Old and newer biomarkers in heart failure: from pathophysiology to clinical significance.

Heart failure is a complex disease in which a careful clinical examination and the measurement of cardiac function may not always be sufficient for making a correct diagnosis. Measuring plasma levels of natriuretic peptides may assist in this process, also offering a good tool for accurate risk stratification. Other alternative biomarkers may give insight into the different pathways of heart failure genesis and pathophysiology, and may help to identify those patients with overt heart failure and a more adverse outcome, or distinguish between those at risk of developing heart failure. Despite a high number of potentially useful biomarkers, only a few will likely be introduced routinely into clinical practice. However, a multi-marker approach might increase the diagnostic accuracy and it might identify different phenotypes of heart failure patients who might benefit from individualized therapy in the future.

How to improve outcomes: should we put more emphasis on programming and medical care and less on patient selection?

Many factors contribute to the pathophysiology and progression of heart failure (HF), offering the potential for many synergistic therapeutic approaches to its management. For patients, who have systolic HF, prolonged QRS and receiving guideline-indicated pharmacological therapy, cardiac resynchronization therapy (CRT) may provide additional benefits in terms of symptom improvement and mortality reduction. Nevertheless, in many patients, moderate or severe symptoms may persist or recur after CRT implantation due to either the severity or progression of the underlying disease, the presence of important co-morbidities or suboptimal device programming. Identifying and, where possible, treating the reasons for persistent or recurrent symptoms in patients who have received CRT is an important aspect of patient care. The present review summarizes the available evidence on this topic.

The European CRT Survey: 1 year (9-15 months) follow-up results.

AIMS: The European CRT Survey is a joint initiative of the Heart Failure Association (HFA) and the European Heart Rhythm Association (EHRA) of the European Society of Cardiology evaluating the contemporary implantation practice of cardiac resynchronization therapy (CRT) in Europe. METHODS AND RESULTS: Patients who had a successful CRT implantation were enrolled from 141 centres in 13 countries between November 2008 and June 2009. Baseline demographics, clinical and implantation data were collected, with a follow-up of ∼1 year (9-15 months). The current report describes clinical outcomes including symptom severity, cardiovascular (CV) hospitalization, and survival. A total of 2438 patients were enrolled, and follow-up data were acquired from 2111 patients (87%). The population included important groups of patients poorly represented in randomized controlled trials, including very elderly patients and those with prior device implantation, atrial fibrillation, and/or QRS duration <120 ms. Investigators reported substantial improvement in New York Heart Association (NYHA) functional class at follow-up. Patient self-assessment indicated that 81% of the patients felt improved, 16% reported no change, and 4% reported deterioration. During follow-up, 207 (10%) patients died, 346 (16%) had a CV hospitalization, and 501 (24%) died or had CV hospitalization. Worse NYHA functional class, atrial fibrillation, ischaemic aetiology, and device type (CRT-P, i.e. CRT alone) were associated with poorer survival. Women had a better outcome, as did patients who had a CRT-D (with an implantable cardioverter defibrillator function) device. CONCLUSIONS: Outcomes including death and hospitalization in this European CRT survey were consistent with results from clinical trials of CRT. At 1 year follow-up, most patients who received a CRT device considered their symptoms improved compared with their pre-implant assessment. Although prospective, this is an observational study of successful CRT implantations, and outcomes in subgroup analyses must be interpreted with appropriate conservatism.

Does the physical examination still have a role in patients with suspected heart failure?

AIMS: The prognostic value of signs of congestion in patients suspected of having chronic heart failure (CHF) is unknown. Our objectives were to define their prevalence and specificity in diagnosing CHF and to determine their prognostic value in patients in a community heart failure clinic. METHODS AND RESULTS: Analysis of referrals to a community clinic for patients with CHF symptoms. Systolic CHF (S-HF) was defined as left ventricular ejection fraction (LVEF) ≤45%, heart failure with normal ejection fraction (HeFNEF) as LVEF > 45%, and amino-terminal pro-brain natriuretic peptide >50 pmol L(-1); other subjects were defined as not having CHF. Signs of congestion were as follows: no signs; right heart congestion (RHC: oedema, jugular venous distension); left heart congestion (LHC: lung crackles); or both (R + LHC). Of 1881 patients referred, 707 did not have CHF, 853 had S-HF, and 321 had HeFNEF. The median inter-quartile range (IQR) age was 72 years (64-78), 40% were women, and LVEF was 47% (35-59). Overall, 417 patients had RHC of whom 49% had S-HF and 21% HeFNEF. Eighty-five patients had LHC of whom 43% had S-HF and 20% had HeFNEF. One hundred and seventy-two patients had R + LHC of whom 71% had S-HF and 16% had HeFNEF. During a median (IQR) follow-up of 64(44-76) months, 40% of the entire patient cohort died. The combination of R + LHC signs was an independent marker of an adverse prognosis (χ(2)-log-rank test = 186.1, P< 0.0001). CONCLUSION: Clinical signs of congestion are independent predictors of prognosis in ambulatory patients with suspected CHF.

Clinical trials update from the American Heart Association meeting 2010: EMPHASIS-HF, RAFT, TIM-HF, Tele-HF, ASCEND-HF, ROCKET-AF, and PROTECT.

This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the American Heart Association held in Chicago in 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. In patients with mild heart failure (HF), EMPHASIS-HF showed that the addition of eplerenone to standard therapy was well tolerated and reduced both the risk of death and hospitalization. The addition of cardiac resynchronization therapy to implantable cardioverter defibrillator (ICD) therapy reduced the incidence of all-cause mortality and HF hospitalizations in patients with NYHA class II-III HF compared with ICD alone in RAFT. Telemonitoring failed to improve outcome compared with a high standard of conventional care in patients with chronic HF (TIM-HF study) and a telephone-based interactive voice response system failed to improve outcome in patients recently hospitalized for HF (Tele-HF study). ASCEND-HF suggested that nesiritide was ineffective but safe in patients with acute decompensated HF. ROCKET-AF suggests that the factor-Xa inhibitor rivaroxaban may be as effective as warfarin in patients with atrial fibrillation. The PROTECT study provided more data to suggest that amino-terminal B-type natriuretic peptide guided therapy may be beneficial in patients with left ventricular systolic dysfunction.

Clinical trials update from the American College of Cardiology meeting 2010: DOSE, ASPIRE, CONNECT, STICH, STOP-AF, CABANA, RACE II, EVEREST II, ACCORD, and NAVIGATOR.

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure presented at the annual meeting of the American College of Cardiology held in March 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. Results from DOSE suggest that giving diuretics using a high-dose, bolus strategy may be better than using lower doses or a continuous infusion for patients with acute decompensated heart failure. In the ASPIRE study, addition of aliskiren to standard therapy failed to attenuate left ventricular remodelling in post-MI patients and was associated with more adverse events. In CONNECT, remote monitoring reduced the time from CRT-D- or ICD-detected events to clinical decision and this was associated with fewer clinic visits and shorter hospitalizations. An analysis from STICH testing the effects of surgical ventricular reconstruction showed no benefit in the sub-group of patients who achieved a greater reduction in LV volume. STOP-AF and CABANA did not provide convincing evidence of the effectiveness or safety of catheter ablation for the treatment of AF. RACE II suggests that lenient heart rate control might be as effective as strict rate control in patients with permanent atrial fibrillation. In EVEREST II, a catheter-based mitral valve repair procedure using the MitraClip system had similar efficacy to traditional surgery but with fewer short-term adverse effects. Valsartan reduced progression to diabetes in patients with impaired glucose tolerance but had no effect on cardiovascular events in NAVIGATOR. In ACCORD, strict blood pressure control failed to reduce the risk of overall cardiovascular events in high-risk diabetic patients.

Clinical trials update from the European Society of Cardiology Meeting 2009: AAA, RELY, PROTECT, ACTIVE-I, European CRT survey, German pre-SCD II registry, and MADIT-CRT.

This article provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the European Society of Cardiology held in Barcelona in 2009. The AAA study does not support the routine use of aspirin for the prevention of vascular events in patients with asymptomatic atherosclerosis. RELY suggests that dabigatran may be more effective than warfarin for the prevention of stroke in patients with atrial fibrillation. Rolofylline was not superior to placebo in improving outcomes in patients with acute heart failure enrolled in the PROTECT study, but dyspnoea was improved. Data from ACTIVE-I suggest that irbesartan does not provide additional therapeutic benefit in patients with atrial fibrillation who are well controlled on current therapy. The European cardiac resynchronization therapy (CRT) survey provides interesting epidemiological data on current CRT device usage. The German pre-SCD II registry identified a low prevalence of patients with a reduced ejection fraction following myocardial infarction. Implantation of CRT-D rather than an implantable cardioverter defibrillator in patients with mild heart failure and QRS >/=130 ms reduced the risk of hospitalization for heart failure in MADIT-CRT; mortality was similarly low with each device.