Hugo Madeira

The EuroHeart Failure survey programme-- a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis.

BACKGROUND The European Society of Cardiology (ESC) has published guidelines for the investigation of patients with suspected heart failure and, if the diagnosis is proven, their subsequent management. Hospitalisation provides a key point of care at which time diagnosis and treatment may be refined to improve outcome for a group of patients with a high morbidity and mortality. However, little international data exists to describe the features and management of such patients. Accordingly, the EuroHeart Failure survey was conducted to ascertain if appropriate tests were being performed with which to confirm or refute a diagnosis of heart failure and how this influenced subsequent management. METHODS The survey screened consecutive deaths and discharges during 2000-2001 predominantly from medical wards over a 6-week period in 115 hospitals from 24 countries belonging to the ESC, to identify patients with known or suspected heart failure. RESULTS A total of 46788 deaths and discharges were screened from which 11327 (24%) patients were enrolled with suspected or confirmed heart failure. Forty-seven percent of those enrolled were women. Fifty-one percent of women and 30% of men were aged >75 years. Eighty-three percent of patients had a diagnosis of heart failure made on or prior to the index admission. Heart failure was the principal reason for admission in 40%. The great majority of patients (>90%) had had an ECG, chest X-ray, haemoglobin and electrolytes measured as recommended in ESC guidelines, but only 66% had ever had an echocardiogram. Left ventricular ejection fraction had been measured in 57% of men and 41% of women, usually by echocardiography (84%) and was <40% in 51% of men but only in 28% of women. Forty-five percent of women and 22% of men were reported to have normal left ventricular systolic function by qualitative echocardiographic assessment. A substantial proportion of patients had alternative explanations for heart failure other than left ventricular systolic or diastolic dysfunction, including valve disease. Within 12 weeks of discharge, 24% of patients had been readmitted. A total of 1408 of 10434 (13.5%) patients died between admission and 12 weeks follow-up. CONCLUSIONS Known or suspected heart failure comprises a large proportion of admissions to medical wards and such patients are at high risk of early readmission and death. Many of the basic investigations recommended by the ESC were usually carried out, although it is not clear whether this was by design or part of a general routine for all patients being admitted regardless of diagnosis. The investigation most specific for patients with suspected heart failure (echocardiography) was performed less frequently, suggesting that the diagnosis of heart failure is still relatively neglected. Most men but a minority of women who underwent investigation of cardiac function had evidence of moderate or severe left ventricular dysfunction, the main target of current advances in the treatment of heart failure. Considerable diagnostic uncertainty remains for many patients with suspected heart failure, even after echocardiography, which must be resolved in order to target existing and new therapies and services effectively.

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.

The Euro Heart Failure Survey of the EUROHEART survey programme. A survey on the quality of care among patients with heart failure in Europe

The EUROHEART programme is a rolling programme of cardiovascular surveys among the member nations of the European Society of Cardiology (ESC). These surveys will provide information on the nature of cardiovascular disease and its management. This manuscript describes a survey into the nature and management of heart failure.

Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.

Predictors of short term mortality in heart failure - insights from the Euro Heart Failure survey.

OBJECTIVE To identify factors associated with short term mortality in hospitalised patients with heart failure. BACKGROUND Hospitalisation is frequent in patients with heart failure and is associated with a high mortality. METHODS The Euro Heart Failure survey collected data from patients with suspected heart failure. We searched this data for predictors of short term mortality. RESULTS Of 10,701 patients, 1404 (13%) died within 12 weeks of admission. On univariate analysis, increasing age, hyponatraemia, renal impairment, hyperkalaemia, anaemia, severe mitral regurgitation, severe LV systolic dysfunction(LVSD), increasing QRS and female sex carried adverse prognosis. ACEI, beta-blockers, nitrates, anti-thrombotic and lipid lowering drugs were associated with a better prognosis. On multivariable analysis the following provided independent prognostic information: increasing age (OR per SD=1.5, 95% CI 1.4-1.6), severe LVSD (1.8, 1.5-2.1), serum creatinine (1.2, 1.2-1.3), sodium (0.9, 0.8-0.9), Hb (0.9, 0.8-0.9) and treatment with ACEI (0.5, 0.5-0.6), beta-blockers (0.7, 0.6-0.8), statins (0.6, 0.5-0.7), calcium channel blockers (0.7, 0.6-0.8), warfarin (0.5, 0.4-0.6), heparin (1.7, 1.4-1.9), anti-platelet drugs (0.6, 0.5-0.6) and need for inotropes (5.5, 4.6-6.6). A simple risk score (range 0-11) identified cohorts with a 12 week mortality ranging from 2% to 44%. CONCLUSIONS Simple and readily available clinical variables and a risk score based on medical history and routine tests that all patients admitted with heart failure have, can identify patients with good, intermediate and high short term mortality.

Relation between severity of left ventricular systolic dysfunction and repolarisation abnormalities on the surface ECG: a report from the Euro heart failure survey

QT prolongation is known to be associated with increased risk of coronary heart disease and cardiovascular death.1,2 A high prevalence of QT prolongation has been reported in heart failure, but whether it is related to the severity of left ventricular systolic dysfunction (LVSD) or poor prognosis remains controversial.3,4 The Euro heart failure survey was conducted to discover whether appropriate tests were being performed according to European Society of Cardiology guidelines in patients hospitalised with or suspected to have heart failure.5 Data from 12 lead ECGs of these patients were used to evaluate whether QT interval is prolonged in LVSD and whether the degree of QT prolongation is related to the severity of LVSD. Data were collected from 11 356 patients with or suspected to have heart failure in 115 hospitals across 24 European countries over six weeks during 2000–2001. For this analysis we considered 5934 patients who had both ECG and an echocardiogram. A single observer, blinded to other data, measured ECG intervals to an accuracy of 0.1 mm (2–4 ms) with digital callipers (ABSolute digimatic, Mitutoyo). QT variables were measured from three non-infarct chest or limb leads and averaged. Co-workers reread and validated 400 ECGs. Bazett’s method of correction for heart rate was used. Local cardiologists reported echocardiograms in the …