First-line catheter ablation of paroxysmal atrial fibrillation: outcome of radiofrequency vs. cryoballoon pulmonary vein isolation.

AIMS: First-line ablation prior to antiarrhythmic drug (AAD) therapy is an option for symptomatic paroxysmal atrial fibrillation (PAF); however, the optimal ablation technique, radiofrequency (RF), or cryoballoon (CB) has to be determined. METHODS AND RESULTS: The FREEZE Cohort Study compares RF and CB ablation. Treatment-naïve patients were documented in the FREEZEplus Registry. Periprocedural data and outcome were analysed. From 2011 to 2014, a total of 373/4184 (8.9%) patients with PAF naïve to AAD were identified. Pulmonary vein isolation (PVI) was performed with RF (n = 180) or CB (n = 193). In the RF group, patients were older (65 vs. 61 years, P < 0.01) compared with the CB group. The procedure time was significantly shorter and radiation exposure higher in the CB group. Major adverse events occurred in 1.6% (CB) and 3.7% (RF) of patients (P = 0.22). AF/atrial tachycardia (AT) recurrence until discharge was 4.5% (RF) and 8.5% (CB, P = 0.2). Follow-up (FU) ≥12 months was available in 99 (RF) and 107 (CB) patients. After 1.4 years of FU, freedom from AF/atrial tachycardia (AT) was 61% (RF) and 71% (CB, P = 0.11). In the RF group, more patients underwent cardioversion, and a trend for more repeat ablations was observed. Persistent phrenic nerve palsy was observed in one patient treated by CB. CONCLUSION: First-line ablation for PAF is safe and effective with either RF or CB. The procedure was faster with the CB, but the radiation exposure was higher. Although there was a trend for more recurrences and complications in the RF group, a more favourable risk profile in patients undergoing CB ablation might have biased the results. CLINICALTRIALSGOV IDENTIFIER: NCT01360008.

Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism.

RATIONALE: Growth differentiation factor (GDF)-15 is a cytokine induced in the heart after ischemia or pressure overload. Circulating levels of GDF-15 provide independent prognostic information in patients with acute coronary syndromes or heart failure. OBJECTIVES: We investigated the prognostic value of GDF-15 in acute pulmonary embolism. METHODS: In a prospective cohort study, plasma levels of GDF-15 were determined by immunoradiometric assay in 123 consecutive patients with confirmed acute pulmonary embolism. MEASUREMENTS AND MAIN RESULTS: GDF-15 concentrations on admission ranged from 553 to 47,274 ng/L; 101 patients (82%) had GDF-15 levels above the upper limit of normal (1,200 ng/L). Patients who experienced pulmonary embolism-related complications during the first 30 days had higher baseline levels of GDF-15 (median, 6,039 [25th to 75th percentiles, 2,778 to 19,772] ng/L) compared with those with an uncomplicated course (median, 2,036 [25th to 75th percentiles, 1,279 to 3,176] ng/L; P < 0.001). By multivariable logistic regression analysis, which included clinical characteristics, cardiac biomarkers (troponin T and NT-proBNP [N-terminal propeptide of B-type natriuretic peptide]), and echocardiographic findings, GDF-15 emerged as an independent predictor of a complicated 30-day outcome (P = 0.033). The c-statistic for GDF-15 was 0.84 (95% confidence interval, 0.76-0.90), as compared with 0.72 for cardiac troponin T, and 0.65 for NT-proBNP. The ability of troponin T, NT-proBNP, and echocardiographic findings of right ventricular dysfunction to predict the risk of a complicated 30-day outcome was enhanced by GDF-15. Furthermore, multivariable Cox regression identified baseline levels of GDF-15 as an independent predictor of long-term mortality (P < 0.001). CONCLUSIONS: GDF-15 is a promising new biomarker for risk stratification of pulmonary embolism.

Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome.

BACKGROUND: An invasive treatment strategy improves outcome in patients with non-ST-elevation acute coronary syndrome at moderate to high risk. We hypothesized that the circulating level of growth differentiation factor 15 (GDF-15) may improve risk stratification. METHODS AND RESULTS: The Fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial randomized patients with non-ST-elevation acute coronary syndrome to an invasive or conservative strategy with a follow-up for 2 years. GDF-15 and other biomarkers were determined on admission in 2079 patients. GDF-15 was moderately elevated (between 1200 and 1800 ng/L) in 770 patients (37.0%), and highly elevated (>1800 ng/L) in 493 patients (23.7%). Elevated levels of GDF-15 independently predicted the risk of the composite end point of death or recurrent myocardial infarction in the conservative group (P=0.016) but not in the invasive group. A significant interaction existed between the GDF-15 level on admission and the effect of treatment strategy on the composite end point. The occurrence of the composite end point was reduced by the invasive strategy at GDF-15 levels >1800 ng/L (hazard ratio, 0.49; 95% confidence interval, 0.33 to 0.73; P=0.001), between 1200 and 1800 ng/L (hazard ratio, 0.68; 95% confidence interval, 0.46 to 1.00; P=0.048), but not <1200 ng/L (hazard ratio, 1.06; 95% confidence interval, 0.68 to 1.65; P=0.81). Patients with ST-segment depression or a troponin T level >0.01 microg/L with a GDF-15 level <1200 ng/L did not benefit from the invasive strategy. CONCLUSIONS: GDF-15 is a potential tool for risk stratification and therapeutic decision making in patients with non-ST-elevation acute coronary syndrome as initially diagnosed by ECG and troponin levels. A prospective randomized trial is needed to validate these findings.

Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is a member of the transforming growth factor-beta cytokine superfamily that is induced in the heart after ischemia-and-reperfusion injury. Circulating levels of GDF-15 may provide prognostic information in patients with non-ST-elevation acute coronary syndrome. METHODS AND RESULTS: Blood samples were obtained on admission from 2081 patients with acute chest pain and either ST-segment depression or troponin elevation who were included in the Global Utilization of Strategies to Open Occluded Arteries (GUSTO)-IV Non-ST-Elevation Acute Coronary Syndrome trial and from a matching cohort of 429 apparently healthy individuals. GDF-15 levels were determined by immunoradiometric assay. Approximately two thirds of patients presented with GDF-15 levels above the upper limit of normal in healthy controls (1200 ng/L); one third presented with levels >1800 ng/L. Increasing tertiles of GDF-15 were associated with an enhanced risk of death at 1 year (1.5%, 5.0%, and 14.1%; P<0.001). By multiple Cox regression analysis, only the levels of GDF-15 and N-terminal pro-B-type natriuretic peptide, together with age and a history of previous myocardial infarction, contributed independently to 1-year mortality risk. Receiver operating characteristic curve analyses further illustrated that GDF-15 is a strong marker of 1-year mortality risk (area under the curve, 0.757; best cutoff, 1808 ng/L). At this cutoff value, GDF-15 added significant prognostic information in patient subgroups defined by age; gender; time from symptom onset to admission; cardiovascular risk factors; previous cardiovascular disease; and the risk markers ST-segment depression, troponin T, N-terminal pro-B-type natriuretic peptide, C-reactive protein, and creatinine clearance. CONCLUSIONS: GDF-15 is a new biomarker of the risk for death in patients with non-ST-elevation acute coronary syndrome that provides prognostic information beyond that provided by established clinical and biochemical markers.

Growth-differentiation factor-15 for long-term risk prediction in patients stabilized after an episode of non-ST-segment-elevation acute coronary syndrome.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) has emerged as a prognostic biomarker in patients with non-ST-segment-elevation acute coronary syndrome. This study assessed the time course and the long-term prognostic relevance of GDF-15 levels measured repetitively in patients with non-ST-segment-elevation acute coronary syndrome during 6 months after the acute event. METHODS AND RESULTS: GDF-15 and other biomarkers were measured at randomization, after 6 weeks, and after 3 and 6 months in 950 patients with non-ST-segment-elevation acute coronary syndrome included in the FRagmin and Fast Revascularization during InStability in Coronary artery disease II study. Study end points were death, recurrent myocardial infarction, and their composite during 5-year follow-up. Median GDF-15 levels decreased slightly from 1357 ng/L at randomization to 1302 ng/L at 6 months (P<0.001). GDF-15 was consistently related to cardiovascular risk factors and biochemical markers of hemodynamic stress, renal dysfunction, and inflammation. Moreover, GDF-15 was independently related to the 5-year risk of the composite end point when measured at both 3 months (adjusted hazard ratio, 1.8 [1.0 to 3.0]) and 6 months (adjusted hazard ratio, 2.3 [1.3 to 4.1]). Serial measurements of GDF-15 at randomization and 6 months helped to identify patient cohorts at different levels of risk, with patients with persistently elevated GDF-15 levels >1800 ng/L having the highest rate of the composite end point. CONCLUSIONS: GDF-15 is independently related to adverse events in non-ST-segment-elevation acute coronary syndrome both in the acute setting and for at least 6 months after clinical stabilization. Therefore, continued research on GDF-15 should be focused on the usefulness of GDF-15 for support of clinical management in acute and chronic ischemic heart disease.

Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay.

BACKGROUND: Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGF-beta) cytokine superfamily. There has been increasing interest in using circulating GDF15 as a biomarker in patients, for example those with cardiovascular disease. METHODS: We developed an IRMA that uses a polyclonal, affinity chromatography-purified goat antihuman GDF15 IgG antibody, assessed the preanalytic characteristics of GDF15, and determined circulating GDF15 concentrations in 429 apparently healthy elderly individuals and 153 patients with chronic heart failure (CHF). RESULTS: The assay had a detection limit of 20 ng/L, an intraassay imprecision of < or =10.6%, and an interassay imprecision of < or =12.2%. Specificity was demonstrated with size-exclusion chromatography, parallel measurements with polyclonal and monoclonal anti-GDF15 antibody, and lack of cross-reactivity with TGF-beta. The assay was not appreciably influenced by the anticoagulant matrix or unrelated biological substances. GDF15 was stable at room temperature for 48 h and resistant to 4 freeze-thaw cycles. Apparently healthy, elderly individuals presented with a median GDF15 concentration of 762 ng/L (25th-75th percentiles, 600-959 ng/L). GDF15 concentrations were associated with age and with cystatin C and C-reactive protein concentrations. CHF patients had increased GDF15 concentrations that were closely related to disease severity. CONCLUSION: The IRMA can detect GDF15 in human serum and plasma with excellent sensitivity and specificity. The reference limits and confounding variables defined for apparently healthy elderly individuals and the favorable preanalytic characteristics of GDF15 are expected to facilitate future studies of GDF15 as a biomarker in various disease settings, including CHF.

Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction.

AIMS: Growth-differentiation factor-15 (GDF-15) is a transforming growth factor-beta-related cytokine that is induced in the heart following ischaemia-reperfusion injury. We explored the prognostic utility of GDF-15 in patients with ST-segment elevation myocardial infarction (STEMI) receiving fibrinolytic therapy. METHODS AND RESULTS: Circulating levels of GDF-15 were determined by an immunoradiometric assay in 741 STEMI patients who were included in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-2 and ASSENT-plus trials. About 72.7% of the patients presented with GDF-15 levels > or =1200 ng/L, the upper limit of normal in apparently healthy elderly individuals. Increased levels of GDF-15 were associated with a higher risk of death during 1-year follow-up. Mortality rates at 1 year were 2.1, 5.0, and 14.0% in patients with GDF-15 levels <1200, 1200-1800, and >1800 ng/L, respectively (P < 0.001). GDF-15 remained an independent predictor of mortality after adjustment for clinical variables, troponin T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). GDF-15 provided prognostic information in clinically relevant patient subgroups, defined according to age, gender, cardiovascular risk factors, haemodynamic status, and the TIMI risk score. Moreover, GDF-15 added prognostic information to the established biomarkers of adverse prognosis in STEMI, troponin T, and NT-proBNP. CONCLUSION: GDF-15 is a new biomarker in STEMI that provides prognostic information beyond established clinical and biochemical markers.

Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure.

OBJECTIVES: We explored the prognostic utility of growth differentiation factor (GDF)-15 in patients with chronic heart failure (CHF). BACKGROUND: Growth differentiation factor-15 is a stress-responsive member of the transforming growth factor-beta cytokine superfamily. It has recently been observed that patients with CHF have increased circulating levels of GDF-15. The relations of GDF-15 to other biomarkers and to mortality in CHF have never been studied. METHODS: Circulating levels of GDF-15 were determined by immunoradiometric assay in 455 patients with CHF with a median left ventricular ejection fraction (LVEF) of 32% (interquartile range 25% to 39%). RESULTS: The median GDF-15 level was 1,949 ng/l (interquartile range 1,194 to 3,577); 74.9% of the patients presented with GDF-15 levels >1,200 ng/l, the upper limit of normal in healthy elderly individuals. The GDF-15 levels were closely related to New York Heart Association (NYHA) functional class and to amino-terminal pro-B-type natriuretic peptide (NT-proBNP). The risk of death during follow-up increased with increasing quartiles of GDF-15. Mortality rates at 48 months were 10.0%, 9.4%, 33.4%, and 56.2% in the respective quartiles (p < 0.001). After adjustment for clinical variables and established biomarkers of adverse prognosis, including NT-proBNP, renal dysfunction, anemia, and hyperuricemia, GDF-15 remained an independent predictor of mortality (adjusted hazard ratio for 1 U in the Ln scale 2.26; 95% confidence interval 1.52 to 3.37; p < 0.001). Growth differentiation factor 15 provided prognostic information in clinically relevant patient subgroups (defined according to age, body mass index, heart failure etiology, concomitant medical therapy, renal function, and the levels of hemoglobin and uric acid) and added prognostic information to NYHA functional class, LVEF, and NT-proBNP. CONCLUSIONS: Growth differentiation factor 15 is a new biomarker of the risk of death in patients with CHF that provides prognostic information beyond established clinical and biochemical markers.