Predictors associated with increased troponin in acute decompensated and chronic heart failure patients

Anp Production Is Impaired in Acute Decompensated Heart Failure

Recent Trends in the Incidence, Treatment, and Prognosis of Patients With Heart Failure and Atrial Fibrillation (the Worcester Heart Failure Study)

This editorial refers to 'Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes', by M. Gheorghiade et al., published in this issue on pages 1056–1066. Over the last decades, pharmacological treatment of patients hospitalized for acute decompensated heart failure have remained unchanged. Virtually all patients are treated with a loop diuretic, and the use of additional drugs depends on the type of heart failure and mainly on blood pressure. Only in patients with a blood pressure >110 mmHg is the addition of intravenous nitrates recommended.1 In rare patients with cardiogenic shock, inotropes are administered. Nevertheless, evidence for this approach is generally lacking. Also, the majority of patients remain symptomatic, and in-hospital mortality remains ∼4%.2 More importantly, outcome after discharge is very poor. Most deaths and re-hospitalizations occur early after discharge, and 1 year mortality or re-hospitalization occurs in ∼40% of the patients.1 Therefore, there is a great need for improvement. In the current issue of this journal, clinical results of the COMPOSE programme are presented. The COMPOSE programme studied the effects of cinaciguat, a novel vasodilator, in three randomized, double-blind, placebo-controlled studies in acute decompensated heart failure patients with (COMPOSE 1 and 2) or without (COMPOSE EARLY) a requirement for invasive haemodynamic monitoring.3 Cinaciguat activates soluble guanylate cyclase, leading to increased cyclic guanosine monophosphate (cGMP). cGMP causes relaxation of smooth muscle cells, and has antiproliferative, anti-inflammatory, and antiremodelling effects.4 Cinaciguat is therefore a potent vasodilator, with specific antiplatelet activity, a long-lasting antihypertensive effect, and a haemodynamic profile similar to that of nitrates. In an uncontrolled clinical study in patients (n = 60) with acute decompensated heart failure, cinaciguat produced strong reductions in preload and afterload, with increased cardiac output and preservation of renal function.5 The drug was well tolerated, with hypotension reported only in 10% of patients. In the present paper in this journal, the authors also referred to another unpublished placebo-controlled study, in which cinaciguat produced rapid, sustained improvement in pulmonary capillary wedge pressure (PCWP) at 8 h compared with placebo. However, the majority (73%) of patients receiving cinaciguat developed hypotension, especially those who received cinaciguat doses ≥200 µg/h. The COMPOSE programme was therefore aimed to study the safety and efficacy of lower doses of intravenous cinaciguat (<200 µg/h) as add-on to standard therapy in patients hospitalized with acute decompensated heart failure and a left ventricular ejection fraction of <40%. COMPOSE was terminated early due to an excess of non-fatal hypotension and recruitment difficulties. COMPOSE was composed of three parts. In COMPOSE 1, a reduction in wedge pressure was confirmed but, considering the low number of patients (n = 12), no meaningful conclusion could be drawn. In COMPOSE 2, only four patients were included, and no results were reported. Both studies had problems with their inclusion, since there had to be a clinical indication requiring invasive haemodynamic monitoring, and recent data indicated that haemodynamic monitoring is no longer routinely recommended in acute decompensated heart failure patients.6 In the third part of this programme, COMPOSE EARLY (n = 62), no meaningful difference in dyspnoea was shown between cinaciguat and placebo. The authors conclude that 'Given the lack of effect on dyspnoea and cardiac index and the hypotensive effect seen even with low doses, it is doubtful that further studies with intravenous cinaciguat would prove beneficial in this patient population.' So, why did cinaciguat fail? A consistent strong reduction in PWCP was found with cinaciguat, which is considered as the main mechanism to improve symptoms and clinical outcome in acute heart failure.7 However, with the same dose that reduced wedge pressure by 6 mm in COMPOSE 1, no effect was found on improvement of dyspnoea in COMPOSE EARLY. This is remarkable, given the general consensus that reducing wedge pressure in acute heart failure is a major treatment goal. However, such a strong and fast reduction of the wedge pressure might also have deleterious effects, and a sudden drop in blood pressure can cause other organs, such as the kidney, to fail as well.8,9 Unfortunately, cinaciguat is not the first acute heart failure drug that fails to demonstrate meaningful beneficial effects in patients with acute heart failure. Other failures include phosphodiesterase inhibitors (e.g. milrinone), endothelin antagonists (e.g. tezosentan), calcium sensitizers (e.g. levosimendan), arginine vasopressin antagonists (e.g. tolvaptan), adenosine A1-receptor antagonists (e.g. rolofylline), and human recombinant natriuretic peptides (e.g. nesiritide). Why do these drugs fail, while many drugs in chronic heart failure have been proven to reduce mortality and morbidity?10 First, the wrong drugs might have been studied. This is unlikely, however, since all of the studied drugs showed promising effects in pre-clinical and mechanistic studies, and in early phase II trials. Secondly, maybe the wrong population has been studied. For example, vasodilators might be harmful in patients with low blood pressure, and several large randomized clinical trials in patients with acute decompensated heart failure have allowed inclusion of patients with a blood pressure of <100 mmHg, which might have negatively influenced the results. However, in COMPOSE, only patients with a systolic blood pressure >120 mmHg were included. Thirdly, maybe the wrong endpoints were chosen for these trials. The PCWP might not be the ideal surrogate marker, as explained before. Also, in phase III trials, is it reasonable to believe that a drug that was given for only 48 h would reduce mortality? However, on the other hand, dyspnoea is a soft endpoint, and difficult to assess in an unbiased way. Recently, there have been attempts proposed to standardize and unify measurements of dyspnoea.11,12 In addition, improvement of renal function was shown to be a bad choice when studying rolofylline.13 Therefore, choosing the correct endpoint might strongly influence the outcome of the trial. Finally, the design of acute heart failure studies might have caused the neutral/negative results. For example, most studies allowed the study drug to be started 24–48 h after hospital admission. It is well known that dyspnoea has already improved in many patients by that time. An early start of treatment (within 6 h) might improve early and sustained relief of dyspnoea. However, in COMPOSE EARLY, treatment was started within 12 h of admission. So, haemodynamically active doses of cinaciguat were used only in patients with elevated blood pressures, and treatment was started early. Therefore, the assumptions above cannot fully explain the failure of cinaciguat. So, maybe it is the drug itself. Ideally, a drug that is used in patients hospitalized for heart failure lowers preload of the heart, leads to decongestion, but maintains cardiac output and organ perfusion, and preferably does not lower arterial blood pressure. For cinaciguat, the arterial effects (i.e. lowering of blood pressure) seem to have outweighed the effects of venous dilatation and decongestion. Of note, the most frequently used drugs in acute decompensated heart failure (i.e. loop diuretics and nitrates) have preferential effects on venous dilatation, with only modest effects on blood pressure. Again, a large and sudden drop in both venous and arterial pressures might be unfavourable in patients with acute decompensated heart failure. Unfortunately, the findings of the present study and similar findings from another unpublished placebo-controlled study seem to be the end of the development of the intravenous form of cinaciguat. Potentially, the oral form might show a different clinical profile, and might deserve further study, either in acute or in chronic heart failure. Conflict of interest: none declared.

NT-proBNP-Guided Preemptive Treatment of Outpatients with Chronic Heart Failure Followed in a Out Hospital Clinic

Aim. To assess the risk factors and diagnostic significance of the N-terminal probrain natriuretic peptide (NT-proBNP) in patients with acute decompensated heart failure (ADHF) and diabetic kidney disease (DKD).Material and methods. A total of 125 patients with ADHF and type 2 diabetes (T2D) were examined. They were divided into 2 groups depending on the presence/ absence of chronic kidney disease (CKD). The first group consisted of 43 (34,4%) patients with DKD, the second — 82 (65,6%) without CKD. The inclusion criterion was the presence of ADHF and T2D. There were following exclusion criteria: cardiogenic shock, pulmonary edema, acute thromboembolic events, type 1 diabetes, prediabetes, acute coronary syndrome, stroke, prior transient ischemic attack (&lt;1 month old), dissecting aneurysm or aortic dissection, acute valvular disorders, major surgery (&lt;1 month old), cardiac trauma, infective endocarditis, acute hepatitis and cirrhosis, terminal CKD, alcohol abuse, non-cardiac edema, cancer, dementia and mental disorders.Results. With the development of a hypertensive crisis and an increase in diastolic blood pressure &gt;100 mm Hg, the odds ratio (OR) and the relative risk (RR) of ADHF in patients with DKD increases by 5,1 and 4,5 times, 2,5 and 1,8 times, respectively. In the presence of grade III-V premature ventricular contractions, OR and RR of ADHF in patients with DKD were 2,6 and 1,9, respectively. OR and RR of ADHD in patients with DKD and prior stroke or transient ischemic attack were 3,8 and 3,2, respectively. Verification of anemia at a hemoglobin level of 5 mmol/l, the OR of ADHF in patients with DKD increases by 3,7 times, the OR — by 2,3 times. The NT-proBNP &gt;1289 pg/ml is diagnostic for verifying ADHF in DKD patients with the sensitivity of 64,3% and specificity of 93,3%.Conclusion. Every third patient with ADHF and T2D is diagnosed with DKD. A certain range of risk factors for the development of ADHF in patients with DKD has been identified. As the glomerular filtration rate (GFR) decreases, the NT-proBNP level increases. With a decrease in GFR of 60 ml/min/1,73 m2 in patients with T2D, the diagnostic value of NT-proBNP &gt;1289 pg/ml should be considered to verify ADF.

Can saline repletion be the true TARGET for achieving fluid balance in acute heart failure?

Background Immediate diagnosis of acute decompensated heart failure (ADHF) is essential in patients with dyspnoea. Remote Dielectric Sensing (ReDS), an electromagnetic non-invasive technology, estimates lung fluid content fast and observer-independently. In previous studies, ReDS discriminated congested heart failure patients from normal subjects with high accuracy. But not all ADHF patients have pulmonary interstitial congestion in the real world, and it is unknown if ReDS detects ADHF in consecutive patients with acute dyspnoea. Purpose To examine if ReDS can detect ADHF in consecutive dyspnoeic emergency patients and to compare ReDS with other diagnostic methods. Method This prospective observational study included consecutive patients with dyspnoea from the emergency departments. The exclusion criteria were age below 50 years, acute coronary syndrome, conditions prohibiting a supine CT scan, and no informed consent. We examined all patients immediately with ReDS, low-dose chest CT, echocardiogram, lung ultrasound (LUS), NT-proBNP, and Boston score. The Boston score used chest X-ray and clinical signs such as orthopnoea, jugular venous elevation, lung crackles and pedal oedema, and a score ≥8 equalled definite ADHF. A “LUS-score” ≥3 with at least 3 B-lines in one zone bilaterally equalled ADHF. ReDS values &amp;gt;35% lung fluid content were positive for pulmonary congestion, according to previous studies. According to ESC guidelines, an expert panel adjudicated the ADHF diagnosis based on clinical signs, chest X-ray image, NT-proBNP, echocardiographic cardiac dysfunction (HFvhd, HFrEF, HFmrEF, HFpEF), and elevated LV filling pressure. Importantly, the panel was blinded to the ReDS values. For sub-analyses, we divided ADHF patients into a “CT-congested” ADHF subgroup if an independent chest CT showed interstitial congestion. We classified ADHF patients without congestion on CT, as the “mildly-congested” subgroup. Results 97 included patients were examined within a median of 4.8 hours from admittance: 39 (40%) had ADHF, and 25 (26%) were ReDS-positive. ADHF patients had median LVEF 48%, NT-proBNP 347 pmol/l, and 85% had echocardiographic elevated LV filling pressure. ReDS detected ADHF with 46% sensitivity, 88% specificity, and 71% accuracy. The AUC for ReDS to detect ADHF (Figure 1), on a continuous scale, was similar to the Boston score (p=0.88) and the LUS score (p=0.74), but lower than NT-proBNP (p=0.02). The 21 (22%) CT-congested ADHF patients had higher ReDS values than the 18 (19%) mildly-congested ADHF patients (Figure 2, median 38% vs 30%, p&amp;lt;0.001). Furthermore, the mildly-congested ADHF patients had ReDS values similar to non-ADHF patients (median 30% vs 28%, p=0.36). Conclusion ReDS detects ADHF similarly to the Boston score and lung ultrasound but is inferior to NT-proBNP. This study suggests that ReDS primarily identifies CT-congested ADHF patients, but not the ADHF patients without interstitial congestion. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): This work was supported by the research fund of Bispebjerg University Hospital and Holger &amp; Ruth Hesse's Mindefond. Sensible Medical Ltd made the ReDS device available for free and provided an unrestricted grant to specifically collect the ReDS measurements. The sponsors did not affect the statistical analyses, study design, data collection, or writing of the paper.

See Article on Page 300-305 Heart failure is a systemic disease based on its chronic inflammation status and because it affects other organs, including the kidneys, lungs, and liver. Acute decompensated heart failure (ADHF) is a more severe form of heart failure that causes an acute change in hemodynamics. ADHF negatively affects renal, hepatic, and pulmonary function and causes peripheral soft tissue edema. Repeated hospital admissions for ADHF is one indicator of a poor clinical outcome in chronic heart failure patients [1,2]. The predictors of readmission and death have been investigated, and major risk factors are a low left ventricular ejection function (LVEF), low initial serum sodium level, increased serum creatinine, anemia, and low admission blood pressure [1,2]. These are markers of hemodynamic change, fluid and electrolyte imbalance, and reduced organ perfusion and function caused by depressed left and right ventricular function. The predictors that indirectly reflect low cardiac function include hepatic congestion, which can be detected with liver function tests (LFTs), including serum bilirubin, alkaline phosphatase, and aminotransferases. These have been suggested as risk factors for future death, cardiovascular events, and readmission [3-6]. Furthermore, recent publications have reported that the type of death from heart failure can be discriminated using the level: increased total was associated with death from pump failure and not with sudden death [5]. Chronic hepatic congestion due to right ventricular dysfunction might increase the possibility of liver cirrhosis, so-called cardiac cirrhosis. In a recent post hoc analysis, the prevalence of LFT abnormalities in ADHF was as much as 46% [2]. The liver and heart are connected intimately, similar to the relationship between the heart and kidney, usually called cardiorenal syndrome, in patients with chronic and acute heart failure. In this issue of Korean Journal of Internal Medicine, Chintanaboina et al. [7] reported an association between serum total and readmission due to ADHF. They demonstrated that patients with a high serum on admission had a high risk of readmission owing to decompensation, and that patients with a >1.3 mg/dL or LVEF <35% were at higher risk. This study once again confirmed the old story that hepatic congestion, which implies advanced heart failure, indicates a poor prognosis in acute and chronic heart failure patients [1-6,8]. Surprisingly, alleged poor risk predictors such as LVEF, serum creatinine, low serum sodium, and B-natriuretic peptide were not independent risk factors for readmission in a multiple regression analysis, as presented in Table 3. Nevertheless, I feel that this small retrospective study had many confounding factors that could not be controlled. Therefore, a refined statistical method should have been applied, and this process should be described in more detail in this article. Although it has substantial limitations, this study has value in that it confirms the correlation between total and hospitalization in ADHF patients, who comprise a small portion of patients compared with those with chronic heart failure in terms of bilirubin and heart failure prognosis. Serum is a potential indicator of risk stratification for rehospitalization, along with other prognostic markers such as low sodium and low initial blood pressure in ADHF. Moreover, it might help to guide the therapeutic options for ADHF. Future studies should aim at improving the prognosis of ADHF patients with the guidance of liver function.

Increased left ventricular filling pressure is a hallmark of heart failure (HF) caused by left ventricular dysfunction (LVD). Within the closed hemodynamic system, increased LV filling pressure results in elevated pressures in the left atrium and pulmonary venous vasculature. When pulmonary hypertension (PH, defined by mean pulmonary artery pressure [mPAP] >25 mm Hg) is associated with an abnormally elevated pulmonary capillary wedge pressure (PCWP >15 mm Hg) or left ventricular end-diastolic pressure (LVEDP >18 mm Hg),1 it has been variably termed World Health Organization (WHO) Group 2 PH,1 pulmonary venous hypertension,2 “postcapillary PH,”3 or “passive PH.”4 Article see p 644 Patients with LVD also have a propensity to develop a precapillary pulmonary arterial contribution to PH, reflected by an increased transpulmonary gradient (TPG, defined as mPAP-PCWP that exceeds 12 to 15 mm Hg) or an elevated pulmonary vascular resistance (PVR, defined as TPG/cardiac output that exceeds 2.5 to 3 Wood units [WU]).5,6 This type of PH, which is “out of proportion” to underlying left-sided disease in the setting of normalized volume status, has been termed “mixed PH,” given both precapillary and postcapillary contributions to elevated PAP.7 PH in HF can be simplistically organized along 2 sequential dyads: (1) the presence or absence of a significant precapillary contribution to elevated PAP (ie, mixed PH as opposed to purely passive PH) and (2) if present, the relative fixed (ie, nonreversible with lowering left-sided filling pressures) or reactive (ie, reversible with reduction of left-sided filling pressures) character of the precapillary contribution to PH (Figure). Figure. Diagnostic framework for pulmonary hypertension in heart failure (HF). mPAP indicates mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; and PH, pulmonary hypertension. There are no widely established cut-points to define PVR and transpulmonary …

Cardiac Natriuretic Peptide And Cgmp Impairment In Human Decompensated Heart Failure: Employing A Novel Ex Vivo Natriuretic Peptide/GC-A/cGMP Potency Assay To Evaluate Natriuretic Peptide Therapeutic Capacity

DOPPLER ULTRASOUND ASSESSMENT OF INTRA-RENAL VENOUS FLOW IN PATIENTS WITH ACUTE DECOMPENSATE HEART FAILURE: A POTENTIAL ACUTE CARDIORENAL SYNDROME BIOMARKER

Objective: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with heart failure, yet little is known about the impact of this condition in patients with acute decompensated heart failure (ADHF), especially from a more generalizable, community-based perspective. The primary objective of this study was to describe the in-hospital and post discharge mortality and treatment of patients hospitalized with ADHF according to COPD status. Methods: The study population consisted of patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 4 study years: 1995, 2000, 2002, and 2004. Results: Of the 9,748 patients hospitalized with ADHF during the years under study, 35.9% had a history of COPD. The average age of this population was 76.1 years, 43.9% were men, and 93.3% were white. At the time of hospital discharge, patients with COPD were less likely to have received evidence-based heart failure medications, including beta-blockers and ACE inhibitors/angiotensin receptor blockers, than patients without COPD. Multivariable adjusted in-hospital death rates were similar for patients with and without COPD. However, among patients who survived to hospital discharge, patients with COPD had a significantly higher risk of dying at 1 (adjusted RR 1.10; 95% CI 1.06, 1.14) and 5-years (adjusted RR 1.40; 95% CI 1.28, 1.42) after hospital discharge than patients who were not previously diagnosed with COPD. Conclusions: COPD is a common co-morbidity in patients hospitalized with ADHF and is associated with a worse long-term prognosis. Further research is required to understand the complex interactions of these diseases and to ensure that patients with ADHF and COPD receive optimal treatment modalities.

Background: Brain natriuretic peptide (BNP) is routinely measured for evaluating the severity of acute decompensated heart failure (ADHF). However, there are no other biomarkers for stratification of ADHF patients in clinical settings. Cardiac myosin I (CM-I) is one of a superfamily of motor proteins, which is mainly distributed in myocardium. Several papers reported that serum CM-I levels increased in patients with acute coronary syndrome (ACS). However, the role of CM-I in ADHF patients is not yet elucidated. Purpose: The aim of this study was to clarify the utility of CM-I in ADHF patients. Methods: We assessed 114 ADHF patients who visited our institution between December 2017 and May 2018 in a retrospective study. All patients were diagnosed ADHF using Framingham criteria. Eight ACS patients and 22 patients lacking in data of serum CM-I levels were excluded. Finally, we analyzed 84 patients. We calculated the difference in serum BNP levels between on admission and at discharge (delta BNP) as a prognostic surrogate marker. Results: Average age was 77.5 years old and 44 patients were male. Numbers of patients with NYHA III and IV were 30 and 36, respectively. Mean serum levels of BNP and Troponin T (TrT) on admission were 934.0 pg/ml and 0.092 ng/ml, respectively. Average left ventricular ejection fraction (LVEF) by echocardiography was 46.1%. Serum CM-I levels on admission and at discharge were 12.8 mg/ml and 7.30 mg/ml, respectively. Serum CM-I levels had a significant correlation with TrT levels (R=0.46, p&lt;0.0001) and a weak correlation with BNP levels (R=0.33, p= 0.006). CM-I levels were not statistically correlated with LVEF. CM-I levels were well correlated with delta BNP(R=0.36, p= 0.0138), but TrT were not associated with delta BNP(R=0.066, p= 0.658). Conclusion: We found CM-I was associated with the difference in BNP between on admission and at discharge in ADHF patients. CM-I may be a new potential prognostic biomarker in ADHF patients.

Introduction: Heart failure (HF) is a clinical syndrome associated with diverse metabolic disturbances. Recent studies suggest that failing heart through secretion of soluble myostatin may induce skeletal muscle wasting in HF patients and skeletal muscle plays an important role in pathogenesis of exercise intolerance in patients with chronic HF. However, the clinical significance of skeletal muscle mass in patients with acute decompensated HF (ADHF) remains unclear. Hypothesis: We hypothesized that low appendicular skeletal muscle mass could predict the occurrence of future cardiovascular (CV) events in patients with ADHF. Methods: We assessed lean body mass by dual energy X-ray absorptiometry in 96 patients with ADHF (age 72±11, left ventricular ejection fraction (LVEF) 38±15%, B-type natriuretic peptide (BNP) levels on admission 752 [377-1398] pg/ml). Low appendicular skeletal muscle mass index (ASMI, appendicular skeletal muscle mass/height 2 ) was defined according to the Asia Working Group for Sarcopenia criteria (&lt;7.0kg/m 2 in male, &lt;5.4kg/m 2 in female). ADHF patients were followed until occurring CV events (CV death, nonfatal myocardial infarction, ischemic stroke, or HF re-hospitalization). Results: ASMI significantly correlated with age (r=-0.51, P&lt;0.001), male sex (r=0.53, P&lt;0.001), body mass index (r=0.63, P&lt;0.001), systolic blood pressure on admission (r=0.21, P=0.04), and BNP levels on admission (r=-0.39, P=0.04). ADHF patients with low ASMI (n=54, 56%) had higher BNP levels (968 [552-1773] versus 498 [273-943], p=0.001) and higher rate of clinical scenario 2-3 (48% versus 12%, p=0.001) than those with normal ASMI. 42 patients developed CV events (median follow-up, 16months). Kaplan-Meier analysis demonstrated a significantly higher probability of CV events in the low ASMI group than those in the normal ASMI group (54% vs. 29%, log-rank test, P=0.02). Multivariate Cox hazard analysis identified low ASMI as an independent predictor of the CV events in patients with ADHF (hazard ratio 2.1, 95%-confidence interval 1.1-4.2, P=0.03). Conclusions: Low ASMI could predict the future CV events in patients with ADHF, irrespective of LV systolic function and other clinical profile.

Calling for Targeted Trials in Cardiorenal Syndromes