The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be ...used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 .
Objectives The purpose of this study was to evaluate whether 123-iodine metaiodobenzylguanidine (123-I MIBG) imaging predicts ventricular arrhythmias causing appropriate implantable ...cardioverter-defibrillator (ICD) therapy (primary end point) and the composite of appropriate ICD therapy or cardiac death (secondary end point). Background Although cardiac sympathetic denervation is associated with ventricular arrhythmias, limited data are available on the predictive value of sympathetic nerve imaging with 123-I MIBG on the occurrence of arrhythmias. Methods Before ICD implantation, patients underwent 123-I MIBG and myocardial perfusion imaging. Early and late 123-I MIBG (planar and single-photon emission computed tomography SPECT) imaging was performed to assess cardiac innervation (heart-to-mediastinum ratio, cardiac washout rate, and 123-I MIBG SPECT defect score). Stress-rest myocardial perfusion imaging was performed to assess myocardial infarction and perfusion abnormalities (perfusion defect scores). During follow-up, appropriate ICD therapy and cardiac death were documented. Results One-hundred sixteen heart failure patients referred for ICD therapy were enrolled. During a mean follow-up of 23 ± 15 months, appropriate ICD therapy (primary end point) was documented in 24 (21%) patients and appropriate ICD therapy or cardiac death (secondary end point) in 32 (28%) patients. Late 123-I MIBG SPECT defect score was an independent predictor for both end points. Patients with a large late 123-I MIBG SPECT defect (summed score >26) showed significantly more appropriate ICD therapy (52% vs. 5%, p < 0.01) and appropriate ICD therapy or cardiac death (57% vs. 10%, p < 0.01) than patients with a small defect (summed score ≤26) at 3-year follow-up. Conclusions Cardiac sympathetic denervation predicts ventricular arrhythmias causing appropriate ICD therapy as well as the composite of appropriate ICD therapy or cardiac death.
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.
Multiple hormonal and metabolic alterations occur in chronic heart failure (CHF), but their proper monitoring during clinically silent progression of CHF remains challenging. Hence, our objective was ...to explore whether temporal patterns of six emerging cardiometabolic biomarkers predict future adverse clinical events in stable patients with CHF.
In 263 patients with CHF, we determined the risk of a composite end point of heart failure hospitalization, cardiac death, left ventricular assist device implantation, and heart transplantation in relation to serially assessed blood biomarker levels and slopes (i.e., rate of biomarker change per year). During 2.2 years of follow-up, we repeatedly measured IGF binding proteins 1, 2, and 7 (IGFBP-1, IGFBP-2, IGFBP-7), adipose fatty acid binding protein 4 (FABP-4), resistin, and chemerin (567 samples in total).
Serially measured IGFBP-1, IGFBP-2, IGFBP-7, and FABP-4 levels predicted the end point univariable hazard ratio (95% CI) per 1-SD increase: 3.34 (2.43 to 4.87), 2.86 (2.10 to 3.92), 2.45 (1.91 to 3.13), and 2.46 (1.88 to 3.24), respectively. Independently of the biomarkers' levels, their slopes were also strong clinical predictors per 0.1-SD increase: 1.20 (1.11 to 1.31), 1.27 (1.14 to 1.45), 1.23 (1.11 to 1.37), and 1.27 (1.12 to 1.48). All associations persisted after multivariable adjustment for patient baseline characteristics, baseline N-terminal pro-hormone brain natriuretic peptide and cardiac troponin T, and pharmacological treatment during follow-up.
The temporal patterns of IGFBP-1, IGFBP-2, IGFBP-7, and adipose FABP-4 predict adverse clinical outcomes during outpatient follow-up of patients with CHF and may be clinically relevant as they could help detect more aggressive CHF forms and assess patient prognosis, as well as ultimately aid in designing more effective biomarker-guided therapy.
Aims
Evidence on the association of macrophage‐ and neutrophil‐related blood biomarkers with clinical outcome in heart failure patients is limited, and, with the exception of C‐reactive protein, no ...data exist on their temporal evolution. We aimed to investigate whether temporal patterns of these biomarkers are related to clinical outcome in patients with stable chronic heart failure (CHF).
Methods and Results
In 263 patients with CHF, we performed serial plasma measurements of scavenger receptor cysteine‐rich type 1 protein M130 (CD163), tartrate‐resistant acid phosphatase type 5 (TRAP), granulins (GRN), spondin‐1 (SPON1), peptidoglycan recognition protein 1 (PGLYRP1), and tissue factor pathway inhibitor (TFPI). The Cardiovascular Panel III (Olink Proteomics AB, Uppsala, Sweden) was used. During 2.2 years of follow‐up, we collected 1984 samples before the occurrence of the composite primary endpoint (PE) or censoring. For efficiency, we selected 567 samples for the measurements (all baseline samples, the last two samples preceding the PE, and the last sample before censoring in event‐free patients). The relationship between repeatedly measured biomarker levels and the PE was evaluated by joint models. Mean (±standard deviation) age was 67 ± 13 years; 189 (72%) were men; left ventricular ejection fraction (%) was 32 ± 11. During follow‐up, 70 (27%) patients experienced the PE. Serially measured biomarkers predicted the PE in a multivariable model adjusted for baseline clinical characteristics hazard ratio (95% confidence interval) per 1‐standard deviation change in biomarker: CD163 2.07(1.47–2.98), P < 0.001, TRAP 0.62 (0.43–0.90), P = 0.009, GRN 2.46 (1.64–3.84), P < 0.001, SPON1 3.94 (2.50–6.50), P < 0.001, and PGLYRP1 1.62 (1.14–2.31), P = 0.006.
Conclusions
Changes in plasma levels of CD163, TRAP, GRN, SPON1, and PGLYRP1 precede adverse cardiovascular events in patients with CHF.
Background We recently demonstrated in a randomized, double-blind, placebo-controlled trial that intramyocardial bone marrow cell (BMC) injection is associated with improvements in myocardial ...perfusion and anginal symptoms in chronic myocardial ischemia patients. In the present study the results of the crossover phase of this trial, in which patients previously treated with placebo received autologous BMC injections are reported. This allows a unique intra-patient comparison on the effect of BMC versus placebo injection with elimination of patient-related confounding factors. Methods In 16 patients (14 male, 64 ± 10 years), who previously received intramyocardial placebo injections in the setting of a randomized trial, 100 × 106 BMC were injected using the NOGA-system. Canadian Cardiovascular Society angina score and quality of life were evaluated at baseline, 3 and 6 months. Tc-99m single photon emission computed tomography and magnetic resonance imaging were performed at baseline and 3 months to assess myocardial perfusion and left ventricular (LV) function. Results Canadian Cardiovascular Society score and quality of life improved significantly after BMC injection as compared to placebo ( P = 0.01 and P = 0.02, respectively). Single photon emission computed tomography revealed a significant greater improvement ( P = 0.03) in summed stress score after BMC injection as compared to placebo. LV end-systolic volume significantly decreased after BMC injection but not after placebo injection. LV end-diastolic volume and LV ejection fraction did not change. Conclusion Intramyocardial BMC injection in patients with chronic myocardial ischemia who previously received intramyocardial placebo treatment resulted in significant improvement in angina symptoms and myocardial perfusion. These results confirm the outcome of our previously reported randomized trial.
Cardiovascular inflammation and vascular endothelial dysfunction are involved in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. We ...evaluated temporal patterns of 12 blood biomarkers of cell adhesion in patients with CHF. In 263 ambulant patients, serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (1.4-2.5) years. The primary endpoint (PE) was a composite of cardiovascular mortality, HF hospitalization, heart transplantation and implantation of a left ventricular assist device and was reached in 70 patients. We selected the baseline blood samples in all patients, the two samples closest to a PE, or, for event-free patients, the last sample available. In these 567 samples, associations between biomarkers and PE were investigated by joint modelling. The median age was 68 (59-76) years, with 72% men and 74% New York Heart Association class I-II. Repeatedly measured levels of Complement component C1q receptor (C1qR), Cadherin 5 (CDH5), Chitinase-3-like protein 1 (CHI3L1), Ephrin type-B receptor 4 (EPHB4), Intercellular adhesion molecule-2 (ICAM-2) and Junctional adhesion molecule A (JAM-A) were independently associated with the PE. Their rates of change also predicted clinical outcome. Level of CHI3L1 was numerically the strongest predictor with a hazard ratio (HR) (95% confidence interval) of 2.27 (1.66-3.16) per SD difference in level, followed by JAM-A (2.10, 1.42-3.23) and C1qR (1.90, 1.36-2.72), adjusted for clinical characteristics. In conclusion, temporal patterns of C1qR, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A are strongly and independently associated with clinical outcome in CHF patients.
Aims
Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement ...guideline‐directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real‐world TITRATE‐HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long‐term outcomes in patients with de novo, chronic, and worsening HF.
Methods and results
A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow‐up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF‐related hospitalizations, HF‐related urgent visits with a need for intravenous diuretics, all‐cause mortality, and cardiovascular mortality.
Conclusions
TITRATE‐HF is a real‐world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF 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.
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