Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

EUROPEAN CARDIAC RESYNCHRONIZATION THERAPY SURVEY II: COMPARISON OF RESULTS IN GEORGIA WITH OTHER COUNTRIES.

Cardiac resynchronization therapy (CRT) is an important treatment modality for patients with heart failure with a reduced ejection fraction and interventricular conduction delay which is supported by current guidelines from major medical societies. One of the largest international clinical practice surveys regarding the CRT - CRT Survey II was conducted from October 2015 to December 2016 in 42 ESC member countries. We compared the outcome data of the CRT Survey II with the Georgian cohort, where 24 patients were enrolled from 2 participating medical centers of Georgia. Despite CRT II Survey analysis did show us some similarities, there were also multiple, notable differencies between Georgian population and all other European countries' data, which can be explained by a number of socio-economic or healthcare-related factors.

Novel endotypes in heart failure: effects on guideline-directed medical therapy.

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

INTRODUCTION: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. METHODS AND RESULTS: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). CONCLUSION: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus.

BACKGROUND: The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. METHODS AND RESULTS: A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. CONCLUSIONS: The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.

Increased interleukin-1ß levels are associated with left ventricular hypertrophy and remodelling following acute ST segment elevation myocardial infarction treated by primary percutaneous coronary intervention.

OBJECTIVES: To assess the relationship between interleukin (IL)-1-related molecules, infarct size and left ventricular (LV) remodelling following acute myocardial infarction (MI). METHODS: Forty-two patients with first-time diagnosis of ST segment elevation MI (STEMI), with a single occluded vessel successfully revascularized by primary percutaneous coronary intervention (PCI), were recruited to this observational study conducted at a university teaching hospital and followed for 1 year. MAIN OUTCOME MEASURES: Plasma levels of IL-1ß, IL-1 receptor antagonist (IL-1Ra), IL-18 and caspase-1 were analysed before and 2 days, 1 week and 2 months after PCI. Serial cardiac magnetic resonance imaging (CMR) was used for the assessment of infarct size and LV remodelling. CMR findings at 1 year was the primary outcome variable. RESULTS: Univariate analysis showed that IL-1-related mediators were strongly (IL-1 ß), moderately (caspase-1) and weakly (IL-1Ra) associated with impaired myocardial function and noninfarct mass, but not infarct size, 1 year after reperfused STEMI. In multivariate analyses, troponin T predicted LV ejection fraction (LVEF), infarct size and LV end-diastolic (LVEDVi) and end-systolic volume index (LVESVi). However, significant additional variance was explained by IL-1ß, IL-18 and caspase-1. IL-1ß levels at 2 months, IL-18 at 2 days and pre-PCI caspase-1 were predictors of LVEF. Caspase-1 and in particular IL-1ß at 2 days were the only predictors of noninfarct mass. IL-1ß and IL-18 at 2 days were predictors of LVEDVi, whilst pre-PCI levels of IL-1ß contributed to prediction of LVESVi. By contrast, pro-B-type natriuretic peptide, C-reactive protein, IL-6 and transforming growth factor-ß1 (TGF-ß1) had no or only a weak (TGF-ß1) association with these CMR parameters in multivariate analyses. CONCLUSIONS: IL-1ß levels after STEMI were strongly associated with impaired myocardial function and noninfarct LV mass after 1 year, suggesting a potential role for IL-1ß as a predictor of maladaptive myocardial remodelling following reperfused MI.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Rapid implementation of therapeutic hypothermia in comatose out-of-hospital cardiac arrest survivors.

BACKGROUND: The implementation of therapeutic hypothermia (TH) into daily clinical practice appears to be slow. We present our experiences with rapid implementation of a simple protocol for TH in comatose out-of-hospital cardiac arrest (OHCA) survivors. METHODS: From June 2002, we started cooling pre-hospitally with sport ice packs in the groin and over the neck. In the intensive care unit (ICU), we used ice-water soaked towels over the torso. All patients were endotracheally intubated, on mechanical ventilation and sedated and paralysed. The target temperature was 33 +/- 1 degrees C to be maintained for 12-24 h. We used simple inclusion criteria: (i) no response to verbal command during the ambulance transport independent of initial rhythm and cause of CA; (ii) age 18-80 years; and (iii) absence of cardiogenic shock (SBP < 90 mmHg despite vasopressors). We compared the first 27 comatose survivors with a presumed cardiac origin of their OHCA with 34 historic controls treated just before implementation. RESULTS: TH was initiated in all 27 eligible patients. The target temperature was reached in 24 patients (89% success rate). ICU- and hospital- length of stay did not differ significantly before and after implementation of TH. Hypokalemia (P= 0.001) and insulin resistance (P= 0.025) were more common and seizures (P= 0.01) less frequently reported with the use of TH. The implementation of TH was associated with a higher hospital survival rate (16/27; 59% vs. 11/34; 32%, respectively; P< or = 0.05). Our results indicate a population-based need of approximately seven cooling patients per 100,000 person-years served. CONCLUSION: Our simple, external cooling protocol can be implemented overnight in any system already treating post-resuscitation patients. It was well accepted, feasible and safe, but not optimal in terms of cooling rate. Neither safety concerns nor costs should be a barrier for implementation of TH.

The effect of altering haemodynamics on the plasma concentrations of natriuretic peptides in heart failure.

BACKGROUND: Natriuretic peptide levels reflect haemodynamics in patients with heart failure and may serve as biochemical markers of cardiac filling pressures. The purpose of this study was to detect differences in the kinetic profile between atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and their N-terminal fragments N-ANP and N-BNP, in response to rapid and persistent vasodilatation. METHODS: Sixteen men and four women aged 63.0+/-10.4 (mean+/-S.D.) with symptomatic congestive heart failure (NYHA III) and pulmonary capillary wedge pressure (PCWP)>18 mm Hg, received a 24-h infusion of nitroglycerin (N=8) or nicorandil (N=12). A reduction of PCWP was achieved for the duration of the study. Natriuretic peptides were measured by radioimmunoassay at baseline, 1, 3, 6, 12 and 24 h. RESULTS: PCWP and right atrial pressure fell rapidly and then increased modestly. ANP and N-ANP demonstrated a similar pattern. In contrast, BNP and N-BNP levels fell steadily throughout the observation period. This was accompanied by a continuous reduction of systemic vascular resistance (SVR). PCWP was highly correlated to the levels of all the natriuretic peptides. Using a longitudinal regression model evaluating responses over time, we found separate, significant relationships between all peptides and haemodynamic variables CONCLUSION: The atrial natriuretic peptides reflect rapid changes in filling pressures while the B-type peptides respond much slower. B-type peptides are less sensitive to short-term changes in filling pressures, but should reflect changes in SVR better during vasodilator therapy.

Exercise training in congestive heart failure. A review of the current status.

Traditionally exercise training was considered contraindicated in heart failure patients. However, during the last 15 years numerous small studies have demonstrated that training is safe in stable heart failure patients and that this intervention improves quality of life in this population. The beneficial effects include improved autonomic balance, reduced neurohumoral activation and reduced inflammatory response in addition to the direct effect on exercise capacity. Pooling of the available data from small randomized studies confirms the positive effect of training on morbidity, and also suggests that this type of intervention improves survival. Large scale studies are on-going to confirm the beneficial effects of training on mortality. This paper reviews the effects of exercise training in patients with the syndrome of heart failure and discusses the different types of training protocols and the tools for assessing the training effect in this population.

Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.

AIMS: Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. METHODS AND RESULTS: DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (> or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups. CONCLUSION: DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.

The added value of spiral computed tomographic angiography after lung scintigraphy for the diagnosis of pulmonary embolism.

OBJECTIVES: The objectives of this study were to evaluate the added clinical value of spiral computed tomographic angiography (CTA) after ventilation-perfusion lung scintigraphy (V/Q) for the management of patients with suspected pulmonary embolism (PE). METHODS: Of 987 patients who had V/Q during 2001, 64 patients (6%) had CTA performed for further evaluation. V/Q and CTA findings were retrospectively analyzed by 2 clinicians who were blinded to the patients' outcome. Patient management was determined based on clinical and V/Q data and was reassessed after the addition of CTA data. RESULTS: CTA was performed in 2 patients with normal V/Q, 16 patients with low probability, 28 patients with intermediate, 4 patients with high probability, and 14 patients with nonconclusive V/Q. Three patients (19%) with low probability, 9 (32%) with intermediate probability, 4 (29%) with nonconclusive, and 4 (100%) with high probability V/Q had PE diagnosed by CTA. CTA findings changed the management in 2 patients (13%) with low probability, 15 (54%) with intermediate probability, and 4 (29%) with nonconclusive V/Q. CONCLUSION: In our institution, V/Q remains the main imaging modality for evaluation of patients with clinically suspected PE. CTA was performed after V/Q in 6% of patients. Patients with intermediate probability and those with nonconclusive V/Q, and to a much lesser extent, patients with low probability V/Q could benefit from the addition of CTA after V/Q. In patients with normal V/Q and those with high-probability V/Q, the addition of CTA does not seem to influence patient management.

Characteristics and prognostic impact of plasma fibrin monomer (soluble fibrin) in patients with coronary artery disease.

We measured fibrin monomer (FM), soluble fibrin, as a marker of thrombin activity in plasma samples obtained in parallel with the first two routine samples for cardiac markers in 165 patients with acute chest pain admitted consecutively to our hospital. A reference limit of FM in a healthy population was set at 3.0 mg/l. Elevated plasma FM was observed in 48.8% of patients with acute coronary syndromes, in 42.3% of patients with specific non-coronary disease, in 31.5% of those with stable angina pectoris and in 18.2% of patients with non-specific chest pain. No significant difference was observed between sample 1 and sample 2 in patients not receiving thrombolytic treatment during the sampling period (P = 0.46). In patients with coronary artery disease, FM was significantly related to the level of cardiac troponin T (P = 0.001), but no correlation was observed between the individual plasma FM and cardiac troponin T values. Outcome analysis during the following 30 months after the index event in patients with acute coronary syndromes revealed higher FM levels in those with coronary re-events or death than in patients without new events (P = 0.001). This observation indicates a prognostic potential of FM in risk evaluation of patients with coronary artery disease.

Comparison of aqueous and gellan ophthalmic timolol with placebo on the 24-hour heart rate response in patients on treatment for glaucoma.

PURPOSE: Topical beta-blocker treatment is routine therapy in the management of patients with glaucoma. Therapy results in systemic absorption, however, the degree of reduction of resting and peak heart rate has not been quantified. DESIGN: This trial evaluated the effect of placebo, 0.5% aqueous timolol (timolol solution) and a 0.5% timolol suspension that forms a gel on application to the conjunctiva (timolol gellan) on the 24-hour heart rate in patients currently being treated for glaucoma to quantify the reduction in mean heart rate. METHODS: Forty-three Caucasian patients with primary open-angle glaucoma or ocular hypertension with a mean (+/-SD) age of 63 (+/-8) years were randomized and crossed over in a double-masked manner to 14 days of treatment with placebo (morning and evening in both eyes), timolol solution (morning and evening in both eyes), or timolol gellan (morning in both eyes with placebo in the evening). On the 13th day of each period, heart rate was recorded continuously during a typical, ambulant 24-hour period. RESULTS: Both timolol solution and timolol gellan reduced the mean 24-hour heart rate compared with placebo (P < or = .001), and this reduction was most pronounced during the daytime (-7.5% change in mean heart rate, -5.7 beats/min). Timolol gellan showed a numerically but not significantly smaller reduction in 24-hour heart rate, compared with timolol solution. During the night, the mean 12-hour heart rate on placebo and timolol gellan were both significantly less than on timolol solution; the difference between solution and gellan treatments was statistically significant (P = .01). CONCLUSIONS: Both timolol solution and timolol gellan decrease the mean 24-hour heart rate compared with placebo. This response was most pronounced during the active daytime period. These data quantify the modest bradycardia associated with ophthalmic beta-blocker therapy in a typical patient population on therapy for glaucoma. Although exercise performance was not assessed in this trial, reductions of this magnitude should not have substantial clinical consequences.

The role of losartan in the management of patients with heart failure.

BACKGROUND: Heart failure places a burden on patients and health care systems worldwide. Although the advent of angiotensin-converting enzyme (ACE) inhibitors markedly improved management of this chronic disorder, treatment is still not optimal, and morbidity and mortality remain high. OBJECTIVE: This review summarizes existing data on losartan, an angiotensin II (AII)-receptor antagonist, and compares its potential role with that of ACE inhibitors in the management of patients with heart failure. METHODS: Relevant primary studies and review articles were identified through a MEDLINE search of the English-language literature for the past 5 years and through examination of the reference lists of the articles so identified. Search terms included, but were not limited to, angiotensin-converting enzyme inhibitors, angiotensin II-receptor antagonists, and losartan. RESULTS: Preclinical and clinical studies of losartan have demonstrated consistent hemodynamic effects (via selective antagonism of the AII type 1 receptor) and a safety profile similar to that of placebo (presumably a reflection of the selective approach to AII blockade). In addition, large-scale end-point studies have shown losartan to have comparable efficacy to ACE inhibitors on a number of morbidity and mortality measures. CONCLUSIONS: There is strong evidence for the broad applicability of AII-antagonists in heart failure and for the use of AII-antagonists in the treatment of a broader population of patients with heart failure, not only those who are unable to tolerate treatment with ACE inhibitors.