Dataset Information

Impact of diabetes on serum biomarkers in heart failure with preserved ejection fraction: insights from the TOPCAT trial.

ABSTRACT:

Aims

Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non-diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs. no diabetes (non-DM) and the impact of spironolactone on these biomarkers. This study aims to address such gaps in the literature.

Methods and results

Biomarkers were measured at randomization and at 12 months in 248 patients enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist's North American cohort. At baseline, DM patients had significantly lower estimated glomerular filtration rate and higher high-sensitivity C-reactive protein, pro-collagen type III amino-terminal peptide, tissue inhibitor of metalloproteinase 1 (TIMP-1), and galectin-3 levels than those without diabetes. There was a significantly larger 12 month increase in levels of high-sensitivity troponin T (hs-TnT), a marker of myocyte death, in DM patients. Elevated pro-collagen type III amino-terminal peptide and galectin-3 levels were associated with an increased risk of the primary outcome (cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization) in DM patients, but not in those without diabetes. A statistically significant interaction between spironolactone and diabetes status was observed for hs-TnT and for TIMP-1, with greater biomarker reductions among those with diabetes treated with spironolactone.

Conclusions

The presence of diabetes is associated with higher levels of cardiac, profibrotic, and proinflammatory biomarkers in HFpEF. Spironolactone appears to alter the determinants of extracellular matrix remodelling in an anti-fibrotic fashion in patients with diabetes, reflected by changes in hs-TnT and TIMP-1 levels over time.

SUBMITTER: De Marco C

PROVIDER: S-EPMC8006665 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHeart failure with preserved ejection fraction (HFpEF) is a growing health problem without effective therapies. Epidemiological studies indicate that diabetes is a strong risk factor for HFpEF, and about 45% of patients with HFpEF are suffering from diabetes, yet the underlying mechanisms remain elusive.MethodsUsing a combination of echocardiography, hemodynamics, RNA-sequencing, molecular biology, in vitro and in vivo approaches, we investigated the roles of SIRT6 (sirtuin 6) in regulation of endothelial fatty acid (FA) transport and HFpEF in diabetes.ResultsWe first observed that endothelial SIRT6 expression was markedly diminished in cardiac tissues from heart failure patients with diabetes. We then established an experimental mouse model of HFpEF in diabetes induced by a combination of the long-term high-fat diet feeding and a low-dose streptozocin challenge. We also generated a unique humanized SIRT6 transgenic mouse model, in which a single copy of human SIRT6 transgene was engineered at mouse Rosa26 locus and conditionally induced with the Cre-loxP technology. We found that genetically restoring endothelial SIRT6 expression in the diabetic mice ameliorated diastolic dysfunction concurrently with decreased cardiac lipid accumulation. SIRT6 gain- or loss-of-function studies showed that SIRT6 downregulated endothelial FA uptake. Mechanistically, SIRT6 suppressed endothelial expression of PPARγ through SIRT6-dependent deacetylation of histone H3 lysine 9 around PPARγ promoter region; and PPARγ reduction mediated SIRT6-dependent inhibition of endothelial FA uptake. Importantly, oral administration of small molecule SIRT6 activator MDL-800 to diabetic mice mitigated cardiac lipid accumulation and diastolic dysfunction.ConclusionsThe impairment of endothelial SIRT6 expression links diabetes to HFpEF through the alteration of FA transport across the endothelial barrier. Genetic and pharmacological strategies that restored endothelial SIRT6 function in mice with diabetes alleviated experimental HFpEF by limiting FA uptake and improving cardiac metabolism, thus warranting further clinical evaluation.

Project description:Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor-deficient db/db mice with a 4-week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium-glucose cotransporter-2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B-type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short-term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone-treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.

Project description:AimThere is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre-diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre-diabetes in PARAGON-HF.Methods and resultsPatients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre-diabetes, 6.0%-6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre-diabetes. Compared to patients with normal HbA1c, patients with pre-diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT-proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35-1.88), total HFH (RR 1.67, 95% CI 1.39-2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07-1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre-diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00-1.60) and HFH (HR 1.35, 95% CI 1.03-1.77), but not of CV death (HR 1.02, 95% CI 0.75-1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with 'lean diabetes' had similar mortality rates to those with a higher body mass index, but lower rates of HFH.ConclusionPre-diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH.Clinical trial registrationClinicalTrials.gov Identifier NCT01920711.