Impact analysis of heart failure across European countries: an ESC-HFA position paper.

Heart failure (HF) is a long-term clinical syndrome, with increasing prevalence and considerable healthcare costs that are further expected to increase dramatically. Despite significant advances in therapy and prevention, mortality and morbidity remain high and quality of life poor. Epidemiological data, that is, prevalence, incidence, mortality, and morbidity, show geographical variations across the European countries, depending on differences in aetiology, clinical characteristics, and treatment. However, data on the prevalence of the disease are scarce, as are those on quality of life. For these reasons, the ESC-HFA has developed a position paper to comprehensively assess our understanding of the burden of HF in Europe, in order to guide future policies for this syndrome. This manuscript will discuss the available epidemiological data on HF prevalence, outcomes, and human costs-in terms of quality of life-in European countries.

Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP and GDF-15, of Heart Failure therapies (STRONG-HF): rationale and design for a multicentre, randomized, parallel-group study.

AIMS: Patients admitted for acute heart failure (HF) are at high risk of readmission and death, especially in the 90 days following discharge. We aimed to assess the safety and efficacy of early optimization of oral HF therapy with beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNi), and mineralocorticoid receptor antagonists (MRA) on 90-day clinical outcomes in patients admitted for acute HF. METHODS: In a multicentre, randomized, open-label, parallel-group study, a total of 900 patients will be randomized in a 1:1 ratio to either 'usual care' or 'high-intensity care'. Patients enrolled in the usual care arm will be discharged and managed according to usual clinical practice at the site. In the high-intensity care arm, doses of oral HF medications - including a BB, ACEi or ARB, and MRA - will be up-titrated to 50% of recommended doses before discharge and to 100% of recommended doses within 2 weeks of discharge. Up-titration will be delayed if the patients develop worsening symptoms and signs of congestion, hyperkalaemia, hypotension, bradycardia, worsening of renal function or significant increase in N-terminal pro-B-type natriuretic peptide between visits. The primary endpoint is 90-day all-cause mortality or HF readmission. CONCLUSIONS: STRONG-HF is the first study to assess whether rapid up-titration of evidence-based guideline-recommended therapies with close follow-up in a large cohort of patients discharged from an acute HF admission is safe and can affect adverse outcomes during the first 90 days after discharge. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03412201.

French Society of Cardiology guidelines on exercise tests (part 2): Indications for exercise tests in cardiac diseases.

The exercise test is performed routinely in cardiology; its main indication is the diagnosis of myocardial ischemia, evaluated along with the subject's pretest probability and cardiovascular risk level. Other criteria, such as analysis of repolarization, must be taken into consideration during the interpretation of an exercise test, to improve its predictive value. An exercise test is also indicated for many other cardiac diseases (e.g. rhythm and conduction disorders, severe asymptomatic aortic stenosis, hypertrophic cardiomyopathy, peripheral artery disease, hypertension). Moreover, an exercise test may be indicated for specific populations (women, the elderly, patients with diabetes mellitus, patients in a preoperative context, asymptomatic patients and patients with congenital heart defects). Some cardiac diseases (such as chronic heart failure or arterial pulmonary hypertension) require a cardiopulmonary exercise test. Finally, an exercise test or a cardiopulmonary exercise test is indicated to prescribe a cardiac rehabilitation programme, adapted to the patient.

French Society of Cardiology guidelines on exercise tests (part 1): Methods and interpretation.

The exercise test is still a key examination in cardiology, used for the diagnosis of myocardial ischemia, as well as for the clinical evaluation of other heart diseases. The cardiopulmonary exercise test can further define functional capacity and prognosis for any given cardiac pathology. These new guidelines focus on methods, interpretation and indications for an exercise test or cardiopulmonary exercise test, as summarized below. The safety rules associated with the exercise test must be strictly observed. Interpretation of exercise tests and cardiopulmonary exercise tests must be multivariable. Functional capacity is a strong predictor of all-cause mortality and cardiovascular events. Chest pain, ST-segment changes and an abnormal ST/heart rate index constitute the first findings in favor of myocardial ischemia, mostly related to significant coronary artery disease. Chronotropic incompetence, abnormal heart rate recovery, QRS changes (such as enlargement or axial deviations) and the use of scores (based on the presence of various risk factors) must also be considered in exercise test interpretation for a coronary artery disease diagnosis. Arrhythmias or conduction disorders arising during the exercise test must be considered in the assessment of prognosis, in addition to a decrease or low increase in blood pressure during the exercise phase. When performing a cardiopulmonary exercise test, peak oxygen uptake and the volume of expired gas/carbon dioxide output slope are the two main variables used to evaluate prognosis.

Imbalanced Angiogenesis in Peripartum Cardiomyopathy　- Diagnostic Value of Placenta Growth Factor.

BACKGROUND: Concentrations of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) are altered in peripartum cardiomyopathy (PPCM). In this study we investigated changes in the angiogenesis balance in PPCM.Methods and Results:Plasma concentrations of sFlt-1 and the pro-angiogenic placenta growth factor (PlGF) were determined in patients with PPCM during the post-partum phase (n=83), in healthy women at delivery (n=30), and in patients with acute heart failure (AHF; n=65). Women with cardiac failure prepartum or associated with any form of hypertension, including pre-eclampsia, were excluded. Compared with non-pregnant women, in women with AHF and PPCM, median PlGF concentrations were greater (19 [IQR 16-22] and 98 [IQR 78-126] ng/mL, respectively; P<0.001) and the sFlt-1/PlGF ratio was lower (9.8 [6.6-11.3] and 1.2 [0.9-2.8], respectively; P<0.001). The sFlt-1/PlGF ratio was lower in PPCM than in normal deliveries (1.2 [0.9-2.8] vs. 94.8 [68.8-194.1], respectively; P<0.0001). The area under the curve for PlGF (cut-off value: 50ng/mL) and/or the sFlt-1/PlGF ratio (cut-off value: 4) to distinguish PPCM from either normal delivery or AHF was >0.94. Median plasma concentrations of the anti-angiogenic factor relaxin-2 were lower in PPCM and AHF (0.3 [IQR 0.3-1.7] and 0.3 [IQR 0.3-1] ng/mL, respectively) compared with normal deliveries (1,807 [IQR 1,101-4,050] ng/mL; P<0.001). CONCLUSIONS: Plasma of PPCM patients shows imbalanced angiogenesis. High PlGF and/or low sFlt-1/PlGF may be used to diagnose PPCM.

Circulating microRNAs and Outcome in Patients with Acute Heart Failure.

BACKGROUND: The biomarker value of circulating microRNAs (miRNAs) has been extensively addressed in patients with acute coronary syndrome. However, prognostic performances of miRNAs in patients with acute heart failure (AHF) has received less attention. METHODS: A test cohort of 294 patients with acute dyspnea (236 AHF and 58 non-AHF) and 44 patients with stable chronic heart failure (CHF), and an independent validation cohort of 711 AHF patients, were used. Admission levels of miR-1/-21/-23/-126/-423-5p were assessed in plasma samples. RESULTS: In the test cohort, admission levels of miR-1 were lower in AHF and stable CHF patients compared to non-AHF patients (p = 0.0016). Levels of miR-126 and miR-423-5p were lower in AHF and in non-AHF patients compared to stable CHF patients (both p<0.001). Interestingly, admission levels of miR-423-5p were lower in patients who were re-admitted to the hospital in the year following the index hospitalization compared to patients who were not (p = 0.0001). Adjusted odds ratio [95% confidence interval] for one-year readmission was 0.70 [0.53-0.93] for miR-423-5p (p = 0.01). In the validation cohort, admission levels of miR-423-5p predicted 1-year mortality with an adjusted odds ratio [95% confidence interval] of 0.54 [0.36-0.82], p = 0.004. Patients within the lowest quartile of miR-423-5p were at high risk of long-term mortality (p = 0.02). CONCLUSIONS: In AHF patients, low circulating levels of miR-423-5p at presentation are associated with a poor long-term outcome. This study supports the value of miR-423-5p as a prognostic biomarker of AHF.

[Shall we Follow the Guidelines for Isosorbide Dinitrate in Acute Pulmonary Edema?]. / Y a-t-il une place pour le dinitrate d'isosorbide dans l'œdème aigu pulmonaire ?

PURPOSE: Prospective evaluation of short (dyspnoea) and mid-term outcomes in 47 consecutive patients admitted in the intensive care unit for acute pulmonary edema treated on a liberal basis. RESULTS: Patients were elderly (83 year-old) and 60% had preserved left ventricular ejection fraction (>50%). Dyspnoea assessed by visual analogue score was weakly associated with treatment posology. Despite low use of inotropes (6%) and intubation (9%), hospital and D90 mortality was high (19% and 32% respectively). Higher mortality was noticed in patients receiving no isosorbide dinitrate (p = 0.04). In the multivariate analysis, only age and delta brain natriuretic peptide (difference between BNP on D1 and D0) remained significantly associated with mortality on D90 (OR 1.13; p = 0.03 and OR 1.004; p = 0.04 respectively). CONCLUSION: Acute pulmonary edema carried a dramatic in-hospital and mid-term mortality in our elderly patients. Isosorbide dinitrate was associated with decreased D90 mortality but not in the multivariate analysis.

Influence of systolic blood pressure on clinical outcomes in elderly heart failure patients treated with nebivolol: data from the SENIORS trial.

AIMS: There is limited information about the effects of beta-blockers in heart failure (HF) stratified by blood pressure, especially in the elderly and those with preserved EF. We evaluate the effects of nebivolol on outcomes in elderly patients with HF stratified by baseline systolic blood pressure (SBP) and EF. METHODS AND RESULTS: The SENIORS trial evaluated the effects of nebivolol and enrolled 2128 patients ≥ 70 years of age with HF. Patients were divided into three baseline pre-treatment SBP categories (<110, 110-130, and >130 mmHg). In addition, we evaluated the influence of SBP (≤ 130 and > 130 mmHg) on patients with LVEF <40% vs. ≥ 40%. Low baseline SBP was associated with worse clinical outcomes irrespective of treatment group, both in patients with reduced EF and in those with preserved EF. Nebivolol had similar benefits irrespective of baseline SBP: the hazard ratio (HR) for primary outcome of all-cause mortality or cardiovascular hospitalization in the three SBP categories for nebivolol vs. placebo was 0.85 [95% confidence interval (CI) 0.50-1.45], 0.79 (95% CI 0.61-1.01), and 0.88 (95% CI 0.72-1.07), respectively (P for interaction = 0.61). Similar results were obtained for the secondary endpoint of all-cause mortality. There was no significant interaction for the effects of nebivolol by baseline SBP stratified by LVEF. CONCLUSIONS: Elderly HF patients with lower SBP have a worse outcome than those with higher SBP, but nebivolol appears to be safe and well tolerated, with similar benefits on the composite outcome of death or cardiovascular hospital admission irrespective of baseline SBP and LVEF.

Pentoxifylline in heart failure: a meta-analysis of clinical trials.

BACKGROUND: Pentoxifylline possess antiinflammatory and rheological properties and has been tested in heart failure (HF). METHODS: A comprehensive search was performed from 1980 until July 2013 in PubMed, to identify randomized controlled trials evaluating pentoxifylline versus placebo in HF, to determine impact on mortality. Search strategy is as follows: "Pentoxifylline" AND "heart" AND "trial". Study selection of six randomized controlled trials evaluating mortality as outcome. Then, we conducted a meta-analysis of randomized controlled trials versus placebo in HF. Determination of Mantel-Haenszel fixed effect and random-effect pooled odds ratios for all-cause mortality and corresponding 95% confidence intervals. RESULTS: Data from a total of 221 patients with LVEF ≤40% from six randomized controlled trials were included in this analysis. Pentoxifylline 1200 mg per day was administered during 6 months, except in one study (administered during 1 month for severe acute HF). The use of pentoxifylline was not significantly associated with a reduction in mortality in HF in individual studies. The pooled data including 221 patients showed a nearly fourfold reduction in mortality (5.4% vs. 18.3%; OR 0.29; CI 0.12-0.74; P < 0.01) with homogenous results (I² 0%). CONCLUSION: A meta-analysis evaluating pentoxifylline versus placebo in HF suggested a significant nearly fourfold decrease in all-cause mortality in the pentoxifylline group.

Comparison of the diagnostic and prognostic values of B-type and atrial-type natriuretic peptides in acute heart failure.

BACKGROUND: We compared diagnostic and prognostic properties of brain natruiretic peptide (BNP), proBNP, NT-proBNP and MR-pro-atrial natriuretic peptide (ANP) in patients admitted with shortness of breath (SOB). METHODS: All 4 NPs were measured in patients admitted to the emergency unit with SOB (in 2 centers) or acute heart failure (AHF) (1 FINN-AKVA cohort) and in a control population of stable chronic HF. Follow-up was 1 (2 centers) and 5 years (1 FINN-AKVA cohort). Area under the curve (AUC) was used to assess diagnostic properties. AUC, multivariate Cox regression, net reclassification improvement (NRI), and Kaplan-Meier analyses were used to assess mortality. RESULTS: We included 710 patients ("Biomarcoeurs" cohort n=336; FINN-AKVA study, n=306; stable chronic HF, n=68). Pro-BNP was almost as powerful as BNP to diagnose AHF (AUC 0.953 vs 0.973 respectively, p=0.003), NT-proBNP also performed well (0.922, p<0.001 vs BNP). MR-proANP performed less well (0.901). AUC over time showed greater MR-proANP values over the first year. At 5 years, MR-proANP had the best prognostic value (AUC 0.668 vs 0.604 for BNP, p=0.042). Kaplan Meier analysis confirmed better survival with MR-proANP≤416.8 pmol/L at 5 years. NRI at 5 years was greater for MR-proANP (0.23, p<0.05) than for proBNP, BNP or NTproBNP (p=NS). CONCLUSION: Our study provides firm evidence that all NPs perform equally well for diagnostic purposes, and that MR-proANP has long term prognostic value in patients with acute heart failure.

Electrocardiographic abnormalities in centenarians and octogenarians: a case-matched study.

BACKGROUND: Centenarians have been proposed as a model of successful aging but recent studies suggest a high prevalence of cardiovascular diseases. Some findings on their electrocardiograms (ECGs) are simply age-related and others mirror underlying diseases. We aimed to identify ECG features truly associated with extreme age. METHODS: Retrospective analysis of 55 centenarians hospitalized between January 2000 and June 2010. Each centenarian was matched with three octogenarians according to gender, presence of hypertension, aortic stenosis, heart failure, and ischemic heart disease. RESULTS: A history of hypertension was present in 32 (58%) centenarians, aortic stenosis in 6 (11%), heart failure in 8 (15%), and ischemic heart disease in 6 (11%). Centenarians had a higher heart rate than octogenarians (81 ± 15 bpm vs. 72 ± 15 bpm, respectively, P < 0.001) but were less frequently on beta-blockers (7% vs. 36%, respectively, P < 0.001). Centenarians displayed more frequently atrial premature beats than octogenarians (18% vs. 3%, respectively, P < 0.001) but tended to have less atrial fibrillation (15% vs. 22% respectively, P = 0.21). Centenarians had more frequently left QRS axis deviation (48% vs. 28%, P = 0.009) and Q waves (14% vs. 1%, P = 0.02). QT interval was more prolonged in centenarians (446 ± 42 ms vs. 429 ± 39 ms, P = 0.008). Two centenarians (4%) and 24 (15%) octogenarians had a strictly normal ECG (P = 0.02). CONCLUSIONS: Abnormal ECG is a common finding in centenarians, with different characteristics than in younger elderly individuals. These differences are unrelated to the presence of cardiac diseases.

Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice.

BACKGROUND: Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of "fetal" gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren). AS-Ren mice had increased (x2) angiotensin II in plasma and increased (x2) aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70%) versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41%) in AS-Ren mice (P<0.05 vs Ren). The increase of ANP (x 2.5; P<0.01) mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (-75%, p<0.001) in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05), an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects. CONCLUSIONS/SIGNIFICANCE: Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of ß-myosin heavy chain expression through the induction of its transcriptional repressor Sox6. Thus, aldosterone inhibits the fetal program and increases cardiac hypertrophy in hypertensive mice.

Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation.

The European Society of Cardiology heart failure guidelines firmly recommend regular physical activity and structured exercise training (ET), but this recommendation is still poorly implemented in daily clinical practice outside specialized centres and in the real world of heart failure clinics. In reality, exercise intolerance can be successfully tackled by applying ET. We need to encourage the mindset that breathlessness may be evidence of signalling between the periphery and central haemodynamic performance and regular physical activity may ultimately bring about favourable changes in myocardial function, symptoms, functional capacity, and increased hospitalization-free life span and probably survival. In this position paper, we provide practical advice for the application of exercise in heart failure and how to overcome traditional barriers, based on the current scientific and clinical knowledge supporting the beneficial effect of this intervention.

Functional mitral regurgitation at rest determines the acute hemodynamic response to cardiac resynchronization therapy during exercise: an acute exercise echocardiographic study.

BACKGROUND: Cardiac resynchronization therapy (CRT) acutely enhances forward stroke volume (FSV) during exercise by reducing the severity of functional mitral regurgitation (MR) in patients with systolic chronic heart failure. Whether CRT increases FSV in patients without functional MR at rest is unknown. Accordingly, the aim of the study was to compare the effect of CRT on exercise-induced increase in FSV in patients with chronic heart failure with or without functional MR at rest. METHODS AND RESULTS: Forty-one patients with systolic chronic heart failure who had recently undergone CRT performed 2 exercise stress echocardiography tests, the first with CRT On and the second with CRT Off. Twenty-six patients had more than trivial MR (effective regurgitant orifice [ERO] < 10 mm2 in 16 patients, < 20 mm2 in 8 patients, and > or = 20 mm2 in 2 patients), and 15 patients had no MR at rest. Mean exercise-induced change (Delta) in mitral ERO was reduced by CRT (8 +/- 7 mm2 vs 1 +/- 4 mm2, P < .00001). In patients with functional MR at rest, Delta FSV during dynamic exercise was greater with CRT On than CRT Off (4 +/- 8 vs -2 +/- 7 mL, P = .0002), whereas CRT did not significantly affect Delta FSV in patients without MR at rest (9 +/- 9 mL vs 9 +/- 9 mL, P = .93). Similarly, Delta cardiac output was greater with CRT On than CRT Off (1.6 +/- 1.2 L/min vs 1.1 +/- 1.2 L/min, P = .002) in patients with functional MR at rest, whereas Delta cardiac output was similar with CRT On and CRT Off in patients without MR at rest (1.9 +/- 1.4 L/min vs 2.0 +/- 1.2 L/min, P = .59). Severity of functional MR decreased or failed to increase, whereas cardiac output improved during exercise in 9 of 26 patients (34%) with CRT On and in only 2 of 26 patients (8%) with CRT Off (P = .039). CONCLUSION: Functional MR at rest may be an important determinant of the acute hemodynamic response to CRT during exercise.