Summary
Background
Karolinska Rennes (KaRen) is a prospective observational study to characterize heart failure patients with preserved ejection fraction (HFpEF) and to identify prognostic factors for long-term mortality and morbidity.
Aims
To report characteristics and echocardiography at entry and after 4–8 weeks of follow-up.
Methods
Patients were included following an acute heart failure presentation with B-type natriuretic peptide (BNP) > 100 ng/L or N-terminal pro-BNP (NT-proBNP) > 300 ng/L and left ventricular ejection fraction (LVEF) > 45%.
Results
The mean ± SD age of 539 included patients was 77 ± 9 years and 56% were women. Patient history included hypertension (78%), atrial tachyarrhythmia (44%), prior heart failure (40%) and anemia (37%), but left bundle branch block was rare (3.8%). Median NT-proBNP was 2448 ng/L ( n = 438), and median BNP 429 ng/L ( n = 101). Overall, 101 patients did not return for the follow-up visit, including 13 patients who died (2.4%). Apart from older age (80 ± 9 vs. 76 ± 9 years; P = 0.006), there were no significant differences in baseline characteristics between patients who did and did not return for follow-up. Mean LVEF was lower at entry than follow-up (56% vs. 62%; P < 0.001). At follow-up, mean E/e′ was 12.9 ± 6.1, left atrial volume index 49.4 ± 17.8 mL/m 2 . Mean global left ventricular longitudinal strain was −14.6 ± 3.9%; LV mass index was 126.6 ± 36.2 g/m 2 .
Conclusions
Patients in KaRen were old with slight female dominance and hypertension as the most prevalent etiological factor. LVEF was preserved, but with increased LV mass and depressed LV diastolic and longitudinal systolic functions. Few patients had signs of electrical dyssynchrony (ClinicalTrials.gov.– NCT00774709 ).
Résumé
Contexte
Karolinska Rennes (KaRen) est une étude observationnelle prospective menée afin de caractériser une cohorte de patients insuffisants cardiaques à fraction d’éjection préservée et afin d’identifier des facteurs pronostiques de morbi-mortalité.
Objectif
Nous rapportons ici, les caractéristiques à l’inclusion et à la visite de 4–8 semaines, incluant les données échocardiographiques analysées au centre de relecture.
Méthodes
Les patients sont inclus suite à une hospitalisation urgente pour une insuffisance cardiaque clinique. Les natriurétique peptide de type B (BNP) > 100 ng/L or N-terminal pro-BNP (NT-proBNP) > 300 ng/L et la fraction d’éjection du ventricule gauche > 45 % étaient des pré-requis à l’inclusion dans l’étude.
Résultats
Parmi les 539 patients inclus, l’âge était de 77 ± 9 ans avec 56 % de femmes. Les patients étaient très fréquemment hypertendus (78 %), avec une histoire d’arythmie atriale (44 %), l’insuffisance cardiaque avant (40 %) et l’anémie (37 %), mais la prévalence du bloc de branche gauche était limitée (3,8 %). Le NT-proBNP médian était de 2448 ng/L ( n = 438) et le BNP médian 429 ng/L ( n = 101). Sur l’ensemble, 101 patients ne sont pas revenus à la visite de suivie dont 13 (2,4 %) qui sont décédés. Outre l’âge plus avancé (80 ± 9 vs 76 ± 9 années ; p = 0,006) il n’y a avait aucune différence dans les caractéristiques des patients vus en urgence puis à la visite de 4–8 semaines. La fraction d’éjection du ventricule gauche était plus basse lors de l’admission en urgence qu’à la visite de 4–8 semaines (56 % vs 62 % ; p < 0,001). À 4–8 semaines, le rapport E/e′ était de 12,9 ± 6,1, le volume de l’oreillette gauche de 49,4 ± 17,8 mL/m 2 . Le strain global longitudinal était de −14,6 ± 3,9 % et a masse ventriculaire gauche était de 126,6 ± 36,2 g/m 2 .
Conclusions
Les patients inclus dans KaRen sont surtout des femmes âgées et hypertendues. La fraction d’éjection du ventricule gauche est préservée avec une augmentation de la masse ventriculaire, une altération de la fonction diastolique et de la composante longitudinale de la fonction systolique. L’asynchronisme électrique est peu fréquent (ClinicalTrials.gov.– NCT00774709 ).
Introduction
In recent years, heart failure with preserved ejection fraction (HFpEF) has been increasingly recognized as a pathophysiological entity . The proportion of patients with heart failure with HFpEF is about 50% of the general heart failure population . In epidemiological surveys, the prognosis of HFpEF is nearly as poor as for heart failure with reduced ejection fraction (HFrEF) . Despite extensive efforts to characterize HFpEF and several randomized therapeutic trials, little is known about the clinical course and treatment options for this condition. Guidelines are therefore still restricted to modifying the risk factors predominant in HFpEF, such as to obtain strict control of blood pressure or to treat symptoms of congestion with diuretics .
Current guidelines highlight the importance of additional objective criteria to signs and symptoms and preserved or normal ejection fraction for the diagnosis of HFpEF . These criteria include normal left ventricular volume, increased left atrial volume, left ventricular hypertrophy and/or diastolic dysfunction and natriuretic peptides , whereas diagnostic criteria for dyssynchrony are not included. Little is known about the role of electrical and mechanical dyssynchrony in HFpEF . A typical left bundle branch block (LBBB) was found in 14.4% of patients included in CHARM-Preserved and 8.1% in I-PRESERVE . In ischemic HFpEF, it has been demonstrated that both left ventricular diastolic and atrial mechanical dyssynchrony may impair diastolic function . It has therefore been suggested that dyssynchrony may contribute to the pathophysiology of HFpEF, warranting the need for a prospective study to analyse the importance of these factors .
To further characterize HFpEF patients and to look for new therapeutic options in these patients, we conducted a prospective registry study of HFpEF patients admitted for an acute heart failure exacerbation in Sweden and France – the Karolinska Rennes (KaRen) study . The aim of this report is to describe and compare the clinical and basic echocardiographic characteristics of the study populations at acute presentation and at 4–8-week follow-up.
Methods
The rationale and design of the KaRen study have previously been published . Briefly, KaRen is a prospective, multicentre, international, observational study with the primary objective to determine whether electrical or mechanical dyssynchrony independently affects the prognosis. The present work sought to characterize the HFpEF patients included in KaRen according to their main clinical, electrocardiographic (ECG) and echocardiographic characteristics. Patients were included in KaRen between 1 May 2007 and 1 December 2011 in 10 French and three Swedish university hospitals. Details on inclusion and exclusion criteria have been published . Patients were recruited consecutively as far as was possible. We aimed to identify at least 400 patients seeking medical attention in the emergency department with clinical signs and symptoms of heart failure according to the Framingham criteria . A left ventricular ejection fraction (LVEF) ≥ 45% by echocardiography and natriuretic peptides (B-type natriuretic peptide [BNP] > 100 ng/L or N-terminal pro-BNP [NT-proBNP] > 300 ng/L) were also required. All three inclusion criteria (clinical heart failure, LVEF and peptides) had to be verified within 72 hours of presentation.
Anemia was defined as hemoglobin < 120 g/L in women and < 130 g/L in men, and renal dysfunction as serum creatinine > 120 μmol/L or an estimated glomerular filtration rate (eGFR) < 60 mL/min. Coronary artery disease was defined as a history of acute myocardial infarction, coronary artery bypass or angioplasty or > 50% coronary artery stenosis on a coronary angiogram. Clinical heart failure signs were classified as signs of left heart failure, right heart failure or both .
Patients who presented acutely with heart failure were screened, and patients were included based on inclusion criteria in the acute state including conventional assessment of ejection fraction, but with no detailed analysis of other parameters. Patients returned to a stable state (with or without hospitalization) according to the conventional treatment decided by individual investigators. After 4–8 weeks, included patients returned to the hospital for exhaustive clinical, ECG and biological reassessment and a detailed echocardiographic study. These half-day visits were stringently analysed in dedicated core centres. Follow-up was continued for ≥ 18 months.
In this report, we describe the clinical and basic echocardiographic characteristics of patients in KaRen at baseline and at 4–8-week follow-up. The description is based on cut-off values published in 2007 in a consensus paper about HFpEF and according to the American Society of Echocardiography (ASE)/European Association of Echocardiography (EAE) recommendations for chamber quantification in echocardiography .
Statistical analysis
Continuous variables are presented as means ± standard deviations (SDs) and/or medians (interquartile ranges [IQR]). Categorical variables are presented as counts and percentages.
To compare the means of measurements performed at two time points (baseline and 4–8 weeks), we used Student’s t test to produce a statistic for the null hypothesis that the mean difference equals zero. All P -values are two-sided and statistical significance was set at 0.05. All analyses were performed using SAS ® 9.3 Statistical Procedures (SAS Institute Inc., Cary, NC, USA).
Results
The flow chart of the KaRen study is shown on Fig. 1 . Patients ( n = 584) were considered for inclusion in KaRen between 1 May 2007 and 1 December 2011. Of these, 29 did not meet inclusion criteria and 16 withdrew consent. Thus, 539 patients were enrolled in the study and assessed at baseline. Of these, 470 patients were admitted to hospital for heart failure treatment and 69 were sent home after treatment revision. Thirteen patients (2.4%) died and 21 (3.9%) were re-hospitalised for heart failure between enrolment and the 4–8-week visit. A total of 101 patients did not return for the 4–8-week follow-up visit, leaving 438 who were re-assessed at the 4–8-week visit. Apart from older mean age (80 ± 9 vs. 76 ± 9 years; P = 0.006), there were no statistically significant differences in baseline characteristics between patients who returned for the follow-up visit and those who did not.
Characteristics at acute admission and 4–8 weeks
The mean age of the 539 patients was 77 ± 9 years, and 56% were women ( Table 1 ). A history of heart failure was found in 40%. The history of heart failure symptoms revealed that 80% of patients had been New York Heart Association (NYHA) class I/II before the exacerbation of acute heart failure, but at admission, most patients (90%) were NYHA III/IV. Mean LVEF at admission was 56 ± 7%, and 303 (56%) had LVEF > 55%. At admission, 456 patients (85%) had ≥ two major and 83 (15%) had one major and ≥ two minor Framingham criteria for heart failure. Median NT-proBNP was 2448 ng/L and median BNP 439 was 429 ng/L ( Table 1 ). Mean systolic blood pressure was 150 ± 31 mmHg and median [IQR] heart rate was 80 [68–100] bpm. The median [IQR] eGFR was 61 [43–76] mL/min. Among the 470 hospitalized patients, the mean length of hospital stay at the acute heart failure admission was 5 days (range 0–58 days). The distributions of Framingham criteria of heart failure at index hospitalization and at 4–8-week follow-up are shown on Fig. 2 . Many patients still had clinical symptoms or signs of heart failure at the 4–8-week visit, e.g. 30% of the population still had peripheral oedema despite 4–8 weeks of dedicated treatments.
| At admission ( n = 539) | At 4–8-week visit ( n = 438) | |
|---|---|---|
| Age (years) | 77 ± 9 | – |
| Women | 303 (56) | – |
| Hypertension | 419 (78) | – |
| Prior heart failure | 216 (40) | – |
| Prior stroke | 56 (10) | – |
| Coronary artery disease | 158 (29) | – |
| Prior myocardial infarction | 77 (15) | – |
| Valvular heart disease | 74 (14) | – |
| Diabetes | 161 (30) | – |
| Renal dysfunction | 146 (27) | – |
| Anemia | 202 (37) | – |
| COPD | 73 (14) | – |
| NYHA class | n = 527 | |
| I | 4 (0.5) | 49 (12) |
| II | 49 (9.5) | 243 (62) |
| III | 211 (40) | 90 (23) |
| IV | 263 (50) | 10 (3.0) |
| Heart failure clinical presentation | ||
| Biventricular | 364 (69) | 63 (35) |
| Isolated LV | 129 (24) | 44 (25) |
| Isolated RV | 36 (7.0) | 71 (40) |
| 3rd heart sound | 31 (6.0) | 11 (3.0) |
| SBP (mmHg) | 150 ± 31 | 138 ± 24 |
| DBP (mmHg) | 77 ± 19 | 73 ± 12 |
| Pulse pressure (mm Hg), median [IQR] | 70 [55–90] | 65 [50–78] |
| Heart rate (bpm), median [IQR] | 80 [68–100] | 68 [60–76] |
| Weight (kg) | 79 ± 20 | 78 ± 19 |
| BMI (kg/m 2 ) | 29 ± 6 | 29 ± 6 |
| NT-proBNP (ng/L) a , median [IQR] | 2448 [1290–4790] | 1409 [517–2635] |
| BNP (ng/L) b , median [IQR] | 429 [229–805] | 277 [136–570] |
| Hemoglobin (g/L) | 123 ± 19 | 125 ± 17 |
| eGFR (mL/min), median [IQR] | 61 [43–76] | 60 [42–77] |
| Atrial arrhythmia | 218 (44) | 171 (39) |
| PR interval > 200 ms | 26 (11) | 25 (14) |
| QRS duration > 120 ms | 69 (15) | 57 (16) |
| LBBB | 16 (3.5) | 14 (3.8) |
| RBBB | 35 (7.6) | 24 (6.6) |
| Paced V rhythm | 35 (7.1) | 29 (7.3) |
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