Glucose-lowering interventions and risk assessment in patients with coronary heart disease and disturbed glucose metabolism

Background Abnormal glucose regulation (AGR) including impaired glucose tolerance (IGT) and diabetes mellitus type 2 (T2DM) are common in patients with stable and unstable coronary artery disease (CAD) and impair their prognosis. Available glucose lowering interventions have not fully succeeded in improving the detrimental prognosis and accurate screening methods and new treatment strategies are needed. The aims of this thesis were to 1. decrease the restenosis rate after percutaneous coronary intervention (PCI) in patients with T2DM 2. validate the oral glucose tolerance test (OGTT) for the detection of glucose disturbances in patients with acute coronary syndromes (ACS) 3. evaluate the accuracy of a technique for continuous glucose monitoring in patients in the coronary care unit (CCU) 4. improve beta-cell function in patients with ACS and newly detected AGR Restenosis in patients with T2DM (Study I) The restenosis rate six months after PCI was investigated in 93 patients with T2DM randomised to either intensive glucose control by means of insulin (I group; n=44) or to continue ongoing glucoselowering treatment (C group; n=49). At the end of the follow-up period restenosis rate was available in 82 patients. The glucose control did not differ between the two groups (change in HbA1c -0.2 vs.-0.1%; p=0.3 and in fasting blood glucose +0.2 vs. -0.3 mmol/L; p=0.3 in the I and C groups). The restenosis rate was 41% in the I and 44% in the C group (p=0.8). Independent predictors for restenosis were previous myocardial infarction (OR 8.0, 95% CI 2.5–25.7; p<0.001) and fasting blood glucose at baseline (OR 1.4, 95% CI 1.1–1.9; p=0.015). Screening for glucose abnormalities in ACS (Studies II and III) The value of an OGTT for screening of unknown AGR in patients with ACS was explored. Infarct size did not influence the result but patients with transmural myocardial infarctions (MI) (n=70) had higher glucose levels at admission and fasting during the next two days (7.0, 5.7, 5.4 mmol/L) compared to those with subendocardial MI (n=102; 6.0, 5.3, 5.0 mmol/L; p<0.001, p=0.01, p=0.004; Study II). More patients were classified as T2DM according to OGTT (n=27) compared to fasting plasma glucose (n=10) and HbA1c (n=2; Study III). Continuous glucose monitoring in the coronary care unit (Study IV) The accuracy of an intravenously inserted microdialysis catheter intended for continuous glucose monitoring was validated in 14 patients in a CCU setting. Although predominantly delivering correct values, the stability over time was insufficient. Thus the microdialysis technique requires further improvements to be useful in this setting. Beta-cell function in ACS (Study V) The effect of a DPP-IV inhibitor on beta-cell function, expressed as insulinogenic index (IGI) and acute insulin response to glucose (AIRg), in patients with ACS and newly discovered AGR was investigated by randomising 34 such patients to sitagliptin (S) and 37 to placebo (P). After 12 weeks of treatment the IGI improved in the sitagliptin group (S: 69.9 to 85.0 vs. P: 66.4 to 58.1 pmol/mmol; p=0.019) as did the AIRg (S:1394 to 1909 vs. P:1106 to 1043 pmol • l-1 • min-1; p<0.0001). Insulin resistance remained unaffected. Conclusion It is difficult to achieve glucose normalisation in patients with T2DM and CAD by means of available drugs. Early detection of AGR in patients with ACS is essential and an OGTT is a useful tool. New technology in the form of equipment for continuous glucose monitoring and novel treatment strategies e.g. DPP-IV inhibitors deserves further attention in attempts to improve the management and thereby prognosis in this vulnerable patient category

The nurse’s experiences with preventing and treatment of overweight in primary health care

Oppgavens hensikt er å belyse sykepleiernes erfaringer med å bidra til livsstilsendring hos overvektige pasienter i primærhelsetjenesten. Sykepleierne bygger relasjon med pasienten for å kunne gi individuell veiledning. Sykepleierne føler mangel på- og ønsker mer veiledningskunnskap. Sykepleierne ønsker å arbeide tverrfaglig med andre profesjoner. Sykepleierne erfarer mangel på tid og pasientens holdninger som barrierer for å lykkes med livsstilsveiledning

Persistent High Burden of Heart Failure Across the Ejection Fraction Spectrum in a Nationwide Setting

Background Heart failure (HF) has a dramatic impact on worldwide health care systems that is determined by the growing prevalence of and the high exposure to cardiovascular and noncardiovascular events. Prognosis remains poor. We sought to compare a large population with HF across the ejection fraction (EF) spectrum with a population without HF for patient characteristics, and HF, cardiovascular, and noncardiovascular outcomes. Methods and Results Patients with HF registered in the Swedish HF registry in 2005 to 2018 were compared 1:3 with a sex-, age-, and county-matched population without HF. Outcomes were cardiovascular and noncardiovascular mortality and hospitalizations. Of 76 453 patients with HF, 53% had reduced EF, 23% mildly reduced EF, and 24% preserved EF. Compared with those without HF, patients with HF had more cardiovascular and noncardiovascular comorbidities and worse socioeconomic status. Incidence of cardiovascular and noncardiovascular events was higher in people with HF versus non-HF, with increased risk of all-cause (hazard ratio [HR], 2.53 [95% CI, 2.50-2.56]), cardiovascular (HR, 4.67 [95% CI, 4.59-4.76]), and noncardiovascular (HR, 1.49 [95% CI, 1.46-1.52]) mortality, 2- to 5-fold higher risk of first/repeated cardiovascular and noncardiovascular hospitalizations, and ~4 times longer in-hospital length of stay for any cause. Patients with HF with reduced EF had higher risk of HF hospitalizations, whereas those with HF with preserved EF had higher risk of all-cause and noncardiovascular hospitalization and mortality. Conclusions Patients with HF exert a high health care burden, with a much higher risk of cardiovascular, all-cause, and noncardiovascular events, and nearly 4 times as many days spent in hospital compared with those without HF. These epidemiological data may enable strategies for optimal resource allocation and HF trial design

General and Eating Disorder Specific Flexibility: Development and Validation of the Eating Disorder Flexibility Index (EDFLIX) Questionnaire

Findings from studies investigating cognitive flexibility in eating disorders (EDs) are inconsistent, and although neuropsychological tests are commonly used to measure these skills, they may not be particularly effective in predicting everyday functioning. Also, extant studies have largely focused on flexibility in anorexia nervosa (AN), with assessments targeting general rather than specific flexibility, and cognitive, rather than behavioral flexibility. Knowledge regarding ED specific flexibility and flexibility in bulimia nervosa (BN) and binge eating disorder (BED) is still scarce. The aim of this study was to develop and validate a novel measure assessing general and ED specific flexibility in a diagnostically diverse sample, and in healthy controls (HCs). A sample of 207 adult individuals with EDs (55% AN, 29% BN, 16% BED) and 288 HCs responded to an online, 51-item, pilot questionnaire on ED specific and general flexibility. In addition, participants completed the shift subscale from the Behavior Rating Inventory of Executive Function Adult version (BRIEF-A), and the Eating Disorder Diagnostic Scale (EDDS). A principal component analysis (PCA) in the clinical sample yielded a 36-item, three-factor solution capturing general flexibility, flexibility related to food and exercise, and flexibility concerning body shape and weight. Results showed that the measure had good to excellent internal consistency, and good convergent validity. A confirmatory factor analysis (CFA) using data from HCs revealed good fit indexes, supporting the original factor solution. A receiver operating characteristics analysis (ROC) demonstrated excellent accuracy in distinguishing scores from those with and without EDs. A cutoff score of 136 yielded the most balanced sensitivity and specificity. Significant differences in general and ED specific flexibility were found between individuals with and without EDs. Overall, HCs achieved the highest flexibility scores, followed by those with BED, BN, and AN. In sum this novel measure, the Eating Disorder Flexibility Index (EDFLIX) questionnaire, was found to be reliable and valid in the assessment of cognitive and behavioral flexibility, with results offering support for the conceptual distinction between general and ED related flexibility. The study also provides strong evidence for the discriminant validity of the EDFLIX with results revealing significant differences in flexibility in people with and without EDs. In addition, significant differences in flexibility also emerged when comparing diagnostic groups, indicating the utility of the assessment instrument for classification purposes

Left atrial strain improves estimation of filling pressures in heart failure: a simultaneous echocardiographic and invasive haemodynamic study

Left ventricular diastolic pressure estimation is essential for characterization of heart failure (HF). Patients with normal resting left atrial (LA) pressures (LAP), but steep LAP elevation on exertion, pose a particular diagnostic challenge. Current recommendations on echocardiographic LAP estimation have limited accuracy. Our aim was to investigate whether LA mechanical alterations assessed by LA strain (LA-GS) can contribute to non-invasive LAP diagnostics.Simultaneous echocardiographic and right heart catheterization (RHC) data at rest and during exercise was analyzed in 164 prospectively enrolled patients, referred for RHC due to HF symptoms. 56% had preserved ejection fraction (pEF). At rest, 97 patients displayed elevated mean pulmonary arterial wedge pressure (PAWPM); further 32 patients had normal resting, but elevated PAWPM during exercise. LA-GS demonstrated a stronger relationship with resting PAWPM (r = - 0.61, p < 0.001) than any of the indices (E/e', LAVi, TRVmax) incorporated in the currently recommended diagnostic algorithm. The diagnostic ability of LA-GS for detecting elevated resting PAWPM (AUC: 0.80, p < 0.001) outperformed that of the recommended algorithm (AUC: 0.69). Importantly, resting LA-GS performed even better in identifying patients with pathological PAWPM either at rest or during stress (AUC: 0.90, p < 0.001), whereas the diagnostic potential of the current algorithm was modest and limited to pEF patients (AUC = 0.72). Finally, among the non-invasive indices, LA-GS entailed the strongest prognostic value for death or heart transplantation (OR: 2.7; p < 0.05).LA-GS comprises a robust method for PAWPM assessment at rest. More importantly, it reliably discerns pathological PAWPM rise on exertion despite normal resting pressures

Association of Coronary Microvascular Dysfunction With Heart Failure Hospitalizations and Mortality in Heart Failure With Preserved Ejection Fraction:A Follow-up in the PROMIS-HFpEF Study

Background: Coronary microvascular dysfunction (CMD) is common in heart failure with preserved ejection fraction (HFpEF). We assessed the association of CMD with hospitalization and mortality in HFpEF. Methods and Results: We assessed the 1-year outcomes in patients from the PROMIS-HFpEF study, a prospective observational study of patients with chronic stable HFpEF undergoing coronary flow reserve measurements. Outcomes were (1) time to cardiovascular (CV) death/first HF hospitalization, (2) CV death/recurrent HF hospitalizations, (3) all-cause death/first HF hospitalization, and (4) first and (5) recurrent all-cause hospitalizations. CMD was defined as coronary flow reserve of Conclusions: In this exploratory assessment of the prognostic role of CMD in HFpEF, CMD was independently associated with primarily CVand HF-specific events. The high prevalence of CMD and its CV and HF specific prognostic role suggest CMD may be a potential treatment target in HFpEF

Sex differences in proteomic correlates of coronary microvascular dysfunction among patients with heart failure and preserved ejection fraction

Aims: Little information is available on sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF). We investigated sex-specific proteomic profiles associated with CMD in patients with HFpEF. Methods and results: Using the prospective multinational PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF; n = 182; 54.6% women), we compared clinical and biomarker correlates of CMD (defined as coronary flow reserve [CFR] <2.5) between men and women with HFpEF. We used lasso penalized regression to analyse 242 biomarkers from high-throughput proximity extension assays, adjusting for age, body mass index, creatinine, smoking and study site. The prevalence of CMD was similarly high in men and women with HFpEF (77% vs. 70%; p = 0.27). Proteomic correlates of CFR differed by sex, with 10 versus 16 non-overlapping biomarkers independently associated with CFR in men versus women, respectively. In men, proteomic correlates of CFR included chemokine ligand 20, brain natriuretic peptide, proteinase 3, transglutaminase 2, pregnancy-associated plasma protein A and tumour necrosis factor receptor superfamily member 14. Among women, the strongest proteomic correlates with CFR were insulin-like growth factor-binding protein 1, phage shock protein D, CUB domain-containing protein 1, prostasin, decorin, FMS-like tyrosine kinase 3, ligand growth differentiation factor 15, spondin-1, delta/notch-like epidermal growth factor-related receptor and tumour necrosis factor receptor superfamily member 13B. Pathway analyses suggested that CMD was related to the inflammation-mediated chemokine and cytokine signalling pathway among men with HFpEF, and the P13-kinase and transforming growth factor-beta signalling pathway among women with HFpEF. Conclusion: While the prevalence of CMD among men and women with HFpEF is similar, the drivers of microvascular dysfunction may differ by sex. The current inflammatory paradigm of CMD in HFpEF potentially predominates in men, while derangement in ventricular remodelling and fibrosis may play a more important role in women

Disproportionate left atrial myopathy in heart failure with preserved ejection fraction among participants of the PROMIS-HFpEF study

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF

Biomarker changes as surrogate endpoints in early-phase trials in heart failure with reduced ejection fraction

Aims: No biomarker has achieved widespread acceptance as a surrogate endpoint for early‐phase heart failure (HF) trials. We assessed whether changes over time in a panel of plasma biomarkers were associated with subsequent morbidity/mortality in HF with reduced ejection fraction (HFrEF). Methods and results: In 1040 patients with HFrEF from the BIOSTAT‐CHF cohort, we investigated the associations between changes in the plasma concentrations of 30 biomarkers, before (baseline) and after (9 months) attempted optimization of guideline‐recommended therapy, on top of the BIOSTAT risk score and the subsequent risk of HF hospitalization/all‐cause mortality using Cox regression models. C‐statistics were calculated to assess discriminatory power of biomarker changes/month‐nine assessment. Changes in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and WAP four‐disulphide core domain protein HE4 (WAP‐4C) were the only independent predictors of the outcome after adjusting for their baseline plasma concentration, 28 other biomarkers (both baseline and changes), and BIOSTAT risk score at baseline. When adjusting for month‐nine rather than baseline biomarkers concentrations, only changes in NT‐proBNP were independently associated with the outcome. The C‐statistic of the model including the BIOSTAT risk score and NT‐proBNP increased by 4% when changes were considered on top of baseline concentrations and by 1% when changes in NT‐proBNP were considered on top of its month‐nine concentrations and the BIOSTAT risk score. Conclusions: Among 30 relevant biomarkers, a change over time was significantly and independently associated with HF hospitalization/all‐cause death only for NT‐proBNP. Changes over time were modestly more prognostic than baseline or end‐values alone. Changes in biomarkers should be further explored as potential surrogate endpoints in early phase HF trials