Search

In patients with ST-elevation myocardial infarction (STEMI) the immune system is activated with an inflammatory response to follow. In STEMI patients with a severe inflammatory response, risk of development of cardiogenic shock (CS) seems increased. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a glycoprotein released from mature neutrophils and plasma concentration may increase immediately after STEMI. We therefore aimed to assess whether admission NGAL plasma concentration in patients with STEMI was associated with CS development after leaving the catheterization laboratory (late CS) and 30-day all-cause mortality. PATIENTS AND METHODS: From 1,892 consecutive patients with STEMI 1,626 (86%) had plasma NGAL concentration measured upon hospital admission before angiography throughout a 1-year period at two tertiary heart centers in Denmark. Patients were stratified according to NGAL quartiles (Q1-4). To assess late CS development, we adjusted for the Observatoire Régional Breton sur l'Infarctus risk score for late CS. For mortality assessment, we adjusted for gender, age, post-PCI culprit Thrombolysis in myocardial infarction flow, left ventricular ejection fraction (LVEF), kidney dysfunction, and being comatose after cardiac arrest. RESULTS: Increasing NGAL concentration was associated with higher age, more comorbidities, and more critical patient conditions including lower blood pressure and LVEF. When adjusted for factors associated with poor outcome, NGAL remained independently associated with both late CS development (Q4 vs. Q1-3) (OR (95% CI) 3.64 (1.79-7.41) and 30-day mortality (HR (95% CI) 3.18 (1.73-5.84)). CONCLUSION: Admission plasma concentration of NGAL in STEMI patients is independently associated with 30-day all-cause mortality and predictive of late CS development.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Rigshospitalets Forskningsfond (Grant number: 07IO) Hjerteforeningen (Grant number A6024) Lundbeckfonden (Grant number R186-2015-2132) BACKGROUND In patients with ST-elevation myocardial infarction (STEMI) increased inflammatory response is associated with development of cardiogenic shock (CS). Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a glycoprotein released from mature neutrophils and the plasma concentration of NGAL likely increases immediately after STEMI. PURPOSE We aimed to assess whether admission NGAL plasma concentration in patients with STEMI was associated with CS development after leaving the catheterization laboratory (late CS) and 30-day all-cause mortality. MATERIALS AND METHODS From 1892 consecutive patients with STEMI 1626 (86%) had plasma NGAL concentration measured upon hospital admission before angiography throughout a 1-year period at two tertiary heart centers in Denmark. Patients were stratified according to NGAL quartiles (Q1-4). To assess late CS development, we adjusted for the Observatoire Régional Breton sur l’Infarctus (ORBI) risk score for late CS. For mortality assessment, we adjusted for gender, age, post-PCI culprit Thrombolysis in myocardial infarction (TIMI) flow, left ventricular ejection fraction (LVEF), kidney dysfunction, admission lactate concentration and being comatose after cardiac arrest. RESULTS Increasing NGAL concentration was associated with higher age, more comorbidities (hypertension, diabetes, heart failure, previous stroke, and kidney dysfunction) and more critical patient conditions at presentation including lower blood pressure and LVEF. Plasma NGAL concentration was associated with both late CS development and 30-day mortality (Figure). When adjusted for factors associated with poor outcome, NGAL remained independently associated with both late CS development (Q4 vs. Q1-3) (OR (95% CI) 2.64 (1.57-6.03)) and 30-day mortality (HR (95% CI) 3.18 (1.46-6.93)). CONCLUSION High admission plasma concentration of NGAL in patients with STEMI was independently associated late CS development and 30-day all-cause mortality. Abstract Figure. NGAL quartiles and late CS/mortality

Glucagon (gcg) regulates hepatic glucose and amino acid (AA) metabolism, and increased gcg levels (hyperglucagonemia) contribute to hyperglycemia in diabetes. We hypothesized that the enzyme neprilysin (NEP) contributes to gcg degradation. We measured plasma gcg levels during a mixed meal in nine healthy men after a single dose of the NEP-inhibitor/angiotensin II receptor blocker (194 mg sacubitril/206 mg valsartan, 30 min prior to meal), a DPP-4 inhibitor (sitagliptin, 2x100mg), these combined, or the meal alone. Postprandial gcg levels were 2.7-fold higher in sacubitril/valsartan treated individuals compared to controls (P=0.005) and this was not significantly altered by the addition of sitagliptin (P=0.28). Sacubitril/valsartan also lowered postprandial plasma AA levels (P=0.01), but glucose levels were unaffected (P=0.76). In obese individuals (n=7), eight weeks sacubitril/valsartan treatment increased fasting gcg levels (P=0.02). To test whether NEP degrades gcg and diminishes its signaling, we performed mass-spectrometry and assessed cells transfected with the gcg receptor (gcgr). We found that NEP cleaves gcg and that the gcg fragments produced were unable to activate the gcgr. In non-sedated C57BL/6JRj female mice (n=8) NEP inhibition (sacubitril, 0.7 nmol/g) increased gcg levels (P=0.02) and tended to increase AA disappearance (P=0.076) and urea formation (P=0.08) during an AA challenge. A gcgr antagonist (Novo Nordisk; 25-2648, 100 mg/kg) abolished the increase in urea formation observed with sacubitril alone. Gcg levels were increased 1.9-fold (P Disclosure S. Kjeldsen: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. S.M. Mongovin: None. L.H. Hansen: None. D. Terzic: None. P.D. Mark: None. P. Plomgaard: None. J.P. Gøtze: None. M. Winther-Soerensen: None. J. Hunt: None. K.D. Galsgaard: None. M.M. Rosenkilde: Board Member; Self; Synklino. Consultant; Self; Antag Therapeutics, Bainan Biotech. G.H. Goossens: None. E.E. Blaak: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. Funding Novo Nordisk Foundation (NNF19OC0055001)

Aims Neprilysin degrades natriuretic peptides in circulation and is also suggested to degrade the gut hormones gastrin and cholecystokinin. Neprilysin inhibition has become a therapeutic strategy and thus a regimen in need of further testing in terms of other hormonal axes besides natriuretic peptides. The aim of this study was to examine whether acute inhibition of neprilysin affects meal-induced responses in gastrin and cholecystokinin concentrations in healthy individuals. Methods and results Nine healthy young men were included in an open-labelled, randomized cross-over clinical trial. The participants received a standardized meal (25 g fat, 26 g protein, 42 g carbohydrate) on two separate days with or without a one-time dosage of sacubitril ((194 mg)/valsartan (206 mg)). Blood pressure, heart rate and blood samples were measured and collected during the experiment. Statistical differences between groups were assessed using area under the curve together with an ANOVA with a Bonferroni post hoc test. Sacubitril/valsartan increased the postprandial plasma concentrations of both gastrin and cholecystokinin (80% (AUC0-270 min, P = 0.004) and 60% (AUC0-270 min, P = 0.003), respectively) compared with the control meal. No significant hemodynamic effects were noted (blood pressure, AUC0-270 min, P = 0.86, heart rate, AUC0-270 min, P = 0.96). Conclusion Our study demonstrates that sacubitril/valsartan increases the postprandial plasma concentrations of gastrin and cholecystokinin in healthy individuals. The results thus suggest that neprilysin-mediated degradation of gastrin and cholecystokinin is physiologically relevant and may have a role in heart failure patients treated with sacubitril/valsartan.

ObjectiveTo determine the predictive value of pro-C-type natriuretic peptide (pro-CNP) measurement in plasma sampled on admission from patients presenting with ST-elevation myocardial infarction (STEMI).DesignProspective cohort study.SettingTwo University Hospitals in Denmark.Participants1760 consecutive patients (470 females and 1290 males) with confirmed STEMI.Main outcomes and measuresThe main outcome was all-cause mortality at 1 year after presentation and the primary measure was pro-CNP concentration in plasma at admission in all patients and longitudinal measurements in a consecutive subgroup of 287 patients. A reference population (n=688) defined cut-off values of increased pro-CNP concentrations.ResultsIn all patients, an increased pro-CNP concentration was associated with a higher all-cause mortality after 1 year (HR 1.6, 95% CI 1.1 to 2.4, Plogrank=0.009) including an interaction of sex (p=0.03). In separate sex-stratified analyses, female patients showed increased all-cause mortality (HR1 year 2.6, 95% CI 1.5 to 4.6), Plogrank 1 year 1.1, 95% CI 0.7 to 1.9, Plogrank=0.66). After adjusting for potential risk factors, we found increased pro-CNP concentrations≥the median value to be independently associated with increased risk of mortality in female patients within 1 year (HR per 1 pmol/L increase: 1.04, 95% CI 1.01 to 1.06, p=0.007). Moreover, we found indications of sex differences in pro-CNP concentrations over time (higher pro-CNP in males (4.4, 95% CI −0.28 to 9.1 pmol/L, p=0.07) and interaction of sex and time (p=0.13)), and that hypertension was independently associated with higher pro-CNP (4.5, 95% CI 0.6 to 8.4 pmol/L, p=0.03).ConclusionsIn female but not male patients presenting with STEMI, high concentrations of pro-CNP (≥median) at admission independently indicate a higher risk of all-cause mortality. The findings are remarkably specific for female patients, suggesting a different vascular phenotype beyond traditional measures of coronary artery flow compared with male patients.

Background: Decreased concentrations of pro-atrial-derived natriuretic peptides (proABP) in plasma have been associated with obesity and suggested as a predictor of type 2 diabetes. However, assays for measuring proANP are generally aimed to quantitate higher concentrations of proANP associated with cardiac disease. Therefore, we aimed to measure plasma proANP concentrations in a non-obese Scandinavian reference material and evaluate potential associations of plasma proANP with body mass index (BMI) and plasma glucose, respectively. Methods: We report an optimized processing-independent assay (PIA) for proANP in the lower concentration range. The assay was optimized by raising the amount of radioactive tracer and modifying the mixing ratio of resuspended plasma and buffer. Blood samples from a Scandinavian plasma cohort of 693 healthy subjects were then analyzed and age and gender-specific reference intervals were determined. Results: Simple linear regression analyses of proANP and both BMI and plasma glucose in fasting subjects displayed insignificant associations. Multiple regression analyses supported these findings. However, a higher median plasma concentration of proANP was noted among women Conclusions: Our results show that in a healthy non-obese population, BMI and plasma glucose in fasting subjects do not affect plasma proANP concentrations. Our method should be considered for future studies on low proANP concentration studies, e.g. in obesity and diabetes.

Introduction Endothelial C-type natriuretic peptide (CNP) contributes to the local regulation of vascular homeostasis including a vasodilatory function in the microcirculation when studied in animal models. Clinical investigations have shown that high concentrations of C-type natriuretic peptides in plasma are associated with adverse clinical outcome in subgroups of patients with cardiac disease. Purpose To determine the prognostic potential of pro-C-type natriuretic peptide (proCNP) measurement in plasma sampled on admission of patients with ST-elevation myocardial infarction (STEMI). Methods In 1760 patients (470 women, 1290 men) with confirmed STEMI, we measured proCNP concentration in plasma obtained on hospital admission before coronary angiography. We divided patients into groups of low, normal or raised proCNP concentrations based on lower and upper cut-off values of sex- and age-specific 95% reference intervals from a reference population (688 individuals). We estimated differences in baseline characteristics including medical history and determined the prognostic value of proCNP measurement by Kaplan-Meier plots including log-rank tests and Cox regression survival analyses (expressed as hazard ratio (HR) and 95% confidence interval). Results Raised proCNP concentrations in plasma were associated with a higher prevalence of hypertension (P median) were independently associated with increased risk of death within one year after adjusting for age, plasma concentrations of creatinine and proANP, and quartiles of plasma troponins (HR: 1.02 (1.00–1.05) per 1 pmol/L increase of proCNP, P=0.047). One-year all-cause mortality rates Conclusion In patients with STEMI, a raised concentration of proCNP from plasma sampled on admission was associated with a higher risk of death within one year. However, only women displayed this difference of mortality rate in sex-specific estimates. Moreover, stepwise increases of proCNP concentration in the upper range independently predicted a higher risk of one-year death in women following STEMI after adjusting for potential confounders.

Context Combined inhibition of neprilysin and dipeptidyl peptidase 4 (DPP-4) has been shown to augment plasma concentrations of glucagon-like peptide-1(GLP-1) in animal models, but whether this occurs in humans is unknown. Objective To investigate the effects of inhibition of neprilysin by sacubitril/valsartan alone or in combination with a DPP-4 inhibitor (sitagliptin) on plasma concentrations of GLP-1 in healthy men. Design Two open-labeled crossover studies were performed in human subjects. Setting General community. Participants Nine and 10 healthy young men were included in study 1 and study 2, respectively. Intervention Study participants received a standardized meal (34% carbohydrates, 45% fat, 21% protein; total caloric content, 2106 kJ) combined with a prior dose of either sacubitril/valsartan (194/206 mg) or control in study 1 and in study 2, with a prior dose of sitagliptin (2 ×100 mg, given ∼10 hours apart) either alone or with sacubitril/valsartan (194/206 mg). Main Outcome Measures Plasma concentrations of total and intact GLP-1. Results Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% [total area under the curve (tAUC)0–240min: 3929 ± 344 vs 2348 ± 181 minutes × pmol/L, P = 0.0023] and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0–240min: 1021 ± 114 vs 660 ± 80 minutes × pmol/L, P = 0.01). Plasma concentrations of glucose, insulin, and GIP were not significantly (P > 0.10) changed upon sacubitril/valsartan treatment. Conclusions Sacubitril/valsartan combined with a DPP-4 inhibitor led to markedly higher concentrations of intact GLP-1 than DPP-4 inhibition alone, supporting a role for both neprilysin and DPP-4 in the metabolism of GLP-1 in humans, a finding that may have therapeutic implications.

PurposeThe aim of this study was to investigate structure and function of the heart in subclinical hyperthyroidism (SH) before and after obtaining euthyroidism by radioactive iodine treatment, using high precision and observer-independent magnetic resonance imaging (MRI) technology.MethodsCardiac MRI was performed before and after euthyroidism was obtained by radioactive iodine treatment in 12 otherwise healthy patients (11 women and one man, mean age 59 years, range 44–71 years) with a nodular goiter and SH, and compared with eight healthy controls investigated at baseline. Cardiac data were expressed as an index, as per body surface area, except for heart rate (HR) and ejection fraction.ResultsPost-treatment cardiac MRI was performed in median 139 days after a normalized serum TSH value had been recorded. During treatment, serum TSH increased from (median (range)) 0.01 (0.01–0.09) to 0.88 (0.27–3.99) mU/l. Patients with untreated SH had increased resting HR (PP2 (P=0.034), in HR of 8 bpm (P=0.001), and in cardiac index of 0.24 l/min per m2 (P=0.017).ConclusionsNormalization of thyroid function by radioactive iodine treatment of SH resulted in significant reductions in clinically important heart parameters such as LVMI, HR, and cardiac index. SH should be regarded as a condition in which aggressive treatment should be considered to protect cardiac function.

SummaryBackground Chronic heart failure (HF) is characterized by reduced serum T3 levels and increased activity of the T3 degrading enzyme deiodinase D3. This may result in an intracellular composition of the cardiomyocyte mimicking that of hypothyroidism. Short-term T3-administration to systolic HF patients might be beneficial. Question Does long-term treatment with T3 have a beneficial effect on cardiac function and neurohormonal activation in chronic systolic HF patients with serum T3 levels below 1·6 nmol/l? Design A randomized, double-blind, cross-over, placebo-controlled intervention study with oral T3 treatment twice daily for 3 months. The T3 dose was uptitrated to a final dose avoiding reduced TSH levels. Primary end-point Left-ventricular ejection fraction (LVEF). Methods Cardiac imaging was performed using multiple gated tomographic radionuclide ventriculography (MUGA-SPECT). Neurohormonal stimulation was evaluated by plasma measurements of natriuretic peptides, aldosterone, renin, noradrenalin and copeptin levels. The patients were monitored for potential cardiac arrhythmias at the start of each treatment period. Results Thirteen patients completed the protocol. Mean LVEF was 43%, range: 37–52 and serum T3 levels 1·4 nmol/l (0·9–1·6). The T3 dose was 20 μg per day (10–40). TSH levels did not change between groups, whereas serum T3 levels increased in the active arm. Cardiac function as measured by LVEF, end-diastolic and end-systolic volumes and cardiac output did not change during T3-treatment and neither did the neurohormonal profile. There were no side-effects in terms of cardiac arrhythmias and no change in resting heart rate. Conclusions This study does not support the hypothesis that oral T3 treatment might be beneficial to patients with chronic, stable systolic HF with a modest degree of reduced LVEF and low-normal serum T3 concentrations. The study included both functional studies of heart contractility as well as measures of the neurohormonal activation.