Volume expansion enhances plasma endothelin-1

We hypothesized that acute volume expansion by saline infusion triggers the release of endothelin-1. Bolus intravenous saline infusion (8 mL/min) in six groups of conscious Wistar rats and spontaneously hypertensive rats did not change mean arterial pressure or heart rate (n = 8 to 12). At 1 min after infusion, the plasma endothelin-1 level was significantly increased in Wistar rats and in spontaneously hypertensive rats by 42% and 61%, respectively (unpaired data). In 12 Wistar rats, the endothelin-1 level increased from 0.68 ± 0.13 to 1.19 ± 0.17 fmol/mL (mean ± SEM, P < .0001, paired data). Thus, acute volume load by rapid saline infusion increases plasma endothelin-1 levels. Vasoconstriction induced by endothelin-1 may counteract enhanced circumferential stretch created by volume expansion. Am J Hypertens 2003;16:1057-1061 @ 2003 American Journal of Hypertension, Lt

Measurement of plasma endothelin-1 in experimental hypertension and in healthy subjects

Background: Endothelin-1 is an endothelium-derived potent vasoconstrictor peptide of 21 amino acids. To establish reference values in different models of hypertension and in human subjects an assay for plasma immunoreactive endothelin-1 (ET-1) was optimized. Methods: ET-1 is extracted by acetone from 1 mL of plasma and subjected to a sensitive enzyme-linked immunosorbent assay. Results: The detection limit for plasma ET-1 is 0.05 fmol/mL. Mean recoveries of the 1, 2, 5, and 10 fmol of ET-1 added to 1 mL of plasma were 66%, 75%, 85%, and 92%, respectively. Within- and between-assay coefficients of variation were ≤12% and ≤10%, respectively. Assay accuracy was demonstrated by consistent recoveries of added ET-1 over the entire physiologic range of plasma concentrations and by the linearity of ET-1 concentrations measured in serially diluted plasma extracts (r = 0.99). No ET-1 was detected when albumin buffer was extracted instead of plasma. Using this method, we found increased ET-1 levels in plasma of three experimental rat models of hypertension: stroke prone spontaneously hypertensive rats (SP-SHR), deoxycorticosterone acetate-salt hypertensive rats, and one kidney-one clip hypertensive rats. In contrast, plasma ET-1 levels of SHR were half those of normotensive Wistar rats. In two kidney-one clip hypertensive rats, plasma ET-1 concentrations were not different from those found in sham-operated control rats. Plasma ET-1 concentrations of 37 healthy men were 0.85 ± 0.26 fmol/ml (mean ± SD). Conclusions: The present assay reliably measures ET-1 levels in rat and human plasma. It allows to discriminate between different forms of hypertension with high or low circulating levels of ET-1. Am J Hypertens 2003;16: 515-521 @ 2003 American Journal of Hypertension, Lt

Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis

Aims Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality. Methods and results Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45-0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45-0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75-1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67-0.94); P = 0.009] or cardiovascular disease [0.82 (0.67-0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF. Conclusion Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalizatio

Impact of sex-specific target dose in chronic heart failure patients with reduced ejection fraction

Aims A recent study suggested that women with heart failure and heart failure reduced ejection fraction might hypothetically need lower doses of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers ( = renin-angiotensin-system inhibitors) and beta-blockers than men to achieve the best outcome. We assessed the current medical treatment of heart failure reduced ejection fraction in men and women in a large contemporary cohort and address the hypothetical impact of changing treatment levels in women. Methods This analysis is part of a large contemporary quality of heart failure care project which includes 5320 (64%) men and 3003 (36%) women with heart failure reduced ejection fraction. Detailed information on heart failure therapy prescription and dosage were collected. Results Women less often received renin-angiotensin-system inhibitors (79% vs 83%, p 100% of the new hypothetical target dose would be 24% for beta-blockers and 52% for renin-angiotensin-system inhibitors, which can be considered as relatively overdosed. Conclusion In this large contemporary heart failure registry, there were significant but relatively small differences in drug dose between men and women with heart failure reduced ejection fraction. Implementation of the hypothetical sex-specific target dosing schedule would lead to considerably more women adequately treated. In contrast, we identified a group of women who might have been relatively overdosed with increased risk of side-effects and intolerance

Impact of sex-specific target dose in chronic heart failure patients with reduced ejection fraction

Aims: A recent study suggested that women with heart failure and heart failure reduced ejection fraction might hypothetically need lower doses of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (= renin-angiotensin-system inhibitors) and β-blockers than men to achieve the best outcome. We assessed the current medical treatment of heart failure reduced ejection fraction in men and women in a large contemporary cohort and address the hypothetical impact of changing treatment levels in women. Methods: This analysis is part of a large contemporary quality of heart failure care project which includes 5320 (64%) men and 3003 (36%) women with heart failure reduced ejection fraction. Detailed information on heart failure therapy prescription and dosage were collected. Results: Women less often received renin-angiotensin-system inhibitors (79% vs 83%, p 100% of the new hypothetical target dose would be 24% for β-blockers and 52% for renin-angiotensin-system inhibitors, which can be considered as relatively overdosed. Conclusion: In this large contemporary heart failure registry, there were significant but relatively small differences in drug dose between men and women with heart failure reduced ejection fraction. Implementation of the hypothetical sex-specific target dosing schedule would lead to considerably more women adequately treated. In contrast, we identified a group of women who might have been relatively overdosed with increased risk of side-effects and intolerance

Revisiting the obesity paradox in heart failure:Per cent body fat as predictor of biomarkers and outcome

Aims - Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2)). Methods - In an individual patient dataset, BMI was calculated as weight (kg)/height (m)2, and PBF through the Jackson–Pollock and Gallagher equations. Results - Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5–2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4–33.0%) with the Jackson–Pollock equation, and 28.0% (23.8–33.5%) with the Gallagher equation, with an extremely strong correlation (r = 0.996, p 2, third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome. Conclusion - In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients

Novel concept to guide systolic heart failure medication by repeated biomarker testing-results from TIME-CHF in context of predictive, preventive, and personalized medicine

Background It is uncertain whether repeated measurements of a multi-target biomarker panel may help to personalize medical heart failure (HF) therapy to improve outcome in chronic HF. Methods This analysis included 499 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF), aged >= 60 years, LVEF = II, who had repeated clinical visits within 19 months follow-up. The interaction between repeated measurements of biomarkers and treatment effects of loop diuretics, spironolactone, beta-blockers, and renin-angiotensin system (RAS) inhibitors on risk of HF hospitalization or death was investigated in a hypothesis-generating analysis. Generalized estimating equation (GEE) models were used to account for the correlation between recurrences of events in a patient. Results One hundred patients (20%) had just one event (HF hospitalization or death) and 87 (17.4%) had at least two events. Loop diuretic up-titration had a beneficial effect for patients with high interleukin-6 (IL6) or high high-sensitivity C-reactive protein (hsCRP) (interaction, P = 0.013 and P = 0.001), whereas the opposite was the case with low hsCRP (interaction, P = 0.013). Higher dosage of loop diuretics was associated with poor outcome in patients with high blood urea nitrogen (BUN) or prealbumin (interaction, P = 0.006 and P = 0.001), but not in those with low levels of these biomarkers. Spironolactone up-titration was associated with lower risk of HF hospitalization or death in patients with high cystatin C (CysC) (interaction, P = 0.021). beta-Blockers up-titration might have a beneficial effect in patients with low soluble fms-like tyrosine kinase-1 (sFlt) (interaction, P = 0.021). No treatment biomarker interactions were found for RAS inhibition. Conclusion The data of this post hoc analysis suggest that decision-making using repeated biomarker measurements may be very promising in bringing treatment of heart failure to a new level in the context of predictive, preventive, and personalized medicine. Clearly, prospective testing is needed before this novel concept can be adopted

Advanced electron cyclotron heating and current drive experiments on the stellarator Wendelstein 7-X

During the first operational phase (OP 1.1) of Wendelstein 7-X (W7-X) electron cyclotron resonance heating (ECRH) was the exclusive heating method and provided plasma start-up, wall conditioning, heating and current drive. Six gyrotrons were commissioned for OP1.1 and used in parallel for plasma operation with a power of up to 4.3 MW. During standard X2-heating the spatially localized power deposition with high power density allowed controlling the radial profiles of the electron temperature and the rotational transform. Even though W7-X was not fully equipped with first wall tiles and operated with a graphite limiter instead of a divertor, electron densities of n e > 3·1019 m-3 could be achieved at electron temperatures of several keV and ion temperatures above 2 keV. These plasma parameters allowed the first demonstration of a multipath O2-heating scenario, which is envisaged for safe operation near the X-cutoff-density of 1.2·1020 m-3 after full commissioning of the ECRH system in the next operation phase OP1.2

Guideline implementation, drug sequencing, and quality of care in heart failure:design and rationale of TITRATE-HF

Aims: Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline-directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real-world TITRATE-HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long-term outcomes in patients with de novo, chronic, and worsening HF. Methods and results: A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in &gt;40 Dutch centres with a follow-up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF-related hospitalizations, HF-related urgent visits with a need for intravenous diuretics, all-cause mortality, and cardiovascular mortality. Conclusions: TITRATE-HF is a real-world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.</p

Acute coronary syndromes and acute heart failure:a diagnostic dilemma and high-risk combination. A statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology

Acute coronary syndrome is a precipitant of acute heart failure in a substantial proportion of cases, and the presence of both conditions is associated with a higher risk of short-term mortality compared to acute coronary syndrome alone. The diagnosis of acute coronary syndrome in the setting of acute heart failure can be challenging. Patients may present with atypical or absent chest pain, electrocardiograms can be confounded by pre-existing abnormalities, and cardiac biomarkers are frequently elevated in patients with chronic or acute heart failure, independently of acute coronary syndrome. It is important to distinguish transient or limited myocardial injury from primary myocardial infarction due to vascular events in patients presenting with acute heart failure. This paper outlines various clinical scenarios to help differentiate between these conditions and aims to provide clinicians with tools to aid in the recognition of acute coronary syndrome as a cause of acute heart failure. Interpretation of electrocardiogram and biomarker findings, and imaging techniques that may be helpful in the diagnostic work-up are described. Guidelines recommend an immediate invasive strategy for patients with acute heart failure and acute coronary syndrome, regardless of electrocardiographic or biomarker findings. Pharmacological management of patients with acute coronary syndrome and acute heart failure should follow guidelines for each of these syndromes, with priority given to time-sensitive therapies for both. Studies conducted specifically in patients with the combination of acute coronary syndrome and acute heart failure are needed to better define the management of these patients