Dataset Information

Abnormal plasma ceramides refine high-risk patients with worsening heart failure.

ABSTRACT:

Background

Worsening heart failure (WHF) is a heterogeneous clinical syndrome with poor prognosis. More effective risk stratification tools are required to identify high-risk patients. Evidence suggest that aberrant ceramide accumulation can be affected by heart failure risk factors and as a driver of tissue damage. We hypothesized that specific ceramide lengths and ratios serve as biomarkers for risk stratification in WHF patients by reflecting pathological changes of distinct organ dysfunctions.

Medthods

We measured seven plasma ceramides using liquid chromatography-mass spectrometry (LC-MS) in 1,558 patients, including 1,262 participants in retrospective discovery set and 296 WHF patients in prospective validation set in BIOMS-HF study (Registry Study of Biomarkers in Heart Failure). Univariable and multivariable logistic regression models were constructed to identify associations of ceramides with organ dysfunctions.

Results

We constructed three ceramide-based scores linked independently to heart, liver, and kidney dysfunction, with ceramides and ratios included in each score specifying systemic inflammation, chronic metabolic disorder, and water-sodium retention. The combined ceramide heart failure score (CHFS) was independently associated with adverse outcomes [Hazard Ratio, 2.80 (95% CI: 1.78-4.40; P < 0.001); 2.68 995% CI: 1.12-6.46; P = 0.028)] and improved the predictive value of Acute Decompensated Heart Failure National Registry score and BNP [net reclassification index, 0.34 (95% confidence interval, CI: 0.19-0.50); 0.42 (95% CI: 0.13-0.70)] in the discovery and validation set, respectively. Lower BNP levels, but higher CHFS had the highest hazard of future adverse events in WHF patients.

Conclusion

Abnormal plasma ceramides, associated with heart and peripheral organ dysfunctions, provide incremental prognostic information over the ADHERE score and brain natriuretic peptide concentration for risk stratification in WHF patients. This may facilitate the reclassification of high-risk patients in need of aggressive therapeutic interventions.

SUBMITTER: Ren L

PROVIDER: S-EPMC10339027 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Abnormal plasma ceramides refine high-risk patients with worsening heart failure.

Ren Lu L Li Fengjuan F Tan Xin X Fan Yangkai Y Ke Bingbing B Zhang Yixin Y Jiang Hongfeng H Jia Lixin L Wang Yuan Y Du Jie J

Frontiers in cardiovascular medicine 20230629

<h4>Background</h4>Worsening heart failure (WHF) is a heterogeneous clinical syndrome with poor prognosis. More effective risk stratification tools are required to identify high-risk patients. Evidence suggest that aberrant ceramide accumulation can be affected by heart failure risk factors and as a driver of tissue damage. We hypothesized that specific ceramide lengths and ratios serve as biomarkers for risk stratification in WHF patients by reflecting pathological changes of distinct organ dys ...[more]

PMID: 37456812

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Project description:BackgroundCeramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the ceramide (Cer). However, the associations of different circulating Cer species, and their sphingomyelin (SM) precursors, with heart failure have received limited attention.Methods and resultsWe studied the associations of plasma Cer and SM species with incident heart failure in the Cardiovascular Health Study. We examined 8 species: Cer and SM with palmitic acid (Cer-16 and SM-16), species with arachidic acid (Cer-20 and SM-20), species with behenic acid (Cer-22 and SM-22), and species with lignoceric acid (Cer-24 and SM-24). During a median follow-up of 9.4 years, we identified 1179 cases of incident heart failure among 4249 study participants. In Cox regression analyses adjusted for risk factors, higher levels of Cer-16 and SM-16 were associated with higher risk of incident heart failure (hazard ratio for one SD increase:1.25 [95% CI, 1.16-1.36] and 1.28 [1.18-1.40], respectively). In contrast, higher levels of Cer-22 were associated with lower risk of heart failure in multivariable analyses further adjusted for Cer-16 (hazard ratio, 0.85 [0.78-0.92]); and higher levels of SM-20, SM-22 and SM-24 were associated with lower risk of heart failure in analyses further adjusted for SM-16 (hazard ratios, 0.83 [0.77-0.90], 0.81 [0.75-0.88], and 0.83 [0.77-0.90], respectively). No statistically significant interactions with age, sex, black race, body mass index, or baseline coronary heart disease were detected. Similar associations were observed for heart failure with preserved (n=529) or reduced (n=348) ejection fraction.ConclusionsThis study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure.Clinical trial registrationURL: https://www.clinicaltrials.gov . Unique identifier: NCT00005133.

Project description:AimsThis study aims to develop and validate an optimal model for predicting worsening heart failure (WHF). Multiple machine learning (ML) algorithms were compared, and the results were interpreted using SHapley Additive exPlanations (SHAP). A clinical risk calculation tool was subsequently developed based on these findings.Methods and resultsThis nested case-control study included 200 patients with chronic heart failure (CHF) from the China-Japan Friendship Hospital (September 2019 to December 2022). Sixty-five variables were collected, including basic information, physical and chemical examinations, and quality of life assessments. WHF occurrence within a 3-month follow-up was the outcome event. Variables were screened using LASSO regression, univariate analysis, and comparison of key variables in multiple ML models. Eighty per cent of the data was used for training and 20% for testing. The best models were identified by integrating nine ML algorithms and interpreted using SHAP, and to develop a final risk calculation tool. Among participants, 68 (34.0%) were female, with a mean age (standard deviation, SD) of 68.57 (12.80) years. During the follow-up, 60 participants (30%) developed WHF. N-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine (Cr), uric acid (UA), haemoglobin (Hb), and emotional area score on the Minnesota Heart Failure Quality of Life Questionnaire were critical predictors of WHF occurrence. The random forest (RF) model was the best model to predict WHF with an area under the curve (AUC) (95% confidence interval, CI) of 0.842 (0.675-1.000), accuracy of 0.775, sensitivity of 0.900, specificity of 0.833, negative predictive value of 0.800, and positive predictive value of 0.600 for the test set. SHAP analysis highlighted NT-proBNP, UA, and Cr as significant predictors. An online risk predictor based on the RF model was developed for personalized WHF risk assessment.ConclusionsThis study identifies NT-proBNP, Cr, UA, Hb, and emotional area scores as crucial predictors of WHF in CHF patients. Among the nine ML algorithms assessed, the RF model showed the highest predictive accuracy. SHAP analysis further emphasized NT-proBNP, UA, and Cr as the most significant predictors. An online risk prediction tool based on the RF model was subsequently developed to enhance early and personalized WHF risk assessment in clinical settings.

Project description:BackgroundHospitalization for heart failure (HF) is associated with increased risk of death among patients with chronic HF. The degree to which hospitalization for HF is a distinct biologic entity with independent prognostic value versus a marker of higher risk chronic HF patients is unclear.MethodsAfter excluding patients with new-onset HF, the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) included 4205 patients hospitalized for worsening chronic HF with reduced or preserved ejection fraction. The present analysis compared patients by presence or absence of prior HF hospitalization within 12 months and by timing of prior HF hospitalization relative to index hospitalization. Associations with 180-day all-cause mortality were assessed, including adjustment for 27 prespecified clinical factors.ResultsOverall, 2241 (53.3%) patients had a HF hospitalization within the prior 12 months and 1964 (46.7%) did not. Mortality rates at 180 days were 15.5% and 11.9%, respectively. In unadjusted analyses, prior HF hospitalization was associated with increased risk of 180-day mortality (HR, 1.35 [95% CI, 1.14-1.59]; P<0.01). After adjustment, the point estimate was attenuated and the association not statistically significant (HR, 1.18 [95% CI, 0.99-1.40]; P=0.064). Similarly, after adjustment, compared with patients without prior hospitalization, prior HF hospitalization was not associated with mortality, irrespective of timing (0-4 months: HR, 1.10 [95% CI, 0.87-1.39], P=0.41; 4-8 months: HR, 0.95 [95% CI, 0.70-1.27]; P=0.72; 8-12 months: HR, 1.06 [95% CI, 0.74-1.51], P=0.77; >12 months: HR, 0.81 [95% CI, 0.63-1.06], P=0.12).ConclusionsIn this cohort of patients hospitalized for worsening HF, prior HF hospitalization was not associated with 180-day mortality after comprehensively accounting for patient characteristics measured during the index patient visit. Clinical confounders measured at the point-of-care may explain previously observed associations between prior HF hospitalization and mortality, and these clinical factors may be a more direct means of predicting patient survival. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00475852.

Project description:AimsThe importance of true worsening renal failure (WRF), which is associated with a poor prognosis, had been suggested in patients with acute heart failure (AHF). The aim of the present study was to establish the biomarker strategy for the prediction of true WRF in AHF.Methods and resultsTwo hundred eighty-one patients with AHF were analysed. Their biomarkers were measured within 30 min of admission. Patients were assigned to the non-WRF (n = 168), pseudo-WRF (n = 56), or true-WRF (n = 57) groups using the criteria of both acute kidney injury on admission and increasing serum creatinine value during the first 7 days. A Kaplan-Meier curve showed that the survival and heart failure event rate of the true-WRF group within 1000 days was significantly lower than that of the non-WRF and pseudo-WRF groups (P ≤ 0.001). The multivariate Cox regression model also indicated that true WRF was an independent predictor of 1000 day mortality and heart failure events [hazard ratio: 4.315, 95% confidence interval (CI): 2.466-7.550, P ≤ 0.001, and hazard ratio: 2.834, 95% CI: 1.893-4.243, P ≤ 0.001, respectively]. The serum heart-type fatty acid-binding protein (s-HFABP) levels were significantly higher in the true-WRF group than in the non-WRF and pseudo-WRF groups (P ≤ 0.001). The multivariate logistic regression model indicated that the predictive biomarker for the true-WRF group was the s-HFABP level (odds ratio: 5.472, 95% CI: 2.729-10.972, P ≤ 0.001). The sensitivity and specificity for indicating the presence of true WRF were 73.7% and 76.8% (area under the curve = 0.831) for s-HFABP in whole patients, respectively, and 94.7% and 72.7% (area under the curve = 0.904) in non-chronic kidney disease (CKD) patients, respectively.ConclusionsCardiac biomarkers, especially the s-HFABP, might predict the development of true WRF in AHF patients. Furthermore, the predictive value was higher in AHF patients without CKD than in those with CKD.

Project description:ImportanceAdditional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes.ObjectiveTo evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes.Design, setting, and participantsExploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019.InterventionsAddition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy.Main outcomes and measuresThe primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%.ResultsAmong 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes.Conclusions and relevanceIn this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status.Trial registrationClinicalTrials.gov Identifier: NCT03036124.

Dataset Information

Abnormal plasma ceramides refine high-risk patients with worsening heart failure.

Background

Medthods

Results

Conclusion

Publications

Abnormal plasma ceramides refine high-risk patients with worsening heart failure.

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