Relationship of Fibroblast Growth Factor 23 With Hospitalization for Heart Failure and Cardiovascular Outcomes in Patients Undergoing Cardiac Surgery.

Background Fibroblast growth factor 23 (FGF-23) is crucial in regulating phosphate and vitamin D metabolism and is moreover associated with an increased cardiovascular risk. The specific objective of this study was to investigate the influence of FGF-23 on cardiovascular outcomes, including hospitalization for heart failure (HHF), postoperative atrial fibrillation, and cardiovascular death, in an unselected patient population after cardiac surgery. Methods and Results Patients undergoing elective coronary artery bypass graft and/or cardiac valve surgery were prospectively enrolled. FGF-23 blood plasma concentrations were assessed before surgery. A composite of cardiovascular death/HHF was chosen as primary end point. A total of 451 patients (median age 70 years; 28.8% female) were included in the present analysis and followed over a median of 3.9 years. Individuals with higher FGF-23 quartiles showed elevated incidence rates of the composite of cardiovascular death/HHF (quartile 1, 7.1%; quartile 2, 8.6%; quartile 3, 15.1%; and quartile 4, 34.3%). After multivariable adjustment, FGF-23 modeled as a continuous variable (adjusted hazard ratio for a 1-unit increase in standardized log-transformed biomarker, 1.82 [95% CI, 1.34-2.46]) as well as using predefined risk groups and quartiles remained independently associated with the risk of cardiovascular death/HHF and the secondary outcomes, including postoperative atrial fibrillation. Reclassification analysis indicated that the addition of FGF-23 to N-terminal pro-B-type natriuretic peptide provides a significant improvement in risk discrimination (net reclassification improvement at the event rate, 0.58 [95% CI, 0.34-0.81]; P<0.001; integrated discrimination increment, 0.03 [95% CI, 0.01-0.05]; P<0.001). Conclusions FGF-23 is an independent predictor of cardiovascular death/HHF and postoperative atrial fibrillation in individuals undergoing cardiac surgery. Considering an individualized risk assessment, routine preoperative FGF-23 evaluation may improve detection of high-risk patients.

Biomarker Prediction of Complex Coronary Revascularization Procedures in the FOURIER Trial.

BACKGROUND: Biomarkers are known to predict major adverse cardiovascular events. However, the association of biomarkers with complex coronary revascularization procedures or high-risk coronary anatomy at the time of revascularization is not understood. OBJECTIVES: We examined the associations between baseline biomarkers and major coronary events (MCE) and complex revascularization procedures. METHODS: FOURIER was a randomized trial of the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab vs placebo in 27,564 patients with stable atherosclerosis. We analyzed adjusted associations among the biomarkers, MCE (coronary death, myocardial infarction, or revascularization), and complex revascularization (coronary artery bypass graft or complex percutaneous coronary intervention) using a multimarker score with 1 point assigned for each elevated biomarker (high-sensitivity C-reactive protein ≥2 mg/L; N-terminal pro-B-type natriuretic peptide ≥450 pg/mL; high-sensitivity troponin I ≥6 ng/L; growth-differentiation factor-15 ≥1,800 pg/mL). RESULTS: When patients were grouped by the number of elevated biomarkers (0 biomarkers, n = 6,444; 1-2 biomarkers, n = 12,439; ≥3 biomarkers, n = 2,761), there was a significant graded association between biomarker score and the risk of MCE (intermediate score: HRadj: 1.57 [95% CI: 1.38-1.78]; high score: HRadj: 2.90 [95% CI: 2.47-3.40]), and for complex revascularization (intermediate: HRadj: 1.33 [95% CI: 1.06-1.67]; high score: HRadj: 2.07 [95% CI: 1.52-2.83]) and its components (Ptrend <0.05 for each). The number of elevated biomarkers also correlated with the presence of left main disease, multivessel disease, or chronic total occlusion at the time of revascularization (P < 0.05 for each). CONCLUSIONS: A biomarker-based strategy identifies stable patients at risk for coronary events, including coronary artery bypass graft surgery and complex percutaneous coronary intervention, and predicts high-risk coronary anatomy at the time of revascularization. These findings provide insight into the relationships between cardiovascular biomarkers, coronary anatomical complexity, and incident clinical events. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633).

Relationship of diabetes, heart failure, and N-terminal pro-B-type natriuretic peptide with cardiovascular outcomes in patients with atrial fibrillation.

AIMS: We aim to explore the relationship of heart failure (HF) and diabetes with cardiovascular (CV) death or hospitalization for HF (HHF) and to study the clinical utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected patient population with atrial fibrillation (AF). METHODS AND RESULTS: Patients with AF admitted to a tertiary academic center between January 2005 and July 2019 were identified through a search of electronic health records. We used Cox regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, HF, body mass index, prior myocardial infarction, coronary artery disease, hypertension, smoking, C-reactive protein, and low-density lipoprotein cholesterol. To select the most informative variables, we performed a least absolute shrinkage and selection operator Cox regression with 10-fold cross-validation. In total, 7412 patients (median age 70 years, 39.7% female) were included in this analysis and followed over a median of 4.5 years. Both diabetes [adjusted (Adj.) HR 1.87, 95% CI 1.55-2.25] and HF (Adj. HR 2.57, 95% CI 2.22-2.98) were significantly associated with CV death/HHF after multivariable adjustment. Compared with patients with diabetes, HF patients had a higher risk of HHF but a similar risk of CV and all-cause death. NT-proBNP showed good discriminatory performance (area under the curve 0.78, 95% CI 0.77-0.80) and the addition of NT-proBNP to the covariates used for adjustment resulted in a significant area under the curve improvement (Δ = 0.04, P < 0.001). With least absolute shrinkage and selection operator, the strongest associations for CV death/HHF were obtained for NT-proBNP [HR 1.91 per 1-SD in log-transformed biomarker], HF (HR 1.72), and diabetes (HR 1.56). CONCLUSIONS: Diabetes and HF were independently associated with an increased risk of CV death/HHF in an unselected AF patient population, and NT-proBNP improved risk assessment. These findings suggest that AF patients with diabetes and/or HF should be managed not only for their risk of stroke and systemic embolic events but also for CV death/HHF.

Early aspirin use, allograft rejection, and cardiac allograft vasculopathy in heart transplantation.

BACKGROUND: Early aspirin (ASA) use after orthotopic heart transplantation (OHT) has been associated with lower rates of cardiac allograft vasculopathy (CAV). We hypothesized that the inverse association between ASA use and CAV incidence may be most pronounced in patients with allograft rejection. METHODS: Patients receiving OHT at a single center 2004-2010 (n = 120) were categorized by early ASA use post-transplant (ASA use for > 6 months in the first year) and the presence of biopsy-defined acute cellular rejection (ACR) and/or antibody-mediated rejection (AMR) during 5-year follow-up. Propensity scores for ASA treatment were estimated using boosting models and applied by inverse probability of treatment weighting. The association between ASA use and time to moderate/severe CAV (ISHLT ≥ 2) was investigated. RESULTS: Among patients with ACR or AMR, ASA therapy was associated with significantly lower rates of CAV≥ 2 (3.3 vs. 30.1%; P = .001; HRadj .07; 95% CI .01-.52), whereas ASA therapy was not associated with lower rates of CAV in patients with no rejection (5.6 vs. 5.3%; P = .90; HRadj 1.26; 95% CI .08-20.30; pinteraction  = .09). CONCLUSIONS: Early ASA use after OHT was associated with lower rates of moderate to severe CAV only in those patients with episodes of allograft rejection.

Relationship between markers of inflammation and hemodynamic stress and death in patients with out-of-hospital cardiac arrest.

Biomarkers that reflect hemodynamic stress, inflammation, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction may improve risk stratification and add valuable pathobiological insight in patients with out-of-hospital cardiac arrest (OHCA). In total, 120 patients with OHCA who survived at least 48 h after return of spontaneous circulation were consecutively included in the present analysis. Concentrations of 30 biomarkers were measured simultaneously using a multi-panel biomarker assay. Cox regression models were adjusted for age, sex, estimated glomerular filtration rate, lactate concentration, bystander resuscitation, initial cardiac rhythm, and type of targeted temperature management. Overall, 57 patients (47.5%) had a favorable neurological outcome (Cerebral Performance Category ≤ 2) at 30 days, while palliative care was initiated in 49 patients (40.8%), and 52 patients (43.3%) died. After correction for multiple testing with Bonferroni-Holm, 8 biomarkers (including Angiopoietin-2, Procalcitonin, Resistin, IL-4Rα, MMP-8, TNFα, Renin, and IL-1α) were significantly associated with all-cause death. After multivariable adjustment, only angiopoietin-2 (Adjusted (Adj) hazard ratio (HR) per 1-unit increase in standardized biomarker concentrations 1.52 (95% CI 1.16-1.99)) and renin (Adj HR 1.32 (95% CI 1.06-1.65) remained independently associated with an increased risk of death. The discriminatory performance indicated good performance for angiopoietin-2 (area under the curve (AUC): 0.75 (95% CI 0.66-0.75) and was significantly higher (P = 0.011) as compared with renin (AUC: 0.60, 95% CI 0.50-0.60). In conclusion, angiopoietin-2 was significantly associated with all-cause mortality in patients with OHCA who survived the first 48 h and may prove to be useful for risk stratification of these patients.

Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization.

OBJECTIVES: This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization. BACKGROUND: PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall. METHODS: FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG). RESULTS: In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years). CONCLUSIONS: Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

Serum neprilysin and the risk of death in patients with out-of-hospital cardiac arrest of non-traumatic origin.

BACKGROUND: Early risk stratification remains an unmet clinical need in patients with in out-of-hospital cardiac arrest. We hypothesised that soluble neprilysin may represent a promising biomarker in patients with out-of-hospital cardiac arrest of non-traumatic origin and provide new pathobiological insight. METHODS: This pilot study was a biomarker analysis from the Heidelberg Resuscitation Registry. Serum soluble neprilysin levels on admission were measured in 144 patients with successful return of spontaneous circulation after out-of-hospital cardiac arrest of non-traumatic origin. The primary endpoint was time to all-cause mortality. KM Event Rates are reported. Cox models were adjusted for age, bystander resuscitation, initial ECG rhythm, baseline estimated glomerular filtration rate, baseline lactate, left ventricular function at baseline, and targeted temperature management. RESULTS: In total, 90 (62.5%) patients died over a follow-up of at least 30 days. Soluble neprilysin correlated weakly with high-sensitivity troponin T (r=0.18, P=0.032) but did not correlate significantly with estimated glomerular filtration rate (r=-0.12) or lactate (r=0.11). Patients with elevated soluble neprilysin levels on admission were at significantly higher risk of all-cause mortality (Q4 69.1% vs. Q1 48.4%). After multivariable adjustment, soluble neprilysin in the top quartile (Q4) was significantly associated with all-cause mortality (Q4 vs. Q1: adjusted hazard ratio 2.48 (1.20-5.12)). In an adjusted multimarker model including high-sensitivity troponin T and high-sensitivity C-reactive protein, soluble neprilysin and high-sensitivity troponin T remained independently associated with all-cause mortality (soluble neprilysin: adjusted hazard ratio 2.27 (1.08-4.78); high-sensitivity troponin T: adjusted hazard ratio 3.40 (1.63-7.09)). CONCLUSION: Soluble neprilysin, measured as early as on hospital admission, was independently associated with all-cause mortality in patients with out-of-hospital cardiac arrest of non-traumatic origin and may prove to be useful in the estimation of risk in these patients.

Biomarker of Collagen Turnover (C-Terminal Telopeptide) and Prognosis in Patients With Non- ST -Elevation Acute Coronary Syndromes.

Background Small studies have suggested an association between markers of collagen turnover and adverse outcomes in heart failure ( HF ). We examined C-terminal telopeptide (beta- CT x) and the risk of cardiovascular death or new or worsening HF in non- ST -elevation acute coronary syndrome. Methods and Results We measured baseline serum beta- CT x, NT -pro BNP (N-terminal pro-B-type natriuretic peptide), hsTnT (high-sensitivity cardiac troponin T) and hs CRP (high-sensitivity C-reactive protein) (Roche Diagnostics) in a nested biomarker analysis (n=4094) from a study of patients with non- ST -elevation acute coronary syndrome. The relationship between quartiles of beta- CT x and cardiovascular death or HF over a median follow-up time of 12 months was analyzed using adjusted Cox models. Higher beta- CT x levels identified a significantly higher risk of cardiovascular death/ HF (Q4 10.9% versus Q1 3.8%, Logrank P<0.001). After multivariable adjustment, beta- CT x in the top quartile (Q4) was associated with cardiovascular death/ HF (Q4 versus Q1: adjusted hazard ratio 2.22 [1.50-3.27]) and its components (Q4 versus Q1: cardiovascular death: adjusted hazard ratio 2.48 [1.46-4.21]; HF : adjusted hazard ratio 2.04 [1.26-3.30]). In an adjusted multimarker model including NT -pro BNP , hsTnT, and hs CRP , beta- CT x remained independently associated with cardiovascular death/ HF (Q4 versus Q1: adjusted hazard ratio 1.98 [1.34-2.93]) and its components. Beta- CT x correlated weakly with NT -pro BNP ( r=0.17, P<0.001) and left ventricular ejection fraction ( r=-0.05, P=0.008) and did not correlate with hsTnT ( r=0.02, P=0.20), or hs CRP ( r=-0.03, P=0.09). Conclusions Levels of beta- CT x, a biomarker of collagen turnover, were associated with cardiovascular death and HF in patients with non- ST -elevation acute coronary syndrome. This biomarker, which correlated only weakly or not significantly with traditional biomarkers of cardiovascular death and HF , may provide complementary pathobiological insight and risk stratification in these patients.

Prognostic role of GDF-15 across the spectrum of clinical risk in patients with NSTE-ACS.

Background Growth differentiation factor (GDF)-15 has been shown to predict cardiovascular (CV) outcomes in acute coronary syndrome (ACS) using non-commercial assays. We evaluated the prognostic performance of GDF-15 measured with the first clinically available assay. Furthermore, we evaluated whether GDF-15 was associated with CV death or heart failure (HF) across the spectrum of risk in non-ST-segment elevation (NSTE)-ACS. Methods We measured baseline GDF-15 (Roche, Elecsys) in 4330 patients with NSTE-ACS enrolled in MERLIN-TIMI 36. Patients were categorized using a priori thresholds of GDF-15 levels (<1200, 1200-1800, ≥1800 ng/L) and stratified according to estimated clinical risk per TIMI risk score (0-2, 3-4, and ≥5). Cox modeling included age, sex, BMI, smoking, HF, diabetes, renal function, NT-proBNP, hsTnT, and hsCRP. Results There were 2286 (53%), 1104 (25%), and 940 (22%) pts with GDF-15 <1200, 1200-1800, and ≥1800 respectively. GDF-15 was significantly associated after multivariable adjustment with CV death/HF modeled either as a categorical (1200-1800 ng/L: Adj hazard ratios [HR] 1.55 [1.09-2.19]; ≥1800 ng/L: Adj HR 1.94 [1.34-2.79]) or continuous variable (Adj HR 1.36 [1.16-1.60] per 1-unit increase in log2-transformed GDF-15). Notably, there was an interaction (Pinteraction=0.003) between TIMI risk score and GDF-15, with GDF-15 identifying the greatest incremental relative risk in those at lowest risk based on the TIMI risk score alone. Conclusions Using a clinically available assay, GDF-15 can be applied using established cut-off points to independently predict risk of CV death/HF in patients with NSTE-ACS. This incremental risk appears to be particularly robust among individuals traditionally identified as low risk.

Early aspirin use and the development of cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains a leading cause of morbidity and mortality after orthotopic heart transplantation (OHT). Little is known about the influence of aspirin on clinical expression of CAV. METHODS: We followed 120 patients with OHT at a single center for a median of 7 years and categorized them by the presence or absence of early aspirin therapy post-transplant (aspirin treatment ≥6 months in the first year). The association between aspirin use and time to the primary end-point of angiographic moderate or severe CAV (International Society for Heart and Lung Transplantation grade ≥2) was investigated. Propensity scores for aspirin treatment were estimated using boosting models and applied by inverse probability of treatment weighting (IPTW). RESULTS: Despite a preponderance of risk factors for CAV among patients receiving aspirin (male sex, ischemic heart disease as the etiology of heart failure, and smoking), aspirin therapy was associated with a lower rate of moderate or severe CAV at 5 years. Event-free survival was 95.9% for patients exposed to aspirin compared with 79.6% for patients without aspirin exposure (log-rank p = 0.005). IPTW-weighted Cox regression revealed a powerful inverse association between aspirin use and moderate to severe CAV (adjusted hazard ratio 0.13; 95% confidence interval 0.03-0.59), which was directionally consistent for CAV of any severity (adjusted hazard ratio 0.50; 95% confidence interval 0.23-1.08). CONCLUSIONS: This propensity score-based comparative observational analysis suggests that early aspirin exposure may be associated with a reduced risk of development of moderate to severe CAV. These findings warrant prospective validation in controlled investigations.