Neurohormonal activation in acute heart failure: results from VERITAS.

OBJECTIVES: Recent heart failure studies have suggested that inflammatory and immune system activation are associated with increased levels of cytokines, chemokines and inflammatory proteins during acutely decompensated heart failure. The objectives of this substudy were to evaluate the role of neurohormonal and inflammatory activation in the pathogenesis and outcome of acute heart failure (AHF) and the correlation between biomarker levels and clinical outcomes. METHODS: Serum levels of B-type natriuretic peptide-32 (BNP-32), endothelin-1 (ET-1), norepinephrine, troponins I and T, C-reactive protein (CRP), von Willebrand factor, plasminogen activator inhibitor-1, interleukin-6 (IL-6) and tissue plasminogen activator (TPA) were measured at baseline, 24 and 48 h and 7 and 30 days in 112 patients with AHF recruited to the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study neurohormonal substudy. RESULTS: On univariable analysis, CRP, BNP and ET-1 were predictive of worsening heart failure by day 30; when considered together, only CRP and BNP were significantly associated with this outcome. On adjustment for age, baseline blood pressure, serum sodium and serum creatinine, only age and BNP remained significant. CRP, IL-6 and TPA levels were significantly correlated with 180-day mortality on univariable analysis. CONCLUSION: Circulating markers of inflammation may be useful in gauging prognosis in patients with AHF.

Patterns of leukocyte counts on admissions for acute heart failure--presentation and outcome--results from a community based registry.

OBJECTIVE: To determine the correlation between differential white blood cell (WBC) count and characteristics and outcome of acute heart failure (AHF) syndromes. BACKGROUND: Previous studies suggested that different white blood cell count patterns are related to outcome in patients with heart failure (HF) and other cardiovascular disorders. METHODS: Data from all qualifying AHF admissions to a city hospital (n=340) was prospectively collected. Patients were followed from admission up to 6 months post-discharge. The relationship between patients' demographics, clinical and laboratory characteristics and outcome were assessed in relation to WBC count and lymphocyte to WBC ratio (LWR). RESULTS: WBC count >10,100×10 (9)/L (upper tertile) on admission was associated with higher admission blood pressure, lower oxygen saturation, higher heart rate and increased troponin, with no impact on either short-term worsening HF or long-term adverse outcome. Lower LWR was associated with higher BUN and troponin and lower hemoglobin, but not with a distinct clinical presentation. The lower LWR tertile (≤13%) was associated with a 60% increase in worsening HF risk and a substantially higher 1 month (15% versus 2%) and 6 months mortality (23% vs. 3%) for lowest versus highest quartile (p<0.0001). CONCLUSIONS: While increased WBC count is associated with a more "vascular presentation" and certain severity markers, it is not related to worse patient outcome. Low LWR (≤13%) is predictive of worse outcome and higher mortality. It is also associated with certain laboratory abnormalities, but not related to a specific clinical profile.

Low lymphocyte ratio as a novel prognostic factor in acute heart failure: results from the Pre-RELAX-AHF study.

BACKGROUND: Previous studies have suggested that a lower lymphocyte ratio (Ly%) in the white blood cell (WBC) differential count is related to worse outcomes in patients with acute heart failure (AHF) and other cardiovascular disorders. METHODS: In the Pre-RELAX-AHF study, 234 patients with AHF, systolic blood pressure >125 mm Hg and brain natriuretic peptide ≥350 pg/ml or equivalent were randomized to 1 of 4 intravenous doses of relaxin or placebo and followed up for 6 months following randomization. Complete blood count and differential were performed by a central laboratory at baseline and then daily to day 5 and on day 14. RESULTS: The WBC count by itself was not associated with measures of disease severity or outcome, and patients with Ly% <13% had similar baseline characteristics to patients with Ly% >13%, except for a higher baseline WBC count, elevated baseline glucose, older age and higher rates of peripheral vascular disease. However, patients with Ly% <13% had less improvement of dyspnea, greater worsening of heart failure, longer length of initial hospital stay and fewer days alive and out of hospital. Statistical significance was reached for all-cause death by days 60 and 180 (hazard ratio = 1.11 per percent decrease, 95% confidence interval 1.03-1.19; p = 0.0048). CONCLUSIONS: Despite no association with any baseline characteristic known to strongly predict outcome in AHF, low Ly% is associated with less symptom relief and worse in-hospital and postdischarge clinical outcomes.

Acute heart failure clinical drug development: from planning to proof of activity to phase III.

Over the last decades, attempts to develop new therapies for acute heart failure (AHF) have largely failed. Limitations in understanding the pathophysiology of AHF, its natural history, the effects of current therapies, the properties of new agents, and, importantly, study designs and execution have contributed to these disappointing results. We propose a novel approach for the development of new agents for AHF. Initial stages of development (proof of activity and phase IIa studies) should provide a granular understanding of the mechanism of the actions and pharmacodynamic properties of the new intervention, first in animal models of HF and then in small tightly designed human studies. This will facilitate the identification of patients who are more likely to show a favorable response. In phase II studies (proof of concept), the assessment of efficacy and final dose selection should not be based on surrogate endpoints but rather on clinically meaningful endpoints such as the relief of AHF symptoms, i.e. breathlessness, as well as consistent trends in the relief of other symptoms and clinical signs of recurrence (worsening HF either in hospital or after discharge) and short-term mortality. Lastly, other safety parameters, i.e. effects such as renal and myocardial damage, should be assessed. In some instances, the decision to move to phase III may be based on clear consistent trends rather than on 1 statistically significant endpoint. In studies that confirm clinical utility (phase III), efficacy will be judged relative to the magnitude of the benefit, i.e. improvements in symptoms (breathlessness), the prevention of symptom recurrence, and short-term mortality, balanced by the consideration of safety signals including an estimation of absolute mortality.

Early worsening heart failure in patients admitted for acute heart failure: time course, hemodynamic predictors, and outcome.

BACKGROUND: The most common outcome currently assessed in acute heart failure trials (AHF) is dyspnea improvement. Worsening hear failure (WHF) is a new outcome measure that incorporates failure to improve or recurrent symptoms of AHF requiring rescue intravenous therapy, mechanical circulatory or ventilatory support, or readmission because of AHF, occurring within 30 days of AHF admission. METHODS AND RESULTS: Retrospective data analysis of 120 patients with AHF requiring hemodynamic monitoring who enrolled in the placebo arm of 2 prospective randomized studies. The incidence of WHF was 42% at 30 days from enrollment. Most WHF events occurred in-hospital during the first 7 days after admission (early WHF). Thirty-day readmission from AHF was an infrequent event in the present cohort (5.0%). The strongest hemodynamic predictors of WHF were cardiac power at baseline and its change during the initial 6 hours of monitoring. Other hemodynamic parameters associated with WHF events were blood pressure and its increase, cardiac output, and pulmonary wedge pressure change during the initial 6 hours of monitoring. WHF was found to be a strong predictor of 6-month mortality. CONCLUSIONS: WHF is a common morbid event clustered mostly during the first week of AHF admission and is associated with higher 6-month mortality. The hemodynamic measurements associated with WHF are similar to those predicting adverse outcome in AHF and cardiogenic shock (low cardiac power, higher pulmonary capillary wedge pressure, and vascular resistance), emphasizing the notion that early WHF should become an important AHF-specific outcome measure.

Early worsening heart failure in patients admitted with acute heart failure--a new outcome measure associated with long-term prognosis?

A major limitation in acute heart failure (AHF) research has been the lack of an outcome measure paralleling re-infarction in acute coronary syndromes. The aim of the present study was to assess the time course, prognostic factors and outcome of early worsening heart failure (WHF) in patients admitted for AHF to a community hospital. All AHF admissions between December 2003 and March 2004 in a regional medical center were recorded. Patients were followed through admission and for 6 months after discharge. Early WHF was defined as WHF occurring during the initial 7 days from admission. Study endpoints were cardiovascular mortality and WHF (defined as worsening or persistent signs or symptoms of AHF requiring rescue therapy or hospital readmission). Early WHF rate was 29% and was associated with markers of AHF severity on presentation (higher troponin I, lower oxygen saturation, need for mechanical ventilation, intravascular diuretics and inotropes). Early WHF was a powerful predictor of death during 6 months of follow up, with an age-adjusted hazard ratio of 3.3 (95% confidence interval 1.7-6.3). Early WHF is a common adverse event in patients admitted with AHF, and is associated with AHF severity and excessive 6-month mortality. WHF should be considered as a clinically important endpoint in AHF studies.

Rapid clinical assessment of patients with acute heart failure: first blood pressure and oxygen saturation--is that all we need?

UNLABELLED: The risk stratification of patients with acute heart failure (AHF) has been addressed repeatedly in recent years. Low oxygen saturation (SaO2) and systolic blood pressure (SBP) are signs of impending respiratory and circulatory failure that can be obtained quickly in patients with AHF. METHODS: Admissions for AHF (340 patients) in a city hospital were recorded and patients were followed for symptoms of heart failure, re-admission and mortality for 6 months. RESULTS: Patients with low (<90%) SaO2 had higher rates of worsening heart failure at 1 month and 6 months (p < 0.001 and p < 0.001, respectively) and higher rates of mortality (p = 0.013). SBP <120 mm Hg was not associated with a significant increase in worsening heart failure, but was associated with a statistically significant increase in mortality at 1 and 6 months (p < 0.001 and p < 0.001, respectively). Combined low SaO2 and SBP had a particularly strong prognostic implication. Patients who developed frank respiratory failure and/or circulatory failure fared the worst. Patients requiring ventilatory support had a recurrent heart failure rate of 81% and a mortality of 41% at 1 month of follow-up. Patients requiring intravenous pressors without respiratory mechanical support had a recurrent heart failure rate of 72% and a mortality rate of 28% at 1 month (p < 0.001). CONCLUSIONS: Simple assessment of impending respiratory and circulatory failure at admission by measuring SaO2 and SBP enables rapid and accurate risk stratification of patients admitted for AHF. This may enable more aggressive therapeutic interventions for stabilization and treatment of AHF.

Vasodilators in the treatment of acute heart failure: what we know, what we don't.

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice.

Improvements in signs and symptoms during hospitalization for acute heart failure follow different patterns and depend on the measurement scales used: an international, prospective registry to evaluate the evolution of measures of disease severity in acute heart failure (MEASURE-AHF).

BACKGROUND: The natural evolution of signs and symptoms during acute heart failure (AHF) is poorly characterized. METHODS AND RESULTS: We followed a prospective international cohort of 182 patients hospitalized with AHF. Patient-reported dyspnea and general well-being (GWB) were measured daily using 7-tier Likert (-3 to +3) and visual analog scales (VAS, 0-100). Physician assessments were also recorded daily. Mean age was 69 years and 68% had ejection fraction <40%. Likert measures of dyspnea initially improved rapidly (day 1, 0.22; day 2, 1.31; P <.001) with no significant improvement thereafter (day 7, 1.51; day 2 versus 7 P = .16). In contrast, VAS measure of dyspnea improved throughout hospitalization (day 1, 50.1; day 2, 64.7; day 7, 83.2; day 1 versus 2 P < .001, day 2 versus 7 P < .001). Symptoms of dyspnea and GWB tracked closely (correlation r = .813, P < .001). Physical signs resolved more completely than did symptoms (eg, from day 1 to discharge/day 7, absence of edema increased from 33% to 72% of patients, whereas significant improvements in dyspnea increased from 27% to 52% of patients; P < .001). CONCLUSIONS: Changes in patient-reported symptoms and physician-assessed signs followed different patterns during an AHF episode and are influenced by the measurement scales used. Multiple clinical measures should be considered in discharge decisions and evaluation of AHF therapies.

Site matters: winning the hearts and minds of patients in a cardiology clinic.

BACKGROUND: In medical care settings, mental health symptoms of depression and distress are associated with poor medical outcomes, yet they are often underrecognized. OBJECTIVE: Authors sought to examine the effect of having immediate mental-health screening in the cardiology clinic. METHOD: The Patient Health Questionnaire and the Impact of Event Scale were used to screen for depression and distress in 316 patients at an urban cardiology clinic. Because of poor follow-up rates, a psychiatrist was placed on the premises of the cardiology clinic to facilitate referrals. RESULTS: Placing a psychiatrist within the cardiology clinic significantly improved the rate of successful referrals. CONCLUSION: Because 45 patients (14%) endorsed suicidal thoughts, authors conclude that mental health screening programs should include an immediate evaluation by a clinician.

Fluid overload in acute heart failure--re-distribution and other mechanisms beyond fluid accumulation.

Although fluid overload is one of the most prominent features of acute heart failure (AHF), its mechanism remains challenging, due to the lack of consistent data from prospective studies. Traditionally, fluid overload was thought to be mainly the result of either increased intake of fluid and salt or non-adherence with diuretic therapy. However, recent data showed little weight change before or during an AHF event suggesting that in many cases fluid overload is caused by other mechanisms such as fluid redistribution and neurohormonal or inflammatory activation. Redistribution may be the result of a combined vascular and cardiac process reducing capacitance in the venous system (and hence increasing preload) and increasing arterial stiffness and resistance (and hence afterload). When these vascular processes occur acutely and are superimposed on reduced cardiac function; fluid is redistributed to the lungs instigating pulmonary congestion. In this paper we elaborate on this possible pathophysiological mechanism and review its potential causes and amplifiers.

Hyponatraemia in acute heart failure is a marker of increased mortality but not when associated with hyperglycaemia.

UNLABELLED: Previous studies suggest that hyponatraemia is a marker of neurohormonal activation and increased mortality in patients with acute heart failure (AHF). Although diabetes is a common co-morbidity in heart failure, no prior study has considered the impact of serum glucose on this relationship. METHODS: Over four consecutive months we prospectively registered all patients admitted due to AHF. Sodium and glucose levels were determined immediately upon admission. Patients were followed through admission and for the next 6 months. Of 342 patients enrolled, complete data were available for 331 patients. RESULTS: Hyponatraemia (sodium <135 mmol/L) was detected in 22% of patients. However, 47% of patients with hyponatraemia had concomitant hyperglycaemia (glucose level >11 mmol/L). Hyponatraemia was associated with increased 6-month mortality (21 vs. 8%, p=0.002). This association was restricted to patients who had hyponatraemia without concomitant hyperglycaemia. The 6-month mortality of patients with and without hyponatraemia was 11% versus 10% (p=0.87) when hyperglycaemia was present versus 29% and 7% (p<0.001) when hyperglycaemia was absent. CONCLUSIONS: In this preliminary study, hyperglycaemia-associated hyponatraemia was present in a significant proportion of patients admitted with AHF. In patients with hyperglycaemia, hyponatraemia had no prognostic significance, whereas in patients without hyperglycaemia, hyponatraemia remained a powerful predictor of mortality. These results need confirmation in a larger study.

Nitric oxide synthase inhibitors in cardiogenic shock: present and future.

Cardiogenic shock (CS) accompanying myocardial infarction carries a case fatality rate of 40-50%. Profound myocardial dysfunction is partially reversible, and possibly related to a state of inflammatory storm accompanied by nitric oxide (NO) overproduction. CS survivors enjoy satisfactory longevity and quality of life. The focus of this review is to describe the available data regarding NO synthase (NOS) inhibitors in CS. In view of supportive evidence from mammalian research (inducible-NOS-knockout mice are less susceptible to ischemic and reperfusion injury), therapies mitigating NO overproduction were tested in human CS subjects. Human randomized clinical trials project excellent safety but lack of efficacy. Although the Phase III, multicenter, prospective, randomized, double-blind, placebo-controlled Study to Assess the Safety and Efficacy of Tilarginine Acetate (L-N(G)-monomethyl arginine citrate [L-NMMA]) in CS (TRIUMPH) trial demonstrated lack of clinical benefit of 5-h infusion of L-NMMA in CS, major design issues regarding the optimal timing, dosing, duration and NOS inhibitor need to be addressed prior to rendering this therapy ineffective.

The pathophysiology of acute heart failure--is it all about fluid accumulation?

Despite significant advancement in chronic heart failure (HF), no breakthroughs have occurred in the last 2 decades in our understanding of the pathophysiology, classification, and treatment of acute HF (AHF). Traditional thinking, which has been that this disorder is a result of gradual fluid accumulation on a background of chronic HF, has been called into question by recent large registries enrolling less selected patient populations. It is increasingly recognized that many patients with this syndrome are elderly, have relatively preserved ejection fraction, and have mild or no preexisting chronic HF. In this review, we propose 2 primary subtypes of AHF: (1) acute decompensated cardiac failure, characterized by deterioration of cardiac performance over days to weeks leading to decompensation; and (2) acute vascular failure, characterized by acute hypertension and increased vascular stiffness. Registry data suggest that the latter is the more common form of AHF in the general population, although the former is often overrepresented in studies focused in academic tertiary care centers. Regardless of the clinical subtype, a variety of pathophysiologic mechanisms may play a role in this disorder, many of which remain poorly understood. In this review, we describe current understanding of the pathophysiology of AHF, including a critical evaluation of the data supporting both traditional and novel mechanisms, and suggest a framework for integrating these mechanisms into an overall model of AHF.

Clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction, associated with secondary pulmonary hypertension--a multi-center randomized study.

OBJECTIVE: To evaluate the effects of bosentan on echo-derived hemodynamic measurements, and clinical variables in symptomatic heart failure (HF) patients. METHOD: Multi- center, double-blind, randomized (2:1), placebo-controlled study comparing bosentan (8-125 mg b.i.d.) to placebo in patients with New York Heart Association class IIIb-IV HF, left ventricular ejection fraction <35% and systolic pulmonary artery pressure (SPAP) >40 mm Hg. Primary and secondary endpoints were change from baseline to 20 weeks in SPAP and cardiac index, respectively. Safety endpoints were treatment emergent adverse events (AEs), change in body weight, hemoglobin, hematocrit, systolic blood pressure and diuretic use. RESULTS: Ninety-four patients enrolled: 60 to bosentan, 34 to placebo. There was no significant difference between the 2 arms in SPAP change (0.1 +/- 11.5 mm Hg , 95% confidence limit (CL) -5.4 to 5.2, p = 0.97), cardiac index shift (0.12 +/- 0.45, 95% CL -0.09 to 0.33 , p = 0.24 ) or any of the other 22 echocardiographic measurements obtained. Therapy-duration was longer in the placebo arm, while more patients in the bosentan arm experienced adverse and serious AEs. CONCLUSION: In HF patients with left ventricular dysfunction and secondary pulmonary hypertension, bosentan did not provide any measurable hemodynamic benefit, and was associated with more frequent AEs, requiring drug discontinuation.

Glycoprotein IIb/IIIa inhibitors: questioning indications and treatment algorithms.

Glycoprotein inhibitors (GPI) are viewed as beneficial adjunctive pharmacotherapy agents for percutaneous coronary interventions (PCIs). The major benefit of GPI is derived from the reduction of ischemic events (mostly non-Q-wave myocardial infarctions) during PCI. There is no single randomized clinical trial demonstrating that any of these agents significantly reduces mortality in any clinical subset of patients. Studies of sustained oral GPI resulted in excessive death and myocardial infarctions. Reduction of ischemic end points was counteracted by excessive bleeding, vascular complications, and thrombocytopenia. These complications bear considerable medical and economic impact. The Acute Catheterization and Early Intervention Triage Strategy trial demonstrated that GPI, when added to heparin, enoxaparine, or bivalirudin, do not reduce mortality or ischemic events but significantly increase bleeding complications. Major bleeding resulted in threefold mortality at 1 year. In view of available data, the use of GPI should be limited to moderate-risk to high-risk PCI patients with low bleeding propensity. Protocols of abbreviated GPI administration and careful bleeding surveillance, in conjunction with lower doses of unfractionated heparin or new and possibly safer antithrombins, can potentially improve patient safety.

Acute heart failure associated with high admission blood pressure--a distinct vascular disorder?

BACKGROUND: Although blood pressure (BP) is elevated in patients with acute heart failure (AHF), first admission BP has not been meticulously recorded before treatment in previous studies. METHODS: During three consecutive months, all AHF admissions (335 patients) to a city hospital which provides the sole inpatient medical service for approximately 500,000 people were registered. First BP was recorded before treatment at the first patient encounter in the ambulance or the emergency room. RESULTS: Mean BP at admission was 164+/-38/88+/-22 mm Hg. Mean BP in the highest quartile was 212+/-22/115+/-13 mm Hg. Patients with higher baseline BP had higher ejection fraction (highest versus lowest quartile 48+/-13% vs. 33+/-14%, p<0.001), less atrial fibrillation (18% vs. 42%, p=0.001) as well as lower mean urea and higher mean haemoglobin. The apparently more favourable baseline characteristics in patients with higher admission BP did not translate into lower morbidity - the rate of worsening heart failure - was not related to admission BP. However, 6 month mortality was lower in patients with higher admission BP (4% vs. 19.3%, p=0.002). CONCLUSIONS: Blood pressure is elevated substantially at the onset of AHF. The different characteristics and outcome of patients admitted with high-BP associated AHF suggest that this presentation may be a specific disorder related to a distinct yet unknown pathophysiological mechanism.