We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3‐monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients ...with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT‐proBNP, troponin T, C‐reactive protein, creatinine, cystatin C; in urine, N‐acetyl‐beta‐d‐glucosaminidase and kidney‐injury‐molecule‐1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03–1.22) per 40 mg higher doses. ACE‐inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE‐inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF.
Background
It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes.
Hypothesis
...Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants.
Methods
During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N‐acetyl‐β‐d‐glucosaminidase (NAG), and kidney‐injury‐molecule (KIM)‐1. The degree of tubular injury was ranked according to NAG and KIM‐1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF‐hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation.
Results
Higher baseline NT‐proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR 95%CI, 95% confidence interval per doubling NT‐proBNP: 1.26 1.07‐1.49; per 10 mL/min/1.73 m2 eGFR decrease 1.16 1.03‐1.31). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 1.08‐1.62; spironolactone per 25 mg decrease: 1.76 1.07‐2.89; per 10 mL/min/1.73 m2 eGFR increase: 1.40 1.20‐1.63). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR 95%CI: WRF 1.9 1.1‐3.4, tubular 8.4 2.6‐27.9; when combined risk was highest 15.0 2.0‐111.0).
Conclusion
Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive.
Clinical Outcome in Cardiac Resynchronization Therapy (CRT) Functional Responders. Introduction: We evaluated clinical outcome and incidence of (in)appropriate shocks in consecutive chronic heart ...failure (CHF) patients treated with CRT with a defibrillator (CRT‐D) according to functional response status. Furthermore, we investigated which factors predict such functional response.
Methods and Results
: In a large teaching hospital, 179 consecutive CHF patients received CRT‐D in 2005–2010. Patients were considered functional responders if left ventricular ejection fraction (LVEF) increased to ≥35% postimplantation. Analysis was performed on 142 patients, who had CRT‐D as primary prevention, complete data and a baseline LVEF <35%. Endpoints consisted of all‐cause mortality, heart failure (HF) hospitalizations, appropriate shocks and inappropriate shocks. Median follow‐up was 3.0 years (interquartile range IQR 1.6–4.4) and median baseline LVEF was 20% (IQR 18–25%). The functional response‐group consisted of 42 patients. In this group no patients died, none were hospitalized for HF, none received appropriate shocks and 3 patients (7.1%) received ≥1 inappropriate shocks. In comparison, the functional nonresponse group consisted of 100 patients, of whom 22 (22%) died (P = 0.003), 17 (17%) were hospitalized for HF (P = 0.007), 17 (17%) had ≥1 appropriate shocks (P = 0.003) and 8 (8.1%) received ≥1 inappropriate shocks (P = 0.78). Multivariable analysis showed that left bundle branch block (LBBB), QRS duration ≥150 milliseconds and no need for diuretics at baseline are independent predictors of functional response.
Conclusion
: Functional responders to CRT have a good prognosis and rarely need ICD therapy. LBBB, QRS duration ≥150 milliseconds and lack of chronic diuretic use predict functional response. (J Cardiovasc Electrophysiol, Vol. 24, pp. 316‐322, March 2013)
We examined the prognostic information of detailed temporal patterns of N-terminal proBNP (NT-proBNP), high-sensitive troponin T (HsTNT), and C-reactive protein (CRP) in patients with chronic heart ...failure.
The first inclusion round (2011-2013, N = 263) from the ongoing Bio-SHiFT study was used. Biomarkers were measured at baseline and every 3 months. The primary end point (PE) comprised heart failure hospitalization, cardiovascular mortality, cardiac transplantation, and left ventricular assist device implantation. Associations between temporal biomarker patterns and the PE were investigated by joint modeling.
Mean age was 67 ± 12 years, 72% were men, 95% had systolic dysfunction, and 73% were in New York Heart Association class I or II. Median follow-up was 2.2 (interquartile range 1.4-2.5) years. We used 2,022 blood samples (median 9 interquartile range 5-10 per patient), and 70 (27%) patients reached the PE. Temporal patterns of NT-proBNP, HsTNT, and CRP level were associated with the PE (multivariable-adjusted hazard ratio per doubling of biomarker: NT-proBNP 2.28 (95% CI 1.82-2.86), HsTNT 2.05 (1.63-2.58), and CRP 1.65 (1.30-2.08). A combined 3-biomarker model demonstrated independent associations for the temporal patterns of NT-proBNP and CRP level (hazard ratios 2.06 1.53-2.79 and 1.38 1.01-1.89, respectively). Instantaneous change in biomarker level was also independently associated with the PE for NT-proBNP and CRP. Long-term biomarker elevation showed an association for NT-proBNP.
Temporal patterns representing evolution of level and rate of change in level of NT-proBNP and CRP, and long-term elevation of NT-proBNP were independently associated with adverse prognosis in patients with chronic heart failure. Individual patterns of change and combining multiple biomarkers could carry value for prognostication and for therapy guidance.
Renal dysfunction is an important component of chronic heart failure (CHF), but its single assessment does not sufficiently reflect clinically silent progression of CHF prior to adverse clinical ...outcome. Therefore, we aimed to investigate temporal evolutions of glomerular and tubular markers in 263 stable patients with CHF, and to determine if their patient-specific evolutions during this clinically silent period can dynamically predict clinical outcome. We determined the risk of clinical outcome (composite endpoint of Heart Failure hospitalization, cardiac death, Left Ventricular Assist Device placement, and heart transplantation) in relation to marker levels, slopes and areas under their trajectories. In each patient, the trajectories were estimated using repeatedly measured glomerular markers: creatinine/estimated glomerular filtration rate (eGFR), cystatin C (CysC), and tubular markers: urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1, plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL). During 2.2 years of follow-up, we collected on average 8 urine and 9 plasma samples per patient. All glomerular markers predicted the endpoint (univariable hazard ratio 95% confidence interval per 20% increase: creatinine: 1.181.07–1.31, CysC: 2.411.81–3.41, and per 20% eGFR decrease: 1.131.05–1.23). Tubular markers, NAG, and KIM-1 also predicted the endpoint (NAG: 1.061.01–1.11 and KIM-1: 1.081.04–1.11). Larger slopes were the strongest predictors (creatinine: 1.571.39–1.84, CysC: 1.761.52–2.09, eGFR: 1.591.37–1.90, NAG: 1.261.11–1.44, and KIM-1: 1.641.38–2.05). Associations persisted after multivariable adjustment for clinical characteristics. Thus, during clinically silent progression of CHF, glomerular and tubular functions deteriorate, but not simultaneously. Hence, patient-specific evolutions of these renal markers dynamically predict clinical outcome in patients with CHF.
Atrial Fibrillation in CRT‐D
Introduction
Knowledge about predictive factors for mortality and (in)appropriate shocks in cardiac resynchronization therapy with a defibrillator (CRT‐D) should be ...available and updated to predict clinical outcome.
Methods
We retrospectively analyzed 543 consecutive patients assigned to CRT‐D in 2 tertiary medical centers. The aim of this study was to assess risk factors for all‐cause mortality, appropriate and inappropriate shocks.
Results
Mean follow‐up time was 3.2 (±1.8) years. A total of 110 (20%) patients died, 71 (13%) received ≥1 appropriate shocks, and 33 (6.1%) received ≥1 inappropriate shocks. No patients received a His bundle ablation and biventricular pacing percentage was not analyzed. Multivariable Cox regression analysis showed that a history of atrial fibrillation (AF) (HR 1.74 CI 1.06–2.86), higher creatinine (HR 1.12; CI 1.08–1.16), and a poorer left ventricular ejection fraction (LVEF) (HR 0.97; CI 0.94–1.01) independently predict all‐cause mortality. In the entire cohort, history of AF and secondary prevention were independent predictors of appropriate shocks and variables associated with inappropriate shocks were history of AF and QRS ≥150 milliseconds. In primary prevention patients, history of AF also predicted appropriate shocks as did ischemic cardiomyopathy and poorer LVEF. History of AF, QRS ≥150 milliseconds, and lower creatinine were associated with inappropriate shocks in this subgroup. Appropriate shocks increased mortality risk, but inappropriate shocks did not.
Conclusion
In symptomatic CHF patients treated with CRT‐D, history of AF is an independent risk factor not only for mortality, but also for appropriate and inappropriate shocks. Further efforts in AF management may optimize the care in CRT‐D patients.
Background Remodeling biomarkers carry high potential for predicting adverse events in chronic heart failure ( CHF ) patients. However, temporal patterns during the course of CHF , and especially the ...trajectory before an adverse event, are unknown. We studied the prognostic value of temporal patterns of 14 cardiac remodeling biomarker candidates in stable patients with CHF from the Bio‐SHiFT (Serial Biomarker Measurements and New Echocardiographic Techniques in Chronic Heart Failure Patients Result in Tailored Prediction of Prognosis) study. Methods and Results In 263 CHF patients, we performed trimonthly blood sampling during a median follow‐up of 2.2 years. For the analysis, we selected all baseline samples, the 2 samples closest to the primary end point ( PE ), or the last sample available for end point–free patients. Thus, in 567 samples, we measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2, 3, and 9, tissue inhibitor metalloproteinase‐4, perlecan, aminopeptidase‐N, caspase‐3, cathepsin‐D, cathepsin‐Z, and cystatin‐B. The PE was a composite of cardiovascular mortality, heart transplantation, left ventricular assist device implantation, and HF hospitalization. Associations between repeatedly measured biomarker candidates and the PE were investigated by joint modeling. Median age was 68 (interquartile range: 59–76) years with 72% men; 70 patients reached the PE . Repeatedly measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2 and 9, tissue inhibitor metalloproteinase‐4, perlecan, cathepsin‐D, and cystatin‐B levels were significantly associated with the PE , and increased as the PE approached. The slopes of biomarker trajectories were also predictors of clinical outcome, independent of their absolute level. Associations persisted after adjustment for clinical characteristics and pharmacological treatment. Suppression of tumorigenicity‐2 was the strongest predictor (hazard ratio: 7.55 per SD difference, 95% CI : 5.53–10.30), followed by growth differentiation factor‐15 (4.06, 2.98–5.54) and matrix metalloproteinase‐2 (3.59, 2.55–5.05). Conclusions Temporal patterns of remodeling biomarker candidates predict adverse clinical outcomes in CHF . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01851538.
ObjectivesTo evaluate the feasibility of three-vessel three-dimensional (3D) quantitative coronary angiography (QCA)-based fractional flow reserve (FFR) computation in patients discussed within the ...Heart Team in whom the treatment decision was based on angiography alone, and to evaluate the concordance between 3D QCA-based vessel FFR (vFFR)-confirmed functional lesion significance and revascularisation strategy as proposed by the Heart Team.DesignRetrospective, cohort.Setting3D QCA-based FFR indices have not yet been evaluated in the context of Heart Team decision-making; consecutive patients from six institutions were screened for eligibility and three-vessel vFFR was computed by blinded analysts.ParticipantsConsecutive patients with chronic coronary syndrome or unstable angina referred for Heart Team consultation. Exclusion criteria involved: presentation with acute myocardial infarction (MI), significant valve disease, left ventricle ejection fraction <30%, inadequate quality of angiogram precluding vFFR computation in all three epicardial coronary arteries (ie, absence of a minimum of two angiographic projections with views of at least 30° apart, substantial foreshortening/overlap of the vessel, poor contrast medium injection, ostial lesions, chronic total occlusions).Primary and secondary outcome measuresDiscordance between vFFR-confirmed lesion significance and revascularisation was assessed as the primary outcome measure. Rates of major adverse cardiac events (MACE) defined as cardiac death, MI and clinically driven revascularisation were reported.ResultsOf a total of 1003 patients were screened for eligibility, 416 patients (age 65.6±10.6, 71.2% male, 53% stable angina) were included. The most important reason for screening failure was insufficient quality of the angiogram (43%). Discordance between vFFR confirmed lesion significance and revascularisation was found in 124/416 patients (29.8%) corresponding to 149 vessels (46/149 vessels (30.9%) were reclassified as significant and 103/149 vessels (69.1%) as non-significant by vFFR). Over a median of 962 days, the cumulative incidence of MACE was 29.7% versus 18.5% in discordant versus concordant patients (p=0.031).ConclusionsvFFR computation is feasible in around 40% of the patients referred for Heart Team discussion, a limitation that is mostly based on insufficient quality of the angiogram. Three vessel vFFR screening indicated discordance between vFFR confirmed lesion significance and revascularisation in 29.8% of the patients.
Objectives
We aimed to develop a model to predict long‐term mortality after percutaneous coronary intervention (PCI), to aid in selecting patients with sufficient life expectancy to benefit from ...bioabsorbable scaffolds.
Background
Clinical trials are currently designed to demonstrate superiority of bioabsorbable scaffolds over metal devices up to 5 years after implantation.
Methods
From 2000 to 2011, 19.532 consecutive patients underwent PCI in a tertiary referral hospital. Patients were randomly (2:1) divided into a training (N = 13,090) and validation (N = 6,442) set. Cox regression was used to identify determinants of long‐term mortality in the training set and used to develop a risk model. Model performance was studied in the training and validation dataset.
Results
Median age was 63 years (IQR 54–72) and 72% were men. Median follow‐up was 3.6 years (interquartile range IQR 2.4‐6.8). The ratio elective vs. non‐elective PCIs was 42/58. During 88,620 patient‐years of follow‐up, 3,156 deaths occurred, implying an incidence rate of 35.6 per 1,000. Estimated 5‐year mortality was 12.9%.Regression analysis revealed age, body mass index, diabetes mellitus, renal insufficiency, prior myocardial infarction, PCI indication, lesion location, number of diseased vessels and cardiogenic shock at presentation as determinants of mortality. The long‐term risk model showed good discrimination in the training and validation sets (c‐indices 0.76 and 0.74), whereas calibration was appropriate.
Conclusions
A simple risk model, containing 9 baseline clinical and angiographic variables effectively predicts long‐term mortality after PCI and may possibly be used to select suitable patients for bioabsorbable scaffolds.
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