 7%, P = 0.002). Cumulative mortality rate was higher in the first (37%), than in the second (28%), and the third tertile (23%, P = 0.005) during 12 months follow-up. pH at presentation was an independent predictor of 12-month mortality in multivariable Cox proportional hazard analysis both for patients with pulmonary (P = 0.043) and non-pulmonary disorders (P = 0.038). CONCLUSIONS: ABGA parameters provide limited diagnostic value in patients with acute dyspnea, but pH is an independent predictor of 12 months mortality.

B-type natriuretic peptide in the early diagnosis and risk stratification of acute chest pain.

BACKGROUND: Myocardial ischemia is a strong trigger of B-type natriuretic peptide (BNP) release. As ischemia precedes necrosis in acute myocardial infarction, we hypothesized that BNP might be useful in the early diagnosis and risk stratification of patients with acute chest pain. METHODS: In a prospective, international multicenter study, BNP was measured in 1075 unselected patients with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long term regarding mortality. RESULTS: Acute myocardial infarction was the adjudicated final diagnosis in 168 patients (16%). BNP levels at presentation were significantly higher in acute myocardial infarction as compared with patients with other diagnoses (median 224 pg/mL vs. 56 pg/mL, P <.001). The diagnostic accuracy of BNP for the diagnosis of acute myocardial infarction as quantified by the area under the receiver operating characteristic curve (AUC) (0.74; 95% confidence interval [CI], 0.70-0.78) was lower compared with cardiac troponin T at presentation (AUC 0.88; 95% CI, 0.84-0.92; P <.001). Cumulative 24-month mortality rates were 0.5% in the first, 2.1% in the second, 7.0% in the third, and 22.9% in the fourth quartile of BNP (P <.001). BNP predicted all-cause mortality independently of and more accurately than cardiac troponin T: AUC 0.81 (95% CI, 0.76-0.86) versus AUC 0.70 (95% CI, 0.62-0.77; P <.001). Net reclassification improvement for BNP was 0.10 (P=.04), and integrated discrimination improvement 0.068 (P=.01). CONCLUSIONS: BNP accurately predicts mortality in unselected patients with acute chest pain independently of and more accurately than cardiac troponin T, but does not seem to help in the early diagnosis of acute myocardial infarction.

Use of neutrophil count in early diagnosis and risk stratification of AMI.

BACKGROUND: Neutrophils are rapidly released into the circulation upon acute stress such as trauma or acute myocardial infarction (AMI). We hypothesized that neutrophil count might provide incremental value in the early diagnosis and risk stratification of AMI. METHODS: We conducted a prospective observational multicenter study to examine the diagnostic accuracy of the combination of neutrophil count and cardiac troponin T from 1125 consecutive patients who presented to the Emergency Department with symptoms suggestive of acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. RESULTS: Neutrophil count was higher in patients with acute myocardial infarction compared with other diagnoses (median 6.7 vs. 5.0×10(9)/L, respectively, P <.001). The accuracy of the neutrophil count for diagnosing acute myocardial infarction, quantified by the area under the receiver operating characteristic curve (AUC) was 0.69, which was significantly lower than that of cardiac troponin T (AUC 0.89, P <.001). The combination of the neutrophil count and cardiac troponin T did not improve the early diagnosis of acute myocardial infarction versus cardiac troponin T alone (P=.79). The prognostic accuracy of neutrophil count for death and AMI was significantly lower than that of cardiac troponin T. However, patients in the highest tertile of neutrophil count had a significantly increased risk of death and AMI at 90 and 360 days compared with patients in the lowest tertile (hazard ratios 2.47 [95% confidence interval, 1.63-3.72] and 2.28 [95% confidence interval, 1.55-3.36], respectively). CONCLUSION: The neutrophil count does not improve the early diagnosis of AMI in patients presenting with chest pain but identifies patients at increased risk of death.

Endogenous stress response in Tako-Tsubo cardiomyopathy and acute myocardial infarction.

BACKGROUND: As the clinical, electrocardiographic and laboratory presentation of Tako-Tsubo cardiomyopathy (TTC) and acute myocardial infarction (AMI) is similar, both entities are in general only distinguishable by coronary angiography. The purpose of this study was to examine the endogenous stress response at presentation, quantified by the copeptin level, of patients with TTC and patients with AMI, as copeptin may be useful in the non-invasive differentiation between both diseases. METHODS: We compared the endogenous stress response at initial presentation, quantified by the plasma copeptin levels, in 21 consecutive patients finally diagnosed with TTC and 21 patients finally diagnosed with AMI matched for sex and time since chest pain onset. RESULTS: The prevalence of cardiovascular risk factors and initial cardiac troponin T levels were comparable in TTC and AMI. Copeptin levels were significantly lower in patients with TTC when compared to patients with AMI (median 4·8 [interquartile range, IQR 3·5-13·5] pM vs. 25·6 [IQR 12·1-63·9] pM, P = 0·002). The accuracy for diagnosing TTC as quantified by the area under the receiver operating characteristics curve was significantly higher for copeptin than for cardiac troponin T (0·782 vs. 0·549, P = 0·031). The optimal cut-off value for differentiation between TTC and AMI was found at a copeptin level of 7·8 pM (sensitivity 67% at a specificity of 86%, negative predictive value 72%, positive predictive value 82%). CONCLUSIONS: The endogenous stress response, quantified by a novel sensitive biomarker, seems to be different in patients with TTC and AMI. Copeptin levels may be helpful in the non-invasive differentiation between TTC and AMI.

Early diagnosis of acute myocardial infarction in the elderly using more sensitive cardiac troponin assays.

AIMS: To examine the diagnostic accuracy of sensitive cardiac troponin (cTn) assays in elderly patients, since elevated levels with sensitive cTn assays were reported in 20% of elderly patients without acute myocardial infarction (AMI). METHODS AND RESULTS: In this multi-centre study, we included 1098 consecutive patients presenting with symptoms suggestive of AMI, 406 (37%) were >70 years old. Measurement of three investigational sensitive cTn assays [Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, and Abbott-Architect cTnI) and the standard assay (Roche cTnT) was performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the adjudicated final diagnosis in 24% of elderly patients. Among elderly patients without AMI, baseline cTn levels were elevated above the 99th percentile in 51% with Roche hs-cTnT, in 17% with Siemens TnI-Ultra, and 13% with Abbott-Architect cTnI. The diagnostic accuracy as quantified by the area under the receiver operating characteristic (ROC) curve (AUC) was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.94; Siemens cTnI-Ultra, 0.95; and Abbott-Architect cTnI, 0.95 vs. AUC for the standard assay, 0.90; P < 0.05 for comparisons). The best cut-offs for the sensitive cTn-assays determined by the ROC-curve in elderly patients differed clearly from those in younger patients. Furthermore, the prognostic value regarding 90-day mortality varied among the sensitive cTn assays. CONCLUSION: Sensitive cTn assays have high diagnostic accuracy also in the elderly. Mild elevations are common in elderly non-AMI patients, therefore the optimal cut-off levels are substantially higher in elderly as compared with younger patients. Furthermore, sensitive cTn assays yielded different prognostic value.

Effect and clinical prediction of worsening renal function in acute decompensated heart failure.

We aimed to establish the prevalence and effect of worsening renal function (WRF) on survival among patients with acute decompensated heart failure. Furthermore, we sought to establish a risk score for the prediction of WRF and externally validate the previously established Forman risk score. A total of 657 consecutive patients with acute decompensated heart failure presenting to the emergency department and undergoing serial creatinine measurements were enrolled. The potential of the clinical parameters at admission to predict WRF was assessed as the primary end point. The secondary end point was all-cause mortality at 360 days. Of the 657 patients, 136 (21%) developed WRF, and 220 patients had died during the first year. WRF was more common in the nonsurvivors (30% vs 41%, p = 0.03). Multivariate regression analysis found WRF to independently predict mortality (hazard ratio 1.92, p <0.01). In a single parameter model, previously diagnosed chronic kidney disease was the only independent predictor of WRF and achieved an area under the receiver operating characteristic curve of 0.60. After the inclusion of the blood gas analysis parameters into the model history of chronic kidney disease (hazard ratio 2.13, p = 0.03), outpatient diuretics (hazard ratio 5.75, p <0.01), and bicarbonate (hazard ratio 0.91, p <0.01) were all predictive of WRF. A risk score was developed using these predictors. On receiver operating characteristic curve analysis, the Forman and Basel prediction rules achieved an area under the curve of 0.65 and 0.71, respectively. In conclusion, WRF was common in patients with acute decompensated heart failure and was linked to significantly worse outcomes. However, the clinical parameters failed to adequately predict its occurrence, making a tailored therapy approach impossible.

Direct comparison of serial B-type natriuretic peptide and NT-proBNP levels for prediction of short- and long-term outcome in acute decompensated heart failure.

INTRODUCTION: Monitoring treatment efficacy and assessing outcome by serial measurements of natriuretic peptides in acute decompensated heart failure (ADHF) patients may help to improve outcome. METHODS: This was a prospective multi-center study of 171 consecutive patients (mean age 80 73-85 years) presenting to the emergency department with ADHF. Measurement of BNP and NT-proBNP was performed at presentation, 24 hours, 48 hours and at discharge. The primary endpoint was one-year all-cause mortality; secondary endpoints were 30-days all-cause mortality and one-year heart failure (HF) readmission. RESULTS: During one-year follow-up, a total of 60 (35%) patients died. BNP and NT-proBNP levels were higher in non-survivors at all time points (all P < 0.001). In survivors, treatment reduced BNP and NT-proBNP levels by more than 50% (P < 0.001), while in non-survivors treatment did not lower BNP and NT-proBNP levels. The area under the ROC curve (AUC) for the prediction of one-year mortality increased during the course of hospitalization for BNP (AUC presentation: 0.67; AUC 24 h: 0.77; AUC 48 h: 0.78; AUC discharge: 0.78) and NT-proBNP (AUC presentation: 0.67; AUC 24 h: 0.73; AUC 48 h: 0.75; AUC discharge: 0.77). In multivariate analysis, BNP at 24 h (1.02 [1.01-1.04], P = 0.003), 48 h (1.04 [1.02-1.06], P < 0.001) and discharge (1.02 [1.01-1.03], P < 0.001) independently predicted one-year mortality, while only pre-discharge NT-proBNP was predictive (1.07 [1.01-1.13], P = 0.016). Comparable results could be obtained for the secondary endpoint 30-days mortality but not for one-year HF readmissions. CONCLUSIONS: BNP and NT-proBNP reliably predict one-year mortality in patients with ADHF. Prognostic accuracy of both biomarker increases during the course of hospitalization. In survivors BNP levels decline more rapidly than NT-proBNP levels and thus seem to allow earlier assessment of treatment efficacy. Ability to predict one-year HF readmission was poor for BNP and NT-proBNP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00514384.

Central venous pressure and impaired renal function in patients with acute heart failure.

AIMS: To determine the relationship between central venous pressure (CVP) and renal function in patients with acute heart failure (AHF) presenting to the emergency department. METHODS AND RESULTS: Central venous pressure was determined non-invasively using compression sonography in 140 patients with AHF at presentation. Worsening renal function (WRF) was defined as an increase in serum creatinine ≥ 0.3 mg/dL during hospitalization. In the study cohort [age 77 ± 12 years, B-type natriuretic peptide 1862 ± 1564 pg/mL, left ventricular ejection fraction 40 ± 15%, estimated glomerular filtration rate (eGFR) 58 ± 28 mL/min, and CVP 13.2 ± 6.9 cmH(2)O], 51 patients (36%) developed WRF. No significant association between CVP at presentation or discharge and concomitant eGFR (r = 0.005, P = 0.419 and r = 0.013, P = 0.313, respectively) was observed. However, in patients with systolic blood pressure (SBP) <110 mmHg and concomitant high CVP (>15 cmH(2)O), eGFR was significantly lower at presentation and discharge (29 ± 17 vs. 47 ± 19 mL/min/1.73 m(2), P = 0.039 and 26 ± 10 vs. 53 ± 26 mL/min/1.73 m(2), P = 0.013, respectively). Central venous pressure at presentation and at discharge did not differ between patients with or without in-hospital WRF (12.6 ± 7.2 vs. 13.5 ± 6.7 cmH(2)O, P = 0.503 and 7.4 ± 6.5 vs. 7.7 ± 5.7 cmH(2)O, P = 0.799, respectively) (receiver-operating characteristic analysis 0.543, P = 0.401 and 0.531, P = 0.625, respectively). However, patients with CVP in the lowest tertile (<10 cmH(2)O) at presentation were more likely to develop WRF within the first 24 h than patients with CVP in the highest tertile (>15 cmH(2)O) (18 vs. 4%, P = 0.046). CONCLUSION: In AHF, combined low SBP and high CVP predispose to lower eGFR. However, lower CVP may also be associated with short-term WRF. The pathophysiology of WRF and the role of CVP seem to be more complex than previously thought.

Patent foramen ovale closure with the SeptRx device initial experience with the first "In-Tunnel" device.

OBJECTIVES: The purpose of this study was to evaluate the safety and effectiveness of the SeptRx patent foramen ovale (PFO) closure device (SeptRx, Inc., Fremont, California). BACKGROUND: A PFO is a relatively common remnant of the fetal circulation that can be associated with cryptogenic stroke, transient ischemic attack, migraine, or decompression sickness. Percutaneous PFO closure with different devices has been performed for many years. However, most of the common devices leave a relatively large amount of material in the left and right atria. The SeptRx PFO device (SeptRx, Inc.) is the first PFO closure device designed to fit directly into the pocket of the PFO. METHODS: From July 2006 to May 2007, 13 patients between 18 and 65 years of age with a history of cryptogenic stroke or transient ischemic attack were included into this first-in-man trial. All patients received 100 mg aspirin and 75 mg clopidogrel for 6 months. Follow-up was done at 1 and 6 months after procedure with transesophageal echocardiography and transcranial Doppler. RESULTS: In 11 of 13 patients, PFO closure with the SeptRx device was successfully performed. In 2 patients, PFO closure with this device was not possible due to the anatomy of the PFO; 1 device was retrieved before release, and the other was recaptured with a snare. After 30 days, 6 of the 11 PFOs were closed; after 6 months, all were closed. No adverse events occurred. CONCLUSIONS: The SeptRx PFO closure device appears to be safe and effective. The advantage of this occluder is that there is only minimal foreign material on the left and right sides of the interatrial septum. This is the first such "in-tunnel" PFO closure device.