First symptoms and health care pathways in hospitalized patients with acute heart failure: ICPS2 survey. A report from the Heart Failure Working Group (GICC) of the French Society of Cardiology.

BACKGROUND: Acute heart failure (AHF) is a common serious condition that contributes to about 5% of all emergency hospital admissions in Europe. HYPOTHESIS: To assess the type and chronology of the first AHF symptoms before hospitalization and to examine the French healthcare system pathways before, during and after hospitalization. MATERIAL AND METHODS: A retrospective observational study including patients hospitalized for AHF RESULTS: 793 patients were included, 59.0% were men, 45.6% identified heart failure (HF) as the main cause of hospitalization; 36.0% were unaware of their HF. Mean age was 72.9 ± 14.5 years. The symptoms occurring the most before hospitalization were dyspnea (64.7%) and lower limb edema (27.7%). Prior to hospitalization, 47% had already experienced symptoms for 15 days; 32% of them for 2 months. Referral to hospital was made by the emergency medical assistance service (SAMU, 41.6%), a general practitioner (GP, 22.3%), a cardiologist (19.5%), or the patient (16.6%). The modality of referral depended more on symptom acuteness than on type of symptoms. A sudden onset of AHF symptoms led to making an emergency call or to spontaneously attending an emergency room (ER), whereas cardiologists were consulted when symptoms had already been present for over 15 days. Cardiologists referred more patients to cardiology departments and fewer patients to the ER than general practitioners or the SAMU. CONCLUSION: This study described the French healthcare system pathways before, during and after hospitalization AHF. AHF clinic network should be developed to provide adequate care for all HF patients and create awareness regarding AHF symptoms.

Left ventricular performance is closely related to the physical properties of the arterial system: Landmark clinical investigations in the 1970s and 1980s.

Left ejection fraction (LVEF)--resulting from the difference between end-diastolic volume (EDV) and end-systolic volume (ESV), divided by EDV--is a poor index of left ventricular (LV) systolic performance due to its dependency on load conditions, inotropic state and LV remodelling. The characteristic impedance of the ascending aorta (Zc) integrates factors opposing LV ejection during the early ejection period when arterial wave reflection can be neglected. Zc is related to the pressure wave velocity (C) and the cross-sectional area of the aorta. The aim is to demonstrate that LV performance and geometry are closely related to the physical properties of the arterial system. LV pressure-volume loops were obtained from simultaneous measurements of LV (or aortic) pressure and LV volume. The slope Ees (also called LV end-systolic elastance) of the ESP-ESV relationship was assessed. Aortic diameters, pressure and flow measurements were synchronized to evaluate C, aortic forward and backward pressure waves, the elasticity of the aorta (Ep) and thereby Zc. In contrast to LVEF, LV end-systolic elastance (Ees), which reflects the stiffness of the chamber at maximal myofilament activation, is relatively insensitive to load conditions and may be considered as an index of ventricular chamber contractility. For a given Ees value, the end-systolic pressure (ESP) determines the LV end-systolic volume. Ees is determined by cardiac myocytes contractility and density, and thereby concentric remodelling. A tight correlation between Zc and the degree of LV concentric remodelling was found in hypertensive and in normal subjects. Zc was found to increase throughout the full lifespan and also with hypertension. Both Zc and wave reflections determine aortic input impedance estimated from the aortic pressure-flow relationship. Increased arterial stiffness resulted in increasing C and overlap of forward and backward waves and thereby in greater pulse pressure and ESP and a greater difference between ESP and diastolic pressure. Ees is an accurate index of LV systolic performance. Besides the inotropic state of myofibers, Ees depends on the concentric remodelling and thereby on the characteristic impedance of the aorta.

A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. METHODS AND RESULTS: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. CONCLUSION: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.

Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06 × 10⁻6, OR  = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21 × 10⁻5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⁻³, OR = 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⁻³, OR  = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10⁻4, OR  = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⁻¹³, OR= 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.

Acute heart failure: How to evaluate left ventricular filling pressure in practice?

Heart failure is one of the most frequent reasons for hospitalization due to a cardiac event. In most instances, the main difficulty is how to accurately evaluate left ventricular filling pressure. It can be evaluated clinically, biologically and invasively. Although historically, invasive management has been the reference, it is being used less and less frequently and expertise in the technique is being lost. This paper discusses the strength and weaknesses of the different techniques for evaluating filling pressure in these patients, and the importance of this parameter for their optimal treatment.

Valve repair for mitral insufficiency secondary to idiopathic juvenile polyarthritis.

A female patient in whom idiopathic rheumatoid polyarthritis was diagnosed at the age of 8 years required surgery for severe mitral valve insufficiency 16 years later. Intraoperative analysis revealed a fibrotic endocarditis involving mainly the posterior leaflet. Granulomatous vegetations as well as a large thrombus which filled the left ventricular apex and simulated endomyocardial fibrosis were noted. Valve repair was achieved using an anterior leaflet augmentation with a patch of mitral homograft associated with a prosthetic ring annuloplasty. Postoperatively, a severe pericardial effusion required surgical drainage. Eight years later, the patient had no cardiac symptoms and echocardiography confirmed a normally functioning mitral valve.

Impact of the history of congestive heart failure on the utility of B-type natriuretic peptide in the emergency diagnosis of heart failure: results from the Breathing Not Properly Multinational Study.

PURPOSE: B-type natriuretic peptide is known to correlate with hemodynamic state, presence and severity of congestive heart failure, and prognosis. Although low-range B-type natriuretic peptide less than 100 pg/mL has a high negative predictive value (90%), and high-range B-type natriuretic peptide greater than 500 pg/mL has a high positive predictive value (87%), there remains some ambiguity in the interpretation of results in the medium range (100-500 pg/mL). We hypothesized that taking into account the history of congestive heart failure along with other clinical variables would be helpful in this range of B-type natriuretic peptide levels. METHOD: The Breathing Not Properly Multicenter Study was an international, 7-center, prospective study including 1475 patients with a mean age of 63 years (57% were male, and 54% were female); 35% of patients with a history of congestive heart failure were enrolled, and a final diagnosis of congestive heart failure was made in 46%. The index criteria was defined as positive if any 2 index findings (ie, history of coronary artery disease, lower extremity edema, pulmonary edema, cephalization of the pulmonary arteries, and cardiomegaly) were present. RESULTS: The interval likelihood ratios (LR) for low, medium, and high B-type natriuretic peptide ranges are 0.13, 1.85, and 8.1, respectively. For medium B-type natriuretic peptide levels a positive history of congestive heart failure makes the diagnosis of congestive heart failure more probable with a cumulative LR of 4.3. Also in this range a positive index criterion was strongly indicative of congestive heart failure even in the absence of a history of congestive heart failure (LR 3.3). Where there are both a positive history of congestive heart failure and a positive index criteria for the medium B-type natriuretic peptide group, the cumulative LR (10.2) is similar to that of a high B-type natriuretic peptide level (8.1). CONCLUSION: Even in the medium range (100-500 pg/mL), when using the history of congestive heart failure and index criteria, B-type natriuretic peptide can be a powerful diagnostic tool in the hands of clinicians in the emergency department.

Impact of age, race, and sex on the ability of B-type natriuretic peptide to aid in the emergency diagnosis of heart failure: results from the Breathing Not Properly (BNP) multinational study.

BACKGROUND: B-type natriuretic peptide (BNP) is secreted from the cardiac ventricles in response to increased wall tension. METHODS: The Breathing Not Properly Multinational Study was a 7-center, prospective study of 1586 patients who presented to the Emergency Department with acute dyspnea and had BNP measured with a point-of-care assay upon arrival. The gold standard for congestive heart failure (CHF) was adjudicated by two independent cardiologists, blinded to BNP results, who reviewed all clinical data and standardized scores. The current study explores the effect of these variables on BNP decision statistics as well as the impact that changing cutoffs might have on the cost-effectiveness of diagnostic decisions that use BNP information. RESULTS: Significant differences in CHF rates were found on the basis of age (P <.001) and racial group (P =.020) but not sex (P =.424). BNP levels increased with increasing age (P <.001). To evaluate potential differences in the diagnostic utility of BNP levels as a function of demographic variables, separate receiver operating characteristic curves were performed. BNP was a stronger predictor in younger subjects than in older subjects and slightly weaker for female patients than for male patients (area under the curve = 0.918 and 0.870, respectively). An even smaller difference was noted between the white and black racial groups (area under the curve = 0.888 and 0.903, respectively). The differences in specificity as a function of age are larger than other differences in specificity or sensitivity. When logistic regression was used in a multivariate approach to combine the demographic variables with BNP information in the prediction of CHF, only BNP contributed significantly to the prediction of acute CHF. When the model was expanded to include terms for the interaction of each of the demographic variables with log(10) BNP, a significant interaction was found for sex. Since the relative consequences of false-positives and false-negatives are unlikely to be equivalent, the BNP cut-points that would be selected based on the current data as a function of relative costs are presented. Sharply rising consequences are seen for BNP cut-points >100 pg/mL. CONCLUSIONS: If one assumes that failing to treat cases of CHF is worse than treating negative cases, then relatively low BNP cut-points (eg, not >100 pg/mL) should be used in patients presenting to the Emergency Department with a chief complaint of dyspnea, regardless of age, sex, or ethnicity.

Diagnostic value of B-Type natriuretic peptide and chest radiographic findings in patients with acute dyspnea.

PURPOSE: To compare chest radiographic findings and circulating B-type natriuretic peptide (BNP) levels as an adjunct to clinical findings in the diagnosis of heart failure in patients presenting with acute dyspnea. METHODS: The diagnostic performance of radiographic evidence of cardiomegaly/redistribution and BNP levels > or =100 pg/mL as indicators of heart failure were assessed in 880 patients presenting with acute dyspnea to the emergency departments of five U.S. and two European teaching hospitals. BNP levels were determined by a rapid, point-of-care device. Two blinded cardiologists reviewed all clinical data and categorized patients as to whether they had acute heart failure (n = 447) or not (n = 433). RESULTS: Three-factor analyses showed that BNP levels > or =100 pg/mL contributed significantly to the prediction of heart failure over each of the radiographic indicators. In a multivariate logistic regression analysis, both BNP levels > or =100 pg/mL (odds ratio [OR] = 12.3; 95% confidence interval [CI]: 7.4 to 20.4) and radiographic findings of cardiomegaly (OR = 2.3; 95% CI: 1.4 to 3.7), cephalization (OR = 6.4; 95% CI: 3.3 to 12.5), and interstitial edema (OR = 7.0; 95% CI: 2.9 to 17.0) added significant, predictive information above historical and clinical predictors of heart failure. CONCLUSION: In patients presenting to the emergency department with acute dyspnea, BNP levels and chest radiographs provide complementary diagnostic information that may be useful in the early evaluation of heart failure.

Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE).

BACKGROUND: Few data are available on the impact of heart failure (HF) across all types of acute coronary syndromes (ACS). METHODS AND RESULTS: The Global Registry of Acute Coronary Events (GRACE) is a prospective study of patients hospitalized with ACS. Data from 16 166 patients were analyzed: 13 707 patients without prior HF or cardiogenic shock at presentation were identified. Of these, 1778 (13%) had an admission diagnosis of HF (Killip class II or III). HF on admission was associated with a marked increase in mortality rates during hospitalization (12.0% versus 2.9% [with versus without HF], P<0.0001) and at 6 months after discharge (8.5% versus 2.8%, P<0.0001). Of note, HF increased mortality rates in patients with unstable angina (defined as ACS with normal biochemical markers of necrosis; mortality rates: 6.7% with versus 1.6% without HF at admission, P<0.0001). By logistic regression analysis, admission HF was an independent predictor of hospital death (odds ratio, 2.2; P<0.0001). Admission HF was associated with longer hospital stay and higher readmission rates. Patients with HF had lower rates of catheterization and percutaneous cardiac intervention, and fewer received beta-blockers and statins. Hospital development of HF (versus HF on presentation) was associated with an even higher in-hospital mortality rate (17.8% versus 12.0%, P<0.0001). In patients with HF, in-hospital revascularization was associated with lower 6-month death rates (14.0% versus 23.7%, P<0.0001; adjusted hazard ratio, 0.5; 95% CI, 0.37 to 0.68, P<0.0001). CONCLUSIONS: In this observational registry, heart failure was associated with reduced hospital and 6-month survival across all ACS subsets, including patients with normal markers of necrosis. More aggressive treatment of these patients may be warranted to improve prognosis.

Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events.

OBJECTIVE: Atherosclerosis is a chronic inflammatory disease of the blood vessels. Toll-like receptor 4 (TLR4) is a transmembrane receptor that is involved in mediating inflammatory responses to bacterial endotoxin and other ligands. The aim of this study was to search for an association between a common functional polymorphism of TLR4--Asp299Gly--and acute coronary syndrome. METHODS AND RESULTS: We conducted a case-control study of 183 patients with acute coronary syndromes and 216 controls. We screened the TLR4 gene for the Asp299Gly polymorphism using a 5' fluorogenic assay. The 299Gly allele was associated with a decreased risk of acute coronary events independently of standard coronary risk factors. The adjusted odds ratio associated with this allele was 0.41 (95% CI, 0.18 to 0.95; P=0.037). In controls, TLR4 heterozygosity was also associated with a significant decrease in plasma fibrinogen and soluble vascular cellular adhesion molecule-1 levels (P<0.01). CONCLUSIONS: These results, which must be confirmed by a prospective longitudinal study, provide evidence of an association between the Asp299Gly polymorphism of the human TLR4 receptor and acute coronary syndromes. They confirm the previously reported involvement of TLR4 in carotid and femoral artery atherosclerosis.

Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study.

OBJECTIVES: This study examines B-type natriuretic peptide (BNP) levels in patients with systolic versus non-systolic dysfunction presenting with shortness of breath. BACKGROUND: Preserved systolic function is increasingly common in patients presenting with symptoms of congestive heart failure (CHF) but is still difficult to diagnose. METHODS: The Breathing Not Properly Multinational Study was a seven-center, prospective study of 1,586 patients who presented with acute dyspnea and had BNP measured upon arrival. A subset of 452 patients with a final adjudicated diagnosis of CHF who underwent echocardiography within 30 days of their visit to the emergency department (ED) were evaluated. An ejection fraction of greater than 45% was defined as non-systolic CHF. RESULTS: Of the 452 patients with a final diagnosis of CHF, 165 (36.5%) had preserved left ventricular function on echocardiography, whereas 287 (63.5%) had systolic dysfunction. Patients with non-systolic heart failure (NS-CHF) had significantly lower BNP levels than those with systolic heart failure (S-CHF) (413 pg/ml vs. 821 pg/ml, p < 0.001). As the severity of heart failure worsened by New York Heart Association class, the percentage of S-CHF increased, whereas the percentage of NS-CHF decreased. When patients with NS-CHF were compared with patients without CHF (n = 770), a BNP value of 100 pg/ml had a sensitivity of 86%, a negative predictive value of 96%, and an accuracy of 75% for detecting abnormal diastolic dysfunction. Using Logistic regression to differentiate S-CHF from NS-CHF, BNP entered first as the strongest predictor followed by oxygen saturation, history of myocardial infarction, and heart rate. CONCLUSIONS: We conclude that NS-CHF is common in the setting of the ED and that differentiating NS-CHF from S-CHF is difficult in this setting using traditional parameters. Whereas BNP add modest discriminatory value in differentiating NS-CHF from S-CHF, its major role is still the separation of patients with CHF from those without CHF.