Camilla Hage

Association between cardiovascular vs. non‐cardiovascular co‐morbidities and outcomes in heart failure with preserved ejection fraction

The prevalence of cardiovascular and non‐cardiovascular co‐morbidities and their relative importance for outcomes in heart failure with preserved ejection fraction (HFPEF) remain poorly characterized. This study aimed to investigate this.

Rationale and design of the Karolinska-Rennes (KaRen) prospective study of dyssynchrony in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFPEF) is common but not well understood. Electrical dyssynchrony in systolic heart failure is harmful. Little is known about the prevalence and the prognostic impact of dyssynchrony in HFPEF.

Contemporary aetiology, clinical characteristics and prognosis of adults with heart failure observed in a tertiary hospital in Tanzania: the prospective Tanzania Heart Failure (TaHeF) study

Objective This study aimed to describe the contemporary aetiology, clinical characteristics and mortality and its predictors in heart failure (HF) in Tanzania. Methods Design; Prospective observational study. Setting; Cardiovascular Center of the Muhimbili National Hospital in Dar es Salaam, Tanzania. Patients ≥18 years of age with HF defined by the Framingham criteria. Main outcome measure All-cause mortality. Results Among 427 included patients, 217 (51%) were females and the mean (SD) age was 55 (17) years. HF aetiologies included hypertension (45%), cardiomyopathy (28%), rheumatic heart disease (RHD) (12%) and ischaemic heart disease (9%). Concurrent atrial fibrillation (AF), clinically significant anaemia, diabetes, tuberculosis and HIV were found in 16%, 12%, 12%, 3% and 2%, respectively, while warfarin was used in 3% of the patients. The mortality rate, 22.4 per 100 person-years over a median follow-up of 7 months, was independently associated with AF, HR 3.4 (95% CI 1.6 to 7.0); in-patient 3.2 (1.5 to 6.8); anaemia 2.3 (1.2 to 4.5); pulmonary hypertension 2.1 (1.1 to 4.2) creatinine clearance 0.98 (0.97 to 1.00) and lack of education 2.3 (1.3 to 4.2). Conclusions In HF in Tanzania, patients are younger than in the developed world, but aetiologies are becoming more similar, with hypertension becoming more and RHD less important. Predictors of mortality possible to intervene against are anaemia, AF and lack of education.

Fasting glucose, HbA1c, or oral glucose tolerance testing for the detection of glucose abnormalities in patients with acute coronary syndromes

Background: Due to the negative prognostic impact, it is important to accurately detect undiagnosed glucose perturbations in patients with acute coronary syndromes (ACS). Design: This study compares oral glucose tolerance test (OGTT) to fasting plasma glucose (FPG) and HbA1c as screening tools. Methods: Patients hospitalized for ACS had an OGTT, FPG, and HbA1c measured 4–21 (median 6) days after admission as a screening process for an intervention study. Results: Out of 174 patients, 75 (43%) had a normal glucose tolerance, 63 (36%) impaired glucose tolerance (IGT), and 36 (21%) diabetes type 2 (T2DM). Of these, 20 were non-eligible, and of the remaining 79 patients, 52 had IGT and 27 T2DM according to the OGTT. In patients with IGT, the median FPG was 6.0 mmol/l and the median HbA1c was 39 mmol/mol. The corresponding levels in patients with T2DM were 6.3 mmol/l and 41 mmol/mol, respectively. Seventeen of the 27 patients with T2DM according to OGTT had not been disclosed if the screening had been based on FPG. HbA1c identified two patients. Conclusions: Compared to OGTT, the use of FPG or HbA1c alone leaves a majority of patients with IGT or T2DM undetected when screening for unknown glucose perturbations as a part of total risk assessment of patients with ACS.

New echocardiographic predictors of clinical outcome in patients presenting with heart failure and a preserved left ventricular ejection fraction: a subanalysis of the Ka (Karolinska) Ren (Rennes) Study

To identify electrocardiographic and echocardiographic predictors of mortality and hospitalizations for heart failure (HF) in the KaRen study.

Glycaemic control and restenosis after percutaneous coronary interventions in patients with diabetes mellitus: a report from the Insulin Diabetes Angioplasty study

Objective: We investigated the impact of glucose control on target lesion restenosis after PCI in patients with type 2 diabetes. Methods: Ninety-three consecutive patients with type 2 diabetes accepted for PCI were randomised to intensified glucose control based on insulin (I-group; n=44) or to continue ongoing glucose-lowering treatment (C-group; n=49).The treatment target was a FBG of 5—7 mmol/L and HbA1c <6.5%. Information on target lesion restenosis after six months was available in 82 patients. Results: At baseline HbA1c and FBG did not differ between the I- and C-groups, respectively (HbA1c: 6.5 vs. 6.5%; p=1.0 and FBG: 7.0 vs. 7.3 mmol/L; p=0.3). After six months there was no significant change in HbA1c or FBG in either group (change in HbA1c: -0.2 vs.-0.1%; p=0.3 and in FBG: +0.2 vs. -0.3 mmol/L; p=0.3 in the I- and C-groups, respectively). Target lesion restenosis at six months did not differ, I vs. C = 41 and 44% (p=0.8). Independent predictors for restenosis were previous myocardial infarction (OR 8.0, 95% CI 2.5—25.7; p=<0.001) and FBG at baseline (OR for an increase by 1 mmol/L = 1.4, 95% CI 1.1—1.9; p=0.015). Conclusions: Restenosis was predicted by baseline FBG suggesting that it would be of interest to target glucose normalisation in future trials. Intensified insulin treatment did not influence the rate of restenosis indicating that the main focus should be on lowering glucose rather than the tool to normalise glucose.

Inflammatory Biomarkers Predict Heart Failure Severity and Prognosis in Patients With Heart Failure With Preserved Ejection FractionCLINICAL PERSPECTIVE: A Holistic Proteomic Approach

Background— Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. Methods and Results— In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3–like protein 1 (1.35), C–C motif chemokine 20 (1.35), fatty acid–binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF-related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e′) and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome. Conclusions— In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov; Unique identifier: NCT00774709.

Sitagliptin improves beta-cell function in patients with acute coronary syndromes and newly diagnosed glucose abnormalities–the BEGAMI study

Newly detected impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM) are common in patients with acute coronary syndrome (ACS; i.e. unstable angina/myocardial infarction) and related to disturbed beta‐cell function. The aim of this study is to test the hypothesis that treatment with a dipeptidyl peptidase‐4 inhibitor initiated soon after a coronary event improves beta‐cell function.

Adaptive cardiovascular hormones in a spectrum of heart failure phenotypes

BACKGROUND/OBJECTIVES In heart failure (HF), activation of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and adrenomedullin (ADM) is adaptive. The activation of these peptides in relation to different HF phenotypes such as HF with preserved ejection fraction (HFpEF), reduced ejection fraction (HFrEF) and after left ventricular assist device (LVAD) and heart transplantation (HTx) remains poorly characterized. METHODS We measured and compared N-terminal (NT)-proBNP, mid-regional (MR)-proANP and mid-regional (MR)-proADM in 86 patients with HFpEF, 49 patients with HFrEF, 13 patients one year post-LVAD and 22 patients one year post-HTx. We assessed their prognostic impact using Kaplan-Meier analysis and multivariable Cox regression. RESULTS In HFpEF, HFrEF, LVAD and HTx, NT-proBNP, median (inter-quartile range), was 1000 (465-2335), 3145 (1475-5190), 1430 (986-2570), and 208 (127-353) pmol/L, p < 0.001. MR-proANP was 313 (192-381), 449 (325-596), 276 (216-305), and 118 (96-163) pmol/L, p < 0.001. MR-proADM was 1.2 (0.9-1.6), 1.3 (0.9-2.0), 0.9 (0.7-1.4), and 0.7 (0.6-0.9) nmol/L, p < 0.001 overall and p = 0.212 HFpEF versus HFrEF. In both HFpEF and HFrEF, NT-proBNP and MR-proANP predicted survival free from HTx or LVAD, independent of age, gender, NYHA class and eGFR, whereas MR-proADM did not. CONCLUSIONS Patterns of the cardiomyocyte stress hormones NT-proBNP and MR-proANP suggest that compared to HFrEF, HFpEF may represent milder disease and LVAD and HTx may represent progressive resolution of HF severity. NT-proBNP and MR-proANP independently predicted prognosis in both HFpEF and HFrEF. In contrast, MR-proADM did not distinguish between HFpEF and HFrEF, did not predict prognosis in either, and may be more non-specific in HF.

Reductions in N-Terminal Pro-Brain Natriuretic Peptide Levels Are Associated With Lower Mortality and Heart Failure Hospitalization Rates in Patients With Heart Failure With Mid-Range and Preserved Ejection Fraction

Background—In heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF), feasible surrogate end points are needed for phase II trials. The aim was to assess whether a reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) is associated with improved mortality/morbidity in an unselected population of HFmrEF and HFpEF patients. Methods and Results—In the Swedish Heart Failure Registry, HFmrEF (EF=40%–49%) and HFpEF (EF≥50%) patients reporting at least 2 consecutive outpatient NT-proBNP assessments were prospectively studied. Associations between reduction in NT-proBNP and overall mortality, HF hospitalization, and their composite were assessed by multivariable Cox regressions, with NT-proBNP changes modeled as binary (decrease/increase) or quantitative predictor by restricted cubic splines. In 650 patients, at a median of 7 months between the 2 measurements of NT-proBNP and over a median follow-up of 1.65 years, 361 patients (55%) showed a reduction and 289 patients (45%) an increase in NT-proBNP. Change in NT-proBNP was associated with risk of outcomes. Fifty-seven patients (16%) who decreased their NT-proBNP versus 78 patients (27%) who increased it died from any cause (adjusted hazard ratio=0.53; 95% confidence interval=0.36–0.77), 61 (17%) versus 86 (30%) were hospitalized for HF (hazard ratio=0.41; 95% confidence interval=0.29–0.60), and 96 (27%) versus 125 (43%) reported the composite outcome (hazard ratio=0.46; 95% confidence interval=0.34–0.62). These findings were replicated in HFmrEF and HFpEF separately. Conclusions—In HFmrEF and HFpEF during routine care, decreases in NT-proBNP were associated with improved mortality and morbidity. Studies to determine whether NT-proBNP changes in response to therapy predict drug efficacy are needed.