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Objectives: This study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF). Background: hs-TnT is a marker of myocardial injury in HF. Methods: The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT. Results: hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07). Conclusions: Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan.

BACKGROUND: Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES: This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS: Analysis of 16,740 individual patients with left ventricular ejection fraction

Background—Heart failure (HF) survival has improved and nowadays many patients with HF die from non-cardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF and the development of cancer. Methods—HF was induced by inflicting large anterior myocardial infarction (MI) in APCmin mice, which are prone to develop precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was employed, where an infarcted or sham-operated heart was transplanted into a recipient mouse, while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post-MI proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and HF patients. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large prospective general population cohort. Results—The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4fold in APCmin mice (all P

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression. OBJECTIVES: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF). METHODS: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores. RESULTS: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance. CONCLUSIONS: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.

BACKGROUND: The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF). OBJECTIVES: This analysis explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo. METHODS: The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization. RESULTS: A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval [CI]: 1.07 to 1.15; p < 0.0001) but not in AF (n = 3,034; HR: 1.03 per 10 beats/min; 95% CI: 0.97 to 1.08; p = 0.38). Beta-blockers reduced ventricular rate by 12 beats/min in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomized to beta-blockers (HR: 0.73 vs. placebo; 95% CI: 0.67 to 0.79; p < 0.001), regardless of baseline heart rate (interaction p = 0.35). Beta-blockers had no effect on mortality in patients with AF (HR: 0.96, 95% CI: 0.81 to 1.12; p = 0.58) at any heart rate (interaction p = 0.48). A lower achieved resting heart rate, irrespective of treatment, was associated with better prognosis only for patients in sinus rhythm (HR: 1.16 per 10 beats/min increase, 95% CI: 1.11 to 1.22; p < 0.0001). CONCLUSIONS: Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm.

AIMS: Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes. METHODS AND RESULTS: We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1 mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00-1.02; P = 0.021]. Similarly, the HR for each 1 mmHg decrease in SBP at 24 h for 180-day all-cause mortality was 1.01 (95% CI 1.00-1.03; P = 0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h. CONCLUSIONS: In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients.

Aims The European CRT Survey is a joint initiative of the Heart Failure Association (HFA) and the European Heart Rhythm Association (EHRA) of the European Society of Cardiology evaluating the contemporary implantation practice of cardiac resynchronization therapy (CRT) in Europe. Methods and results Patients who had a successful CRT implantation were enrolled from 141 centres in 13 countries between November 2008 and June 2009. Baseline demographics, clinical and implantation data were collected, with a follow-up of ∼1 year (9–15 months). The current report describes clinical outcomes including symptom severity, cardiovascular (CV) hospitalization, and survival. A total of 2438 patients were enrolled, and follow-up data were acquired from 2111 patients (87%). The population included important groups of patients poorly represented in randomized controlled trials, including very elderly patients and those with prior device implantation, atrial fibrillation, and/or QRS duration

We recently identified 68 genomic loci where common sequence variants are associated with platelet count and volume. Platelets are formed in the bone marrow by megakaryocytes, which are derived from hematopoietic stem cells by a process mainly controlled by transcription factors. The homeobox transcription factor MEIS1 is uniquely transcribed in megakaryocytes and not in the other lineage-committed blood cells. By ChIP-seq, we show that 5 of the 68 loci pinpoint a MEIS1 binding event within a group of 252 MK-overexpressed genes. In one such locus in DNM3, regulating platelet volume, the MEIS1 binding site falls within a region acting as an alternative promoter that is solely used in megakaryocytes, where allelic variation dictates different levels of a shorter transcript. The importance of dynamin activity to the latter stages of thrombopoiesis was confirmed by the observation that the inhibitor Dynasore reduced murine proplatelet for-mation in vitro.

OBJECTIVES We sought to investigate the effect of angiotensin-converting enzyme (ACE) inhibition

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets. © 2013 Nature America, Inc. All rights reserved.

Context Plasma concentrations of the vasoconstrictor peptide endothelin-1 are increased in patients with heart failure, and higher concentrations are associated with worse outcomes. Tezosentan is an intravenous short-acting endothelin receptor antagonist that has favorable hemodynamic actions in heart failure. Objective To determine if tezosentan improves outcomes in patients with acute heart failure. Design, Setting, and Participants The Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies, 2 independent, identical, and concurrent randomized, double-blind, placebo-controlled, parallel-group trials conducted from April 2003 through January 2005 at sites in Australia, Europe, Israel, and North America. Patients admitted within the previous 24 hours with persisting dyspnea and a respiratory rate of 24/min or greater were eligible provided they fulfilled 2 of 4 criteria: (1) elevated plasma concentrations of B-type or N-terminal pro-B-type natriuretic peptide, (2) clinical pulmonary edema, (3) radiologic pulmonary congestion or edema, or (4) left ventricular systolic dysfunction. Intervention Infusion of tezosentan (5 mg/h for 30 minutes, followed by 1 mg/h for 24 to 72 hours [n = 730]) or placebo (n = 718). Main Outcome Measures The coprimary end points were change in dyspnea (measured at 3, 6, and 24 hours using a visual analog scale from 0-100) over 24 hours (as area under the curve) in the individual trials and incidence of death or worsening heart failure at 7 days in both trials combined. Results Of the 1435 patients who received treatment as assigned, 855 (60%) were men; mean age was 70 years. Mean left ventricular ejection fraction (measured in 779 patients [54%]) was 29% (SD, 11%). Baseline dyspnea scores were similar in the 2 treatment groups. Tezosentan did not improve dyspnea more than placebo in either trial, with a mean treatment difference of -12 (95% confidence interval [CI], -105 to 81) mm . h (P = .80) in the first trial and -25 (95% CI, -119 to 69) mm . h (P = .60) in the second. The incidence of death or worsening heart failure at 7 days in the combined trials was 26% in each treatment group (odds ratio, 0.99; 95% confidence interval, 0.82-1.21; P = .95). Conclusion The endothelin receptor antagonist tezosentan did not improve symptoms or clinical outcomes in patients with acute heart failure.

Aims: Because of the prognostic importance of LV dysfunction following an AMI and the increasing use of electrical and/or mechanical interventions in patients with LV systolic dysfunction, this retrospective analysis of EPHESUS patients with LVEF Methods and results: In EPHESUS, 6632 patients with LVEF Conclusions: Treatment with eplerenone plus standard therapy in patients with post-AMI HF and LVEF

Background: Chronic heart failure (CHF) is a potential indication for the administration of EMD 87 580, a selective Na+/H+ exchange inhibitor. CHF is often accompanied by renal dysfunction, which is known to affect the pharmacokinetics of compounds predominately cleared by the kidneys. We examined the influence of renal dysfunction on the pharmacokinetics of EMD 87 580 in patients with CHF. Methods: 21 patients with CHF and normal renal function (Group 1) and 9 patients with CHF and renal dysfunction (Group 2) received EMD 87 580 orally over 8 days. The mean creatinine clearance (CrCl) in Group 1 was 99.7 ml/min. 12 patients in this group were randomized to receive two doses of EMD 8 7580 (7 patients 2 x 5 0 mg and 5 patients 2 x 100 mg). The 9 patients in Group 2 with renal dysfunction (mean CrCl = 49.5 ml/min) received 50 mg EMD 87580 once daily. Plasma and urine samples were collected for pharmacokinetic assessment. Results: In CHF patients with renal dysfunction EMD 87580 clearance was reduced to approximately 50% compared to Group 1, i.e. 6.80 ml/min (4.89 - 11.60) vs. 12.73 ml/min (8.93 - 22.2 1), p

Both angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) interfere with the activity of the renin-angiotensin system (RAS) in a different way. Theoretically, one might expect beneficial effects when they are used in combination, as a more complete suppression of the RAS can be achieved. But can this additional effect still be seen in patients on full-dose ACE-inhibition? Several controlled trials demonstrated that combination therapy can have additional benefits in hypertensive patients, in chronic heart failure patients, and in both diabetic and non-diabetic nephropathy patients. However, the clinical benefit was not always as pronounced as expected and not every patient will benefit from dual blockade of the RAS. There is some evidence of a less pronounced effect of combination therapy when a full dose of the ACE-inhibitor is given. However, it is well known that ACE-inhibitors cannot completely suppress the formation of angiotensin II, in particular, when the RAS is activated. Indeed, clinical trials indicated that add-on therapy with an ARB was especially of use when the RAS remained activated despite full-dose ACE-inhibitor treatment. In summary, combination of a full-dose ACE-inhibitor and an ARB can be a rational choice in selected patients.

Objective Repeated left ventricular ejection fraction (LVEF) analyses with sequential single-dose radionuclide ventriculography might be an interesting technique for monitoring the effect of positive inotropic interventions. The aim of the study was to assess the reproducibility of LVEF measurement with planar radionuclide ventriculography within 3 h, using a standard single dose of radioactive tracer. Methods Sixteen patients underwent routine planar radionuclide ventriculography with a standard dose of 500 MBq of [[Tc-99m]pertechnetate and returned after 3 h for a repeat planar radionuclide ventriculography without administration of additional tracer. Results The average initial LVEF was 35.1 +/- 18.6%-point (range, 12%-point to 68%-point). The mean difference of the LVEF between the initial planar radionuclide ventriculography and the repeat planar radionuclide ventriculography was 2.8% +/- 6.3% (range, - 11.8% to 13.3%, P= NS). The correlation between both measurements was significant with a correlation coefficient of 0.995 (P Conclusion Repeated radionuclide ventriculography with a 3 h interval using a single standard dose of 500 MBq of [Tc-99m]pertechnetate is highly reproducible and will be useful for monitoring the effect of positive inotropic interventions.

Aims Large randomized trials have shown that beta-Mockers reduce mortality and hospital admissions in patients with heart failure. The effects of beta-blockers in elderly patients with a broad range of left ventricular ejection fraction are uncertain. The SENIORS study was performed to assess effects of the beta-blocker, nebivolol, in patients >= 70 years, regardless of ejection fraction. Methods and results We randomly assigned 2128 patients aged >= 70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction 35%), and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.74-0.99; P=0.039]. There was no significant influence of age, gender, or ejection fraction on the effect of nebivolol on the primary outcome. Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (HR 0.88, 95% CI 0.71-1.08; P=0.21). Conclusion Nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly.

Erythropoietin (EPO) is a hormone known to stimulate hematopoiesis. However, recent research suggests additional properties of EPO, such as protection against ischemia/reperfusion (I/R) injury in various tissues. We studied the effect of timing of EPO administration on cardioprotection during I/R in the heart. Male Sprague-Dawley rats were subjected to 45 minutes of coronary occlusion, followed by 24 hours of reperfusion. Animals were randomized to receive saline or single dose of EPO (5000 IU/kg) either 2 hours before I/R, at the start of ischemia, or after the onset of reperfusion. The ratio of infarct area/area at risk (planimetry), left ventricular (LV) function (pressure development), and apoptosis (number of active caspase-3 positive cells) were determined after 24-hour reperfusion. Administration of EPO during different time points resulted in a 19 to 23% (P

The purpose of this study was to appraise the value of PET in the assessment of the effect of supposedly proangiogenic new therapies such as gene therapy with vascular endothelial growth factor (VEGF) gene and endomyocardial laser therapy. Methods: Thirty-five patients with end-stage coronary artery disease and class III (Canadian Cardiovascular Society) angina were included. Myocardial ischemia was evaluated with dipyridamole PET scanning and exercise tolerance with bicycle ergometry. Ten patients were treated with naked plasmid DNA encoding for human VEGF(165) (VEGF) and 12 patients were treated with laser therapy (direct myocardial revascularization [DMR]) using an electromechanical mapping system. Thirteen patients were treated with standard medical therapy (control). Results: In both active treatment groups, angina was reduced in most subjects, except in 2 VEGF and 5 DMR patients. In the control group, no improvement in anginal classification was found, except in 3 subjects. On the PET scan, solely in the VEGF group, the stress perfusion was significantly improved (from 57 +/- 33 to 81 +/- 55 mL/min/100 g; P = 0.031). Furthermore, in the VEGF group, the number of ischemic segments was reduced from 274 +/- 41 to 234 +/- 48 segments (P = 0.004) but not in the DMR group (from 209 +/- 43 to 215 +/- 52 segments) or in the control group (from 218 +/- 18 to 213 +/- 28 segments). Bicycle exercise duration showed slight nonsignificant changes in the VEGF group (from 3.6 +/- 2.0 to 4.6 +/- 2.1 min), in the DMR group (from 5.1 +/- 1.5 to 4.7 +/- 1.3 min), and in the control group (from 3.3 +/- 1.8 to 3.5 +/- 2.3 min). Conclusion: PET showed that intramyocardial gene therapy with the human VEGF(165) gene in contrast to laser DMR treatment effectively reduces myocardial ischemia.

Aim Differential drug treatment guided by the underlying heart disease may improve outcome of rhythm control therapy. In the present study we investigated in a well-defined group with either lone atrial. fibrillation (AF) or hypertension whether there were differences in rhythm control outcome between both groups in relation to the use of cardiovascular drugs. Methods and results One hundred sixty-two patients were included after successful cardioversion of persistent AF. None of the patients was given a class I or III antiarrhythmic drug. Patients' heart rhythm was checked 3 times a day, using transtelephonic monitoring for 1 month after cardioversion. One month after cardioversion up to 68% of patients had a recurrence of persistent AF. During the first 3 days almost no recurrences were seen on beta-blocker therapy whereas recurrences peaked on day 2-3 in the absence of beta-blockers. Univariate analysis showed that the use of beta-adrenergic receptor blockers and the presence of hypertension were associated with a lower recurrence rate at 1 month. Multivariate logistic regression analysis demonstrated that beta-blockade was the only statistically significant parameter predicting sinus rhythm at 1 month (OR 0.40, 95% CI 0.19-0.86, P = 0.02). Conclusions Compared with lone AF patients, patients in the setting of hypertension maintain sinus rhythm much better after cardioversion when treated with a beta-blocker. Beta-blockade protects, in particular, against the early subacute recurrences. These findings underscore the importance of a differential approach towards drug prevention of post-cardioversion recurrences depending on the underlying heart disease. (C) 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

The aim of this study was to compare left ventricular (LV) volumes and regional wall motion determined by PET with those determined by the reference technique, cardiovascular MRI. Methods: LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were measured and regional wall motion was scored in 38 patients with chronic coronary artery disease by both gated F-18-FDG PET and MRI. A 9-segment model was used for PET and MRI to assess regional wall motion. Results: Good correlations were observed between MRI and gated PET for all parameters (r values ranging from 0.91 to 0.96). With PET, there was a significant but small underestimation of LVEDV and LVEF. Mean+/-SD LVEDV, LVESV, and LVEF for MRI were 131+/-57 mL, 91+/-12 mL, and 33%+/-12%, respectively, and those for gated PET were 117+/-56 mL, 85+/-51 mL, and 30%+/-11%, respectively. For regional wall motion, an agreement of 85% was found, with a kappa-statistic of 0.79 (95% confidence interval, 0.70-0.89; SE, 0.049). Conclusion: LV volumes, LVEF, and regional wall motion can be assessed with gated F-18-FDG PET and correlate well with these parameters assessed by MRI.

Planar gated blood-pool imaging (GBPI) is a standard method for non-invasive assessment of left ventricular (LV) function. Gated blood-pool single photon emission computed tomographic (GBPS) data acquisition can be accomplished in the same time as GBPI, with the benefit of enabling visualization of all cardiac chambers simultaneously. The purpose of this investigation was to evaluate the degree to which automated and manual LVEF calculations agree with one another and with conventional GBPI LVEF measurements. GBPI studies were performed in 22 consecutive, unselected patients, followed by GBPS data acquisition. GBPS left ventricular ejection fraction (LVEF) calculations were performed by available software (NuSMUGA, Northwestern University, Chicago, IL) automatically and manually, using all LV gated short axis slices. Automatic LVEF assessed by GBPS correlated well with conventional planar GBPI (r = 0.88, P

Chronic heart failure (CHF) is a large medical problem, but in recent years significant progress has been made in its treatment. Angiotensin converting enzyme (ACE) inhibitors and beta-blockers are now the cornerstones in the treatment of CHF, usually in combination with diuretics digoxin. Many other drugs have been developed, but apart from angiotensin II receptor blockers, and possibly aldosterone receptor antagonists, these drugs have not gained a place. The place of device therapy has increased in recent years. Indications for the implantable cardioverter-defibrillator (ICD) are expanding, and new biventricular pacing techniques (cardiac resynchronization therapy [CRT]) are gaining a place. The recent COMPANION study has shown that the combination of CRT and ICD may be the most optimal treatment strategy. Given these rapidly expanding treatment options in CHF, new questions are now emerging. The order in which the various agents are administered is under debate, and it has been suggested that beta-blockers and not ACE inhibitors should be first-line drugs. Also, patient-tailored treatment and pharmacogenomics appear attractive, as is treatment guided by plasma (neurohormonal) parameters. Use of devices (ICD and CRT) is now so common and effective that the indication for implantating them is rapidly moving from advanced to early CHF, but wide application of these devices is expensive. In conclusion, treatment options are still expanding for patients with CHF, which generate new questions, and these must be addressed in future studies. (C) 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. AR rights reserved.

Background: In comparison with planar imaging gated blood-pool single photon emission computed tomography (GBPS) has the advantage of separating left and right ventricle. The purpose of this investigation was to evaluate the right ventricular ejection fraction (RVEF) calculations by GBPS software ('NuSMUGA(TM)', Northwestern University, Chicago, IL) in comparison to first-pass radionuclide angiography (FPRNA). Methods: In 22 consecutive patients FPRNA and GBPS acquisition was performed. GBPS RVEF calculations were manually and automatically performed, using all gated short-axis-slices of the right ventricle. Results: Automatic RVEF assessed by GBPS did not correlate with conventional FPRNA (r = 0.40, p = 0.065). Mean FPRNA RVEF was 55 +/- 10% and mean GBPS automatic RVEF was 32 +/- 8%. Also manual GBPS RVEF did not correlate with conventional FPRNA (r = 0.41, p = 0.055). Mean RVEF measurement by manual GBPS was 33 +/- 8%. Manual GBPS RVEF values correlated well with automatically determined GBPS RVEF values (r = 0.96, p

Aims For ethical and economic reasons, interim analysis of phase III clinical trials is essential. This study was conducted to compare the efficiency of two interim analysis procedures, which could be used to allow early termination of a clinical trial. Methods We made a post hoc application of two interim analysis methods (Lan & DeMets with O'Brien-Flemming modification, and the triangular test according to Whitehead) by using individual patient data from four published placebo-controlled survival trials. We determined the date the trial would have been stopped had each method been used, and we estimated consequent results in terms of events and patient numbers included in the trial, the duration of the trial, and on treatment effect. Results The triangular test provided the lowest number of events required to reach a conclusion of the trials while providing an accurate estimate of experimental treatment effects. The triangular test thus indicated the smallest number of patients that would have been enrolled, and the shortest trial duration. The difference between the methods was most important with a detrimental effect of experimental treatment: the number of required events was reduced by 75% and the trial duration was shortened by 48% with the triangular test compared to the Lan & DeMets method. Conclusions Stopping a trial early must depend on the clinical context. It is most important to stop a placebo-controlled trial as soon as possible when the experimental treatment can be shown deleterious. In such a situation the triangular test is more appropriate than the Lan & DeMets method. When a treatment effect is no different from, or better than, placebo the triangular test is also superior but the importance of premature termination of the trial in such cases has to be balanced against the inevitable reduction of information that the trial can provide.

Background: Brain natriuretic peptide (BNP) levels have been used to assess clinical status and predict prognosis of patients with chronic heart failure (CHF). However, BNP levels can only be measured in specialized laboratories which has hampered its use in daily clinical practice. We compared a new, rapid, BNP assay with a conventional BNP measurement and evaluated the applicability to current practice by comparing it with standard clinical parameters. Methods: BNP levels were determined in 78 stable CHF patients and 20 controls. The severity of CHF was assessed by determination of New York Heart Association functional class (NYHA), left ventricular ejection fraction (LVEF) and peak oxygen consumption (peak Vo(2)), and these parameters were compared to BNP levels. Results: Overall, rapid BNP assessment was highly correlated with the conventional BNP assay (r = 0.95, P 200 pmol/l), however, correlation was less accurate, and tended to overestimate. BNP levels also strongly correlated with both NYHA class, LVEF and peak Vo2 (all P

Objective: To examine retrospectively the changes in ECG parameters over time and their correlation with other quantitative right ventricular (RV) function parameters in patients with chronic RV pressure overload caused by congenital heart disease. Methods: 48 patients with chronic RV pressure overload caused by the following congenital heart diseases were studied: nine with congenitally corrected transposition of the great arteries (TGA), 12 with surgically corrected TGA, and 27 with a subpulmonary pressure overloaded RV. QRS duration and dispersion were measured manually from standard ECG recorded twice within five years. RV end diastolic volume (EDV) and RV mass were determined by magnetic resonance imaging. Brain natriuretic peptide (BNP) plasma concentrations were measured. Results: QRS duration and QRS dispersion increased in all patient groups during the follow up period. QRS duration increased significantly in the congenitally corrected TGA (p = 0.04) and the subpulmonary pressure overloaded RV groups (p = 0.01). QRS dispersion increased significantly in patients with surgically corrected TGA (p = 0.03) and in the subpulmonary pressure overloaded RV group (p = 0.02). A significant correlation was found between QRS duration and RVEDV (r = 0.71, p

Background: Target intensity-level of exercise training in patients with coronary artery disease is adjusted usually by a target heart rate (THR). This THR is aimed to be at or nearby the anaerobic threshold (AT) and is calculated commonly from parameters of regular exercise training, instead of an actual measurement of AT and its related heart rate. Therefore, this study evaluated whether a calculation is reliable. Methods: In 91 male patients (age 52 9 years) exercise capacity was measured after a recent (>4 weeks) coronary event. AT was compared with peak exercise capacity and heart rate at AT,was compared with THR, using the Karvonen method. Results: Mean AT (18.2 ml/min/kg, range 9.2-32.2) and mean peak V-O2 (24.5, range 10.9-43.9) were slightly decreased (respectively 0.83 and 0.79 of predicted). When related to peak exercise capacity, AT showed a large inter-individual variation. For example, heart rate at AT ranged from 0.55 to 0.96 of peak heart rate. As a result heart rate at AT varied considerably with THR. The mean THR, although significantly higher, correlated well with mean heart rate at AT (respectively, 109 and 105/min, P

Objectives. To evaluate and compare the functional type and the degree of antagonism of the selective angiotensin II type I receptor blockers (ARB) losartan, EXP 3174 (the active metabolite of losartan), valsartan and candesartan in human internal mammary arteries. Methods. Human internal mammary arteries were obtained as excess graft material during coronary bypass surgery. Vessels were prepared as rings and mounted in an organ bath in which vasoconstriction and -dilation can be measured. Concentration-response curves of angiotensin II-mediated vasoconstriction were measured in absence or presence of different concentrations of one of the ARBs. Results. Losartan showed a rightward shift of the angiotensin II-mediated vasoconstriction, whereas addition of its metabolite EXP 3174 caused a decrease of the maximal effect of angiotensin II. Incubation with valsartan and candesartan also resulted in a decrease of the maximal effect. The inhibiting effects on the angiotensin II-mediated vasoconstriction by the highest concentration of EXP 3174, valsartan and candesartan did not differ significantly. Conclusion. In human internal mammary arteries, losartan acts as a surmountable antagonist. On the other hand, EXP 3174, valsartan and candesartan demonstrate an insurmountable type of antagonism. Furthermore, the inhibiting effects of EXP 3174, valsartan and candesartan in our study are equal in the highest concentrations.

Background: Congestive heart failure (CHF) is characterized by neurohormonal activation, including increased plasma concentrations of atrial natriuretic peptide (ANP) and N-terminal ANP (N-ANP). Onset of atrial fibrillation (AF) further increases these peptides, but it may be hypothesized that concentrations decrease during longstanding AF due to inherent atrial degeneration. Aim: We sought to investigate the relation between neurohormonal activation in patients with CHF and the duration of concomitant AF Methods: The study group comprised 60 patients (age 70+/-8 years) with advanced CHF due to left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF) 0.25 ANP and N-ANP increased along with the duration of AF, whereas in patients with LVEFless than or equal to0.25 an inverse relation between ANP (P=0.02) and N-ANP (P=0.04) and the duration of AF was present, longer-standing AF being associated with lower concentrations. Conclusion: In patients with advanced CHF with low LVEF plasma ANP and N-ANP concentrations decrease during longstanding AF. This finding agrees with the concept that longstanding AF leads to impaired ability of the atria to produce these neurohormones due to inherent degenerative changes. (C) 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.

In this case report, we describe a 33-year-old woman with a history of two unprovoked thrombo-embolic events presenting with acute myocardial ischaemia. She had a normal coronary angiogram (CAG). The diagnosis primary antiphospholipid syndrome (APS), an acquired hypercoagulability disorder, was established by the presence of antibodies directed against phospholipids. The primary A-PS should be considered as a cause of myocardial ischaemia in patients with a normal CAG and a history of unprovoked thrombo-embolic events. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

The dimension is a basic concept in non linear dynamics. The box counting dimension (BCD) is one of the methods that is available to determine the dimension. We studied the dimension of the heartrate signal in both 2 and 3D Poincare plots in a group of twenty five post myocardial infarction (MI) patients together with an age and sex matched control group. The average BCD from the normal subjects based on a 2D first return plot was 1.46 +/- 0,09, while in the in infarction group this was significantly lower: 1.34 +/- 0.17 (p=0.003). Excluding ectopic data from the analysis caused large changes in the resulting dimension.