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The Prognostic Significance of Diabetes and Microvascular Complications in Patients With Heart Failure With Preserved Ejection Fraction.

ABSTRACT: OBJECTIVE:This study examined the prognostic significance of diabetes and microvascular complications in patients with heart failure with preserved ejection fraction (HFpEF). RESEARCH DESIGN AND METHODS:This analysis included 3,385 patients (mean age 69 ± 9.6 years; 49% male; 89% white) with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT). Diabetes and microvascular complications were ascertained by self-reported history and medical record review. Microvascular complications included neuropathy, nephropathy, and retinopathy. Outcomes included hospitalization, hospitalization for heart failure, death, and cardiovascular death. Cox regression was used to examine the risk of each outcome associated with diabetes and microvascular complications. RESULTS:Of the 1,109 subjects (32%) with diabetes, 352 (32%) had at least one microvascular complication. Patients with diabetes and microvascular complications had an increased risk for hospitalization (no diabetes: referent; diabetes + no microvascular complication: hazard ratio [HR] 1.18, 95% CI 1.01, 1.37; diabetes + microvascular complications: HR 1.54, 95% CI 1.25, 1.89; P-trend <0.001), hospitalization for heart failure (no diabetes: referent; diabetes + no microvascular complication: HR 1.51, 95% CI 1.14, 1.99; diabetes + microvascular complications: HR 1.97, 95% CI 1.38, 2.80; P-trend <0.001), death (no diabetes: referent; diabetes + no microvascular complication: HR 1.35, 95% CI 1.04, 1.75; diabetes + microvascular complications: HR 1.73, 95% CI 1.22, 2.45; P-trend = 0.0017), and cardiovascular death (no diabetes: referent; diabetes + no microvascular complication: HR 1.34, 95% CI 0.96, 1.86; diabetes + microvascular complications: HR 1.70, 95% CI 1.09, 2.65; P-trend = 0.018). When the analysis was limited to participants who reported prior hospitalization for heart failure (n = 2,449), a higher risk of rehospitalization for heart failure was observed across diabetes categories (no diabetes: referent; diabetes + no microvascular complication: HR 1.40, 95% CI 1.01, 1.96; diabetes + microvascular complications: HR 1.78, 95% CI 1.18, 2.70; P-trend = 0.0036). CONCLUSIONS:Diabetes is associated with adverse cardiovascular outcomes in HFpEF, and the inherent risk of adverse outcomes in HFpEF patients with diabetes varies by the presence of microvascular complications.

SUBMITTER: Sandesara PB

PROVIDER: S-EPMC5741155 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Heart failure with preserved ejection fraction (HFpEF) is an increasingly studied entity accounting for 50% of all diagnosed heart failure and that has claimed its own dignity being markedly different from heart failure with reduced EF in terms of etiology and natural history (Graziani et al., 2018). Recently, a growing body of evidence points the finger toward microvascular dysfunction as the major determinant of the pathological cascade that justifies clinical manifestations (Crea et al., 2017). The high burden of comorbidities such as metabolic syndrome, hypertension, atrial fibrillation, chronic kidney disease, obstructive sleep apnea, and similar, could lead to a systemic inflammatory state that impacts the physiology of the endothelium and the perivascular environment, engaging complex molecular pathways that ultimately converge to myocardial fibrosis, stiffening, and dysfunction (Paulus and Tschope, 2013). These changes could even self-perpetrate with a positive feedback where hypoxia and locally released inflammatory cytokines trigger interstitial fibrosis and hypertrophy (Ohanyan et al., 2018). Identifying microvascular dysfunction both as the cause and the maintenance mechanism of this condition has opened the field to explore specific pharmacological targets like nitric oxide (NO) pathway, sarcomeric titin, transforming growth factor beta (TGF-β) pathway, immunomodulators or adenosine receptors, trying to tackle the endothelial impairment that lies in the background of this syndrome (Graziani et al., 2018;Lam et al., 2018). Yet, many questions remain, and the new data collected still lack a translation to improved treatment strategies. To further elaborate on this tangled and exponentially growing topic, we will review the evidence favoring a microvasculature-driven etiology of this condition, its clinical correlations, the proposed diagnostic workup, and the available/hypothesized therapeutic options to address microvascular dysfunction in the failing heart.

Project description:AimsThe relationship between diabetic microvascular complications and the incidence of two types of heart failure-heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] < 40%) and non-HFrEF (LVEF ≥ 40%)-in patients without prior heart failure has not been clarified. We herein examined the association between diabetic microvascular complications and HFrEF or non-HFrEF in patients with type 2 diabetes mellitus (T2DM) without prior heart failure.Methods and resultsIn this retrospective cohort study, we assessed the relationship between the presence of diabetic microvascular complications or severity of diabetic retinopathy (no apparent, non-proliferative and proliferative retinopathy) and nephropathy (normoalbuminuria, microalbuminuria, and macroalbuminuria) at baseline, with the primary outcome of first heart failure hospitalization classified as HFrEF or non-HFrEF in patients with type 2 diabetes mellitus without prior heart failure. Among 568 patients (69.2% males, mean age 66.2 ± 9.6 years), 70 experienced heart failure hospitalization (HFrEF: 24 and non-HFrEF: 46). Non-HFrEF hospitalization but not HFrEF hospitalization was significantly associated with the presence of diabetic microvascular complications. The incidence of non-HFrEF hospitalization was significantly higher in the proliferative retinopathy group than that in the no apparent retinopathy group (adjusted hazard ratio [HR] 2.96, 95% confidence interval [CI]: 1.09-6.83, P = 0.035) and in those with macroalbuminuria than in those with normoalbuminuria (adjusted HR 4.23, 95% CI: 2.24-7.85, P < 0.001) even after adjustment for age and sex. When non-HFrEF was classified into heart failure with mildly reduced ejection fraction (HFmrEF) (40% ≤ LVEF < 50%) and heart failure with preserved ejection fraction (HFpEF) (50% ≤ LVEF), HFmrEF and HFpEF hospitalizations were also found to be associated with the progression of retinopathy and nephropathy.ConclusionsIn patients with T2DM without prior heart failure, non-HFrEF hospitalization was more closely associated with the progression of diabetic microangiopathy than HFrEF. The development of non-HFrEF may be mediated through a mechanism similar to that of microvascular complications in these patients.

Project description:AimsThe HFA-PEFF score is a part of the stepwise diagnostic algorithm of heart failure with preserved ejection fraction (HFpEF). We aimed to evaluate the prognostic significance of the HFA-PEFF score on the clinical outcomes in patients with HFpEF.Methods and resultsThe Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) study is a prospective, multicentre, observational study in which collaborating hospitals in Osaka record clinical, echocardiographic, and outcome data of patients with acute decompensated heart failure with preserved left ventricular ejection fraction (≥50%) [UMIN-CTR ID: UMIN000021831]. Acute decompensated heart failure was diagnosed on the basis of the following criteria: (i) clinical symptoms and signs according to the Framingham Heart Study criteria; and (ii) serum N-terminal pro-B-type natriuretic peptide level of ≥400 pg/mL or brain natriuretic peptide level of ≥100 pg/mL. The HFA-PEFF score has functional, morphological, and biomarker domains. We evaluated the prognostic significance of the HFA-PEFF score (calculated based on the data at hospital discharge) on post-discharge clinical outcomes in this cohort. The primary endpoint of the present study was a composite of all-cause death and heart failure readmission. Between June 2016 and December 2019, 871 patients were enrolled from 26 hospitals (mean follow-up duration 399 ± 349 days). A total of 804 patients were finally analysed after excluding patients with scores of 0 (N = 5) and 1 (N = 15) from 824 patients with available HFA-PEFF score based on the echocardiographic and laboratory data at discharge. According to the laboratory and echocardiographic data at the time of discharge, 487 patients (59.1%) were diagnosed as HFpEF (HFA-PEFF score ≥ 5) while 317 patients (38.5%) had intermediate score. Kaplan-Meier analysis divided by the HFA-PEFF score [low, score 2-5 (N = 494) vs. high, score 6 (N = 310)] indicated that the HFA-PEFF score successfully stratified the patients for the primary endpoint (log-rank test P < 0.001). Cox proportional hazard model showed that the HFA-PEFF score was significantly associated with the primary endpoint (high score with reference to low score, adjusted hazard ratio 1.446, 95% confidence interval [1.099-1.902], P = 0.008).ConclusionThe HFA-PEFF score at discharge was significantly associated with the post-discharge clinical outcomes in acute decompensated heart failure patients with preserved ejection fraction. This study suggested clinical usefulness of the HFA-PEFF score not only as a diagnostic tool but also a practical prognostic tool.

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.

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The Prognostic Significance of Diabetes and Microvascular Complications in Patients With Heart Failure With Preserved Ejection Fraction.

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