The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: The optimal timing of invasive coronary angiography (ICA) and revascularization in patients with non-ST-segment elevation acute coronary syndrome is not well defined. We tested the hypothesis that a strategy of very early ICA and possible revascularization within 12 hours of diagnosis is superior to an invasive strategy performed within 48 to 72 hours in terms of clinical outcomes. METHODS: Patients admitted with clinical suspicion of non-ST-segment elevation acute coronary syndrome in the Capital Region of Copenhagen, Denmark, were screened for inclusion in the VERDICT trial (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) ( ClinicalTrials.gov NCT02061891). Patients with ECG changes indicating new ischemia or elevated troponin, in whom ICA was clinically indicated and deemed logistically feasible within 12 hours, were randomized 1:1 to ICA within 12 hours or standard invasive care within 48 to 72 hours. The primary end point was a combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure. RESULTS: A total of 2147 patients were randomized; 1075 patients allocated to very early invasive evaluation had ICA performed at a median of 4.7 hours after randomization, whereas 1072 patients assigned to standard invasive care had ICA performed 61.6 hours after randomization. Among patients with significant coronary artery disease identified by ICA, coronary revascularization was performed in 88.4% (very early ICA) and 83.1% (standard invasive care). Within a median follow-up time of 4.3 (interquartile range, 4.1-4.4) years, the primary end point occurred in 296 (27.5%) of participants in the very early ICA group and 316 (29.5%) in the standard care group (hazard ratio, 0.92; 95% CI, 0.78-1.08). Among patients with a GRACE risk score (Global Registry of Acute Coronary Events) >140, a very early invasive treatment strategy improved the primary outcome compared with the standard invasive treatment (hazard ratio, 0.81; 95% CI, 0.67-1.01; P value for interaction=0.023). CONCLUSIONS: A strategy of very early invasive coronary evaluation does not improve overall long-term clinical outcome compared with an invasive strategy conducted within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, very early invasive therapy improves long-term outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02061891.

Long-term L-Triiodothyronine (T3) treatment in stable systolic heart failure patients: a randomised, double-blind, cross-over, placebo-controlled intervention study.

BACKGROUND: 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.

A multidisciplinary, shared care clinic using personalized medicine and coordinated care in patients with concomitant type 2 diabetes and cardiovascular disease. Protocol and baseline characteristics.

Background: Concomitant type 2 diabetes (T2DM) and cardiovascular disease (CVD) is frequent with a poor prognosis with high risk of comorbidities. Strict risk factor control reduces the risk for complications - yet many people do not achieve treatment targets. The complexity and fragmentation of the healthcare system may, together with the vulnerability of these patients, be a reason. Objective: The purpose of this paper is to describe the protocol of a non-randomized interventional pilot study testing the feasibility and effect of a multidisciplinary, shared care clinic using personalized medicine and coordinated care in people living with concomitant T2D and CVD. Methods: Participants were included from the Holbaek area in Denmark. People suffered from T2DM and CVD and were dysregulated regarding to HbA1c, cholesterol, micro/macroalbuminuaria or blood pressure. Participants went through a thorough evaluation to identify their needs and resources and received consultations every three months for one year. Results: A total of 63 participants with T2DM and CVD were enrolled in the clinic. The participants had a mean age of 69 years and a BMI of 30.9 kg/m2. Almost 50 % had heart failure, 95 % dyslipidemia and 91 % hypertension. Around 54 % received GLP-1 agonists and 39 % received SGLT-2-inhibitors. Perspectives: To our knowledge, a similar study with a multidisciplinary, shared care, outpatient clinic treating people living with concomitant T2DM and CVD, has not been performed previously. This study will provide information about the feasibility and efficacy of a multidisciplinary clinic based on changes in cardiovascular risk factors and medication.

Lenient rate control versus strict rate control for atrial fibrillation: a statistical analysis plan for the Danish Atrial Fibrillation (DanAF) randomized clinical trial.

BACKGROUND: A key decision in the treatment of atrial fibrillation is choosing between a rhythm control strategy or a rate control strategy as the main strategy. When choosing rate control, the optimal heart rate target is uncertain. The Danish Atrial Fibrillation trial is a randomized, multicenter, two-group, superiority trial comparing strict rate control versus lenient rate control in patients with either persistent or permanent atrial fibrillation at inclusion. To prevent bias arising from selective reporting and data-driven analyses, we developed a predefined description of the statistical analysis. METHODS: The primary outcome of this trial is the physical component score of the SF-36 questionnaire. A total of 350 participants will be enrolled based on a minimal important difference of 3 points on the physical component score of the SF-36 questionnaire, a standard deviation of 10 points, a statistical power of 80% (beta of 20%), and an acceptable risk of type I error of 5%. All secondary, exploratory, and echocardiographic outcomes will be hypothesis-generating. The analyses of all outcomes will be based on the intention-to-treat principle. We will analyze continuous outcomes using linear regression adjusting for "site," type of atrial fibrillation at inclusion (persistent/ permanent), left ventricular ejection fraction (≥ 40% or < 40%), and the baseline value of the outcome (all as fixed effects). We define our threshold for statistical significance as a p-value of 0.05 and assessments of clinical significance will be based on the anticipated intervention effects defined in the sample size and power estimations. Thresholds for both statistical and clinical significance will be assessed according to the 5-step procedure proposed by Jakobsen and colleagues. DISCUSSION: This statistical analysis plan will be published prior to enrolment completion and before any data are available and is sought to increase the validity of the DANish Atrial Fibrillation trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT04542785. Registered on Sept 09, 2020.

Prognostic Value of Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

BACKGROUND: Severity and extent of coronary artery disease (CAD) assessed by invasive coronary angiography (ICA) guide treatment and may predict clinical outcome in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). OBJECTIVES: This study tested the hypothesis that coronary computed tomography angiography (CTA) is equivalent to ICA for risk assessment in patients with NSTEACS. METHODS: The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial evaluated timing of treatment in relation to outcome in patients with NSTEACS and included a clinically blinded coronary CTA conducted prior to ICA. Severity of CAD was defined as obstructive (coronary stenosis ≥50%) or nonobstructive. Extent of CAD was defined as high risk (obstructive left main or proximal left anterior descending artery stenosis and/or multivessel disease) or non-high risk. The primary endpoint was a composite of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or heart failure. RESULTS: Coronary CTA and ICA were conducted in 978 patients. During a median follow-up time of 4.2 years (interquartile range: 2.7 to 5.5 years), the primary endpoint occurred in 208 patients (21.3%). The rate of the primary endpoint was up to 1.7-fold higher in patients with obstructive CAD compared with in patients with nonobstructive CAD as defined by coronary CTA (hazard ratio [HR]: 1.74; 95% confidence interval [CI]: 1.22 to 2.49; p = 0.002) or ICA (HR: 1.54; 95% CI: 1.13 to 2.11; p = 0.007). In patients with high-risk CAD, the rate of the primary endpoint was 1.5-fold higher compared with the rate in those with non-high-risk CAD as defined by coronary CTA (HR: 1.56; 95% CI: 1.18 to 2.07; p = 0.002). A similar trend was noted for ICA (HR: 1.28; 95% CI: 0.98 to 1.69; p = 0.07). CONCLUSIONS: Coronary CTA is equivalent to ICA for the assessment of long-term risk in patients with NSTEACS. (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes [VERDICT]; NCT02061891).

Associations between plasma insulin-like growth factor-I and the markers of inflammation interleukin 6, C-reactive protein and YKL-40 in an elderly background population.

BACKGROUND AND OBJECTIVE: The objective of the present study was to test the hypothesis that circulating levels of insulin-like growth factor-I (IGF-I) are inversely associated with inflammatory processes in an elderly background population. PATIENTS AND DESIGN: We conducted a population-based study comprising 629 individuals, aged 50-89 years. Associations between plasma IGF-I versus interleukin 6 (IL-6) and the acute phase proteins high sensitive C-reactive protein (hsCRP) and YKL-40 were evaluated by linear regression analyses. Subsequently, the population was dichotomised at a CRP level of 3.0 mg/L and the associations were re-evaluated in the two subgroups. RESULTS: Adjusted for confounding variables, plasma IGF-I was inversely related to IL-6, hsCRP and YKL-40 (all P < 0.001). The strongest association was found for YKL-40 with a 34% reduction in YKL-40 per twofold increase in IGF-I. A significant inverse association between IGF-I and all markers of inflammation persisted in individuals with hsCRP below 3.0 mg/L whereas only YKL-40 was significantly associated with IGF-I in individuals with hsCRP above 3.0 mg/L. CONCLUSIONS: The data support the hypothesis of an inverse association between GH/IGF-I signalling and inflammation, and suggest that the relationship between the IGF-I and inflammation might be more predominant in healthy individuals with a low inflammatory activity.

Plasma YKL-40 levels are elevated in patients with chronic heart failure.

OBJECTIVES: Congestive heart failure (CHF) has been associated with elevated biomarker levels reflecting chronic low-grade inflammation. YKL-40 is a biomarker with increasing levels in patients with cardiovascular disease (CVD) of increasing severity. Furthermore, YKL-40 is associated with all-cause and cardiovascular mortality. We investigated plasma YKL-40 levels in patients with CHF and evaluated the possible predictive value with respect to overall mortality and recurrent cardiovascular outcomes. DESIGN: Plasma YKL-40 was measured in 194 CHF patients and in 117 age-matched individuals without CVD. RESULTS: Median YKL-40 levels were approximately 77% higher in patients with CHF (106 (IQR, 66-184) ng/ml vs. 60 (IQR, 42-97) ng/ml, p < 0.0001). We found a trend towards an association of YKL-40 levels with urinary albumin/creatinine ratio (UACR) (beta = 0.12, p = 0.08). YKL-40 levels were not predictive of overall mortality (p = 0.59), major cardiovascular events (p = 0.23) or events of incompensation (p = 0.56). CONCLUSIONS: Plasma YKL-40 levels are elevated in patients with CHF but show no association with other clinical or paraclinical variables. YKL-40 levels were not predictive of overall mortality or incident cardiovascular events. Most likely, elevated YKL-40 levels in CHF patients are explained by the presence of concomitant diseases but a role of YKL-40 in low-grade inflammation is not excluded.

Beneficial and harmful effects of sacubitril/valsartan in patients with heart failure: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

Current guidelines recommend angiotensin receptor blocker neprilysin inhibitors (ARNI) (sacubitril/valsartan) as a replacement for angiotensin-converting-enzymeinhibitor (ACE-I) in heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy. The effects of ARNIs have not previously been assessed in a systematic review. We searched for relevant trials until October 2019 in CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, CNKI, VIP, WanFang and CBM. Our primary outcomes were all-cause mortality and serious adverse events. We systematically assessed the risks of random errors and systematic errors. PROSPERO registration: CRD42019129336. 48 trials randomising 19 086 participants were included. The ARNI assessed in all trials was sacubitril/valsartan. ACE-I or ARB were used as control interventions. Trials randomising HFrEF participants (27 trials) and heart failure with preserved ejection fraction (HFpEF) participants (four trials) were analysed separately. In HFrEF participants, meta-analyses and Trial Sequential Analyses showed evidence of a beneficial effect of sacubitril/valsartan when assessing all-cause mortality (risk ratio (RR), 0.86; 95% CI, 0.79 to 0.94) and serious adverse events (RR, 0.89; 95% CI, 0.86 to 0.93); and the results did not differ between the guideline recommended target population and HFrEF participants in general. We found no evidence of an effect of sacubitril/valsartan in HFpEF participants. Sacubitril/valsartan compared with either ACE-I or ARB seems to have a beneficial effect in patients with HFrEF. Our results indicate that sacubitril/valsartan might be beneficial in a wider population of patients with heart failure than the guideline recommended target population. Sacubitril/valsartan does not seem to show evidence of a difference compared with valsartan in patients with HFpEF.

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: In patients with non-ST-segment elevation acute coronary syndrome (NSTEACS), coronary pathology may range from structurally normal vessels to severe coronary artery disease. OBJECTIVES: The purpose of this study was to test if coronary computed tomography angiography (CTA) may be used to exclude coronary artery stenosis ≥50% in patients with NSTEACS. METHODS: The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial (NCT02061891) evaluated the outcome of patients with confirmed NSTEACS randomized 1:1 to very early (within 12 h) or standard (48 to 72 h) invasive coronary angiography (ICA). As an observational component of the trial, a clinically blinded coronary CTA was conducted prior to ICA in both groups. The primary endpoint was the ability of coronary CTA to rule out coronary artery stenosis (≥50% stenosis) in the entire population, expressed as the negative predictive value (NPV), using ICA as the reference standard. RESULTS: Coronary CTA was conducted in 1,023 patients-very early, 2.5 h (interquartile range [IQR]: 1.8 to 4.2 h), n = 583; and standard, 59.9 h (IQR: 38.9 to 86.7 h); n = 440 after the diagnosis of NSTEACS was made. A coronary stenosis ≥50% was found by coronary CTA in 68.9% and by ICA in 67.4% of the patients. Per-patient NPV of coronary CTA was 90.9% (95% confidence interval [CI]: 86.8% to 94.1%) and the positive predictive value, sensitivity, and specificity were 87.9% (95% CI: 85.3% to 90.1%), 96.5% (95% CI: 94.9% to 97.8%) and 72.4% (95% CI: 67.2% to 77.1%), respectively. NPV was not influenced by patient characteristics or clinical risk profile and was similar in the very early and the standard strategy group. CONCLUSIONS: Coronary CTA has a high diagnostic accuracy to rule out clinically significant coronary artery disease in patients with NSTEACS.

Characteristics and reference ranges of Insulin-Like Growth Factor-I measured with a commercially available immunoassay in 724 healthy adult Caucasians.

BACKGROUND AND OBJECTIVE: Measurements of Insulin-Like Growth Factor-I (IGF-I) play a pivotal role in the evaluation of the growth hormone-IGF-I axis. Due to assay variation IGF-I reference ranges are assay specific. We provide serum IGF-I reference ranges for adult men and women obtained by a commercially available assay. METHOD: IGF-I was measured by an enzyme-linked immunosorbent assay (R&D Systems). Assay precision was evaluated in low, medium and high IGF-I pools and in single samples from outpatients. The reference ranges were obtained in 724 healthy Caucasians, mean age 48 years (range 19-91). RESULTS: IGF-I was measured higher in serum compared to plasma samples (p<0.001, R2=0.96). To convert EDTA plasma values to serum values a factor of 1.22 was calculated. The intraassay coefficients of variation (CV) for the low: 56.4+/-2.7 ng/mL, medium: 179.7+/-5.9 ng/mL and high pool: 445.61+/-3.2 ng/mL (mean 1 SD) were 5, 3 and 3%. Interassays CVs for the low, medium and high pool varied between 7-10, 5-7, and 6-9%. Reproducibility between 4 different lots showed a intraclass CV of 0.99 (95%CI 0.98-0.96). Logarithmically transformed IGF-I levels were linearly associated with age with a 13% reduction in IGF-I per decade in females and 11% in males. CONCLUSION: We have provided IGF-I reference ranges obtained by an assay that showed variations and reproducibility that was considered of sufficient high quality for clinical and scientific use.

The effects of adding angiotensin receptor neprilysin inhibitors to usual care in patients with heart failure: a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

BACKGROUND: Heart failure is a highly prevalent disease with a global prevalence of 37 million, and the prevalence is increasing. Patients with heart failure are at an increased risk of death and morbidity. Traditionally, patients with heart failure have been treated with a beta-blocker in addition to an inhibitor of the renin-angiotensin-aldosterone system. However, new drugs are currently being added to the recommended guideline therapy. The latest drug to be added combines inhibition of the renin-angiotensin-aldosterone system pathway with inhibiting the neprilysin enzyme and is therefore classified as an ARNI. Our objective is to identify the beneficial and harmful effects of ARNIs in the treatment of patient with heart failure. METHODS: This protocol for a systematic review was undertaken using the recommendations of the Cochrane, the Preferred Report Items of Systematic reviews with Meta-Analysis Protocols, and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ARNIs in the treatment of patients with heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS to identify relevant trials. We will also search for grey literature and unpublished trials. Extracted data will be analysed using Review Manager 5, STATA 5, and Trial Sequential Analysis. Our primary outcomes will be all-cause mortality and serious adverse events. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the GRADE assessment. DISCUSSION: The present systematic review will have the potential to aid clinicians in decision-making and thereby, benefit patients with heart failure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019129336.

Biomarkers of endothelial dysfunction are elevated and related to prognosis in chronic heart failure patients with diabetes but not in those without diabetes.

BACKGROUND: Biomarkers of endothelial dysfunction, such as soluble E-selectin, and von Willebrand factor (vWf) are elevated in patients with chronic heart failure (CHF). The impact of diabetes mellitus (DM) on these biomarkers, and their relation to prognosis remains unknown. AIMS: to investigate the impact of DM on plasma levels and the prognostic value of E-selectin and vWf in patients with CHF. METHODS AND RESULTS: Plasma levels of E-selectin and vWf were measured in 195 CHF patients with (n=48, 24.5%), and without DM, and in 116 age-matched healthy controls. Compared with controls, median plasma E-selectin levels were higher in CHF patients with DM (P=0.012), but not in CHF patients without DM (P=0.45); vWf levels were also higher in CHF patients with DM (P<0.001), but not without DM (P=0.108). E-selectin was associated with risk of recurrent ischaemic cardiovascular events among CHF patients with DM (HR 2.60; P=0.009), but not among patients without DM (HR 1.09; P=0.60) per 1 SD increment in log transformed variable. vWf was not related with outcome in CHF patients with or without DM. CONCLUSIONS: Plasma levels of E-selectin and vWf are elevated in CHF patients with DM but not in those without DM. High E-selectin levels may be associated with ischaemic events in patients with DM.

N-terminal-pro-B-type natriuretic peptide in acute hyperthyroidism.

OBJECTIVE: Serum N-terminal-pro-B-type natriuretic peptide (NT-proBNP) is elevated in systolic heart failure due to volume expansion and pressure overload. Recent data suggest a direct stimulatory effect of thyroid hormones on NT-proBNP synthesis. We examined the influence of acutely induced hyperthyroidism on serum levels of NT-proBNP. DESIGN: Forty-three healthy women were evaluated before and after treatment with 60 mug triiodothyronine (T(3)) daily for 7 days in a noncontrolled study. MAIN OUTCOME: Before treatment, NT-proBNP was independently and inversely associated with thyrotropin (TSH), (r = -0.34, p = 0.02). T(3) therapy induced an increase in free T(3) (3.3 times, p < 0.0001) and suppression of TSH ( p < 0.0001). Heart rate increased by 14% ( p < 0.0001); weight decreased 0.6 kg ( p < 0.0001). Median NT-proBNP increased from 53 to 66 pg/mL ( p < 0.0001). The increase in NT-proBNP levels was independently associated with increase in free T(3) ( p = 0.05) and with reduction in TSH ( p = 0.04), without any association to the changes in cardiac workload. CONCLUSIONS: NT-proBNP is influenced by thyroid function among healthy women, as demonstrated by an inverse association between TSH and NT-proBNP. Induction of an acute hyperthyroid state resulted in an increase in NT-proBNP, which seems to reflect a direct action of T(3) on the NT-proBNP secretion rather than an effect of increased cardiac workload.

Prevalence of diastolic dysfunction as a possible cause of dyspnea in the elderly.

PURPOSE: Symptoms in patients with heart failure and preserved left ventricular ejection fraction may be caused by isolated diastolic dysfunction. The purpose of this study was to assess the prevalence of diastolic dysfunction as a potential cause of dyspnea in a sample of elderly subjects, as well as of isolated diastolic dysfunction as a potential cause of dyspnea in a subgroup with a preserved left ventricular ejection fraction and normal lung function. METHODS: A total of 152 subjects with dyspnea underwent echocardiography, electrocardiography, and lung function testing. Subjects with normal lung function test results (n = 60) underwent cardiac magnetic resonance imaging, chest radiography, bicycle exercise tests, and blood tests. Left ventricular diastolic function was assessed by a variety of echocardiographic/Doppler techniques. RESULTS: Of 129 subjects with dyspnea, 81 (63%) had signs of lung disease or 'obvious' cardiac disease. In the remaining 48 subjects, 32 (67%) had a potential cardiac/noncardiac cause of dyspnea. In all subjects with dyspnea, 1% to 11% had diastolic dysfunction, and in the 48 remaining subjects, 0% to 10% had isolated diastolic dysfunction, depending on the definition used. CONCLUSION: The frequency of diastolic dysfunction was low in the sample of elderly subjects with dyspnea as well as in the subgroup of persons with no signs of lung disease, left ventricular systolic dysfunction, atrial fibrillation, or valvular heart disease. Diastolic dysfunction was infrequent as a possible cause of dyspnea, and coexisting potential causes of dyspnea were often present.

N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults.

CONTEXT: B-type natriuretic peptides have been shown to predict cardiovascular disease in apparently healthy individuals but their predictive ability for mortality and future cardiovascular events compared with C-reactive protein (CRP) and urinary albumin/creatinine ratio is unknown. OBJECTIVE: To assess the prognostic value of the N-amino terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) vs CRP and urinary albumin/creatinine ratio in an older adult population. DESIGN, SETTING, AND PARTICIPANTS: A population-based prospective study of 764 participants aged 50 to 89 years from a community in Copenhagen, Denmark, in which 658 participants provided blood and urinary samples and were examined between September 1, 1998, and January 24, 2000. Of these participants, 626 without heart or renal failure were enrolled. A subgroup of 537 had no history of cardiovascular disease at baseline. During 5 years of follow-up (to December 31, 2003), 94 participants died and 65 developed a first major cardiovascular event. MAIN OUTCOME MEASURES: Risk of mortality and first major cardiovascular event by baseline levels of NT-proBNP, CRP, and urinary albumin/creatinine ratio levels. RESULTS: After adjustment for the cardiovascular risk factors of age, sex, smoking, diabetes mellitus, hypertension or ischemic heart disease, total cholesterol, and serum creatinine, the hazard ratio (HR) of mortality for values above the 80th percentile of NT-proBNP was 1.96 (95% confidence interval [CI], 1.21-3.19); for CRP, 1.46 (95% CI, 0.89-2.24); and for urinary albumin/creatinine ratio, 1.88 (95% CI, 1.18-2.98). Additional adjustment for left ventricular systolic dysfunction did not markedly attenuate the predictive value of NT-proBNP (HR, 1.82; 95% CI, 1.11-2.98). The absolute unadjusted increase in mortality risk for participants with values above the 80th percentile vs equal to or below the 80th percentile was 24.5% for NT-proBNP, 7.8% for CRP, and 19.5% for urinary albumin/creatinine ratio. The NT-proBNP levels were associated with first major cardiovascular events (nonfatal myocardial infarction, fatal coronary heart disease, unstable angina, heart failure, stroke, and transient ischemic attack) with an adjusted HR of 3.24 (95% CI, 1.80-5.79) vs 1.02 (95% CI, 0.56-1.85) for CRP and 2.32 (95% CI, 1.33-4.05) for urinary albumin/creatinine ratio when comparing participants with values above the 80th percentile with those with values equal to or below the 80th percentile. CONCLUSIONS: Measurements of NT-proBNP provide prognostic information of mortality and first major cardiovascular events beyond traditional risk factors. NT-proBNP was a stronger risk biomarker for cardiovascular disease and death than CRP was in nonhospitalized individuals aged 50 to 89 years.

Biochemical cardiac risk markers in the general population, hypertension and coronary artery disease.

Recently there has been a growing interest in risk assessment of individuals, using biochemical markers of cardiac risk, with an increasing focus on a multi-marker strategy. Natriuretic peptides (BNP and NT-proBNP) are well-established markers of increased risk in the general population and in high-risk groups with hypertension, and coronary heart disease. However, there is at present no indication for routine measurements of natriuretic peptides in the risk assessment of individuals or patients, as there is no evidence for subsequent therapeutic initiatives. Natriuretic peptides are useful when screening for heart failure in symptomatic individuals. However, the use of NT-proBNP screening for risk or left ventricular systolic dysfunction in the general population is still a matter of debate.

The prognosis of impaired left ventricular systolic function and heart failure in a middle-aged and elderly population in an urban population segment of Copenhagen.

AIMS: To determine the prognosis, total mortality and cardiac morbidity, of patients with left ventricular systolic dysfunction and heart failure (HF) in a general population sample. METHODS AND RESULTS: A total of 764 subjects, 432 females and 332 males, median age (range) 66 years (50-89), participated in this cross sectional survey. The study population was recruited from randomly selected general practitioners and stratified to include a minimum of 150 persons in each age decade stratum. Each participant filled in a heart failure questionnaire and ECG, blood tests and echocardiography were performed. Median (range) follow-up was 1145 (51-1197) days. Subjects with LVEF < or = 0.40 had a significantly higher all-cause mortality (27.8% vs. 5.6%, P<0.0001), admission rate for HF (25.0% vs. 1.9%, P<0.0001) and for other cardiac causes (25.0% vs. 6.3%, P<0.0001) than in subjects with LVEF>0.40. The age and gender adjusted 2-year relative risk of death was 4.6 (95% C.I.=1.6-13.2). No significant difference in mortality was found between subjects with or without heart failure symptoms. CONCLUSION: Significantly higher mortality as well as cardiac morbidity was found in subjects with symptomatic and asymptomatic LV systolic dysfunction compared to those with normal systolic function. These conditions were among the strongest predictors of all-cause mortality and cardiac morbidity.

Echocardiographic indices of left ventricular diastolic dysfunction in 647 individuals with preserved left ventricular systolic function.

BACKGROUND: Knowledge about the occurrence of isolated diastolic dysfunction (DD) in the general population is limited. AIMS: This population study was performed to assess the frequency and distribution pattern of echocardiographic indices of left ventricular (LV) DD in an elderly population aged 50-89 years in which LV systolic function is preserved. METHODS AND RESULTS: The study population (n=764) recruited from the background population answered a heart failure questionnaire and underwent echocardiography. Excluding subjects with a LV ejection fraction <50% or atrial fibrillation, diastolic function was evaluated in 647 subjects. The frequency of impaired relaxation according to earlier guidelines was 0.5%, vs. 2.5% using age- and gender-specific normal values of 'E/A-ratio' and 'deceleration time'. In a subpopulation of 167 participants, 6.6% had 'pseudonormalisation'. No difference was found in the frequency of dyspnea in subjects with impaired relaxation or 'pseudonormalisation' compared to subjects with normal filling pattern. CONCLUSION: The prevalence of LV impaired relaxation was highly dependent on the choice of normal (cut-off) values for Doppler indices. Furthermore, our findings suggest that either isolated DD is often asymptomatic, or that Doppler flow derived parameters as a diagnostic method for assessing DD have a low specificity when used as a screening tool in the general population.

Plasma calprotectin levels reflect disease severity in patients with chronic heart failure.

BACKGROUND: Low-grade inflammation has been associated with cardiovascular disease (CVD) and chronic heart failure (CHF). The aim of the present study was to investigate the potential usefulness of the inflammatory protein calprotectin as a biomarker in CHF. METHODS: Plasma calprotectin was measured in 193 CHF patients with left ventricular function <45% and in 100 healthy controls at baseline. Patients with CHF were followed for a median period of 2.6 years according to mortality. RESULTS: The levels of plasma calprotectin were significantly increased in the CHF patients compared to the control group (P < 0.01), primarily due to elevated levels in the patients with New York Heart Association (NYHA) class III and IV. Furthermore, plasma calprotectin was a superior biomarker of high NYHA classes than other parameters reflecting CHF severity, OR 2.2 (1.1-4.3) (P = 0.019). After the follow-up period, 46 patients had died. Plasma calprotectin levels did not predict mortality in CHF patients. CONCLUSIONS: Plasma calprotectin is increased in CHF patients, indicating that inflammatory activity is upregulated in CHF and may be associated with the severity of CHF.