Neurohumoral,cardiac and inflammatory markers in the evaluation of heart failure severity and progression

Heart failure is common in adult population,accounting for substantial morbidity and mortality worldwide.The main risk factors for heart failure are coronary artery disease,hypertension,obesity,diabetes mellitus,chronic pulmonary diseases,family history of cardiovascular diseases,cardiotoxic therapy.The main factor associated with poor outcome of these patients is constant progression of heart failure.In the current review we present evidence on the role of established and candidate neurohumoral biomarkers for heart failure progression management and diagnostics.A growing number of biomarkers have been proposed as potentially useful in heart failure patients,but not one of them still resembles the characteristics of the"ideal biomarker."A single marker will hardly perform well for screening,diagnostic,prognostic,and therapeutic management purposes.Moreover,the pathophysiological and clinical significance of biomarkers may depend on the presentation,stage,and severity of the disease.The authors cover main classification of heart failure phenotypes,based on the measurement of left ventricular ejection fraction,including heart failure with preserved ejection fraction,heart failure with reduced ejection fraction,and the recently proposed category heart failure with mid-range ejection fraction.One could envisage specific sets of biomarker with different performances in heart failure progression with different left ventricular ejection fraction especially as concerns prediction of the future course of the disease and of left ventricular adverse/reverse remodeling.This article is intended to provide an overview of basic and additional mechanisms of heart failure progression will contribute to a more comprehensive knowledge of the disease pathogenesis.     

Elevated homocysteine levels in young male patients with schizophrenia

OBJECTIVE: Elevated plasma homocysteine has been found to be a risk factor for Alzheimer's disease as well as cerebral vascular disease, suggesting that some risk factors can accelerate or increase the severity of several CNS disease processes. The authors measured plasma homocysteine levels in patients with chronic schizophrenia in their catchment area. METHOD: A one-way analysis of covariance with age and sex as covariates was performed on the total plasma homocysteine levels of 193 patients with schizophrenia compared with 762 subjects without the diagnosis of schizophrenia who were evaluated in a screening program for employee health. RESULTS: The effect of schizophrenia was marked: the mean homocysteine level was 16.3 micro M (SD=11.8) in patients with schizophrenia compared with 10.6 micro M (SD=3.6) in healthy comparison subjects. The difference between groups was almost entirely attributable to the homocysteine levels of young male patients with schizophrenia. CONCLUSIONS: Elevated levels of homocysteine in young male patients with schizophrenia could be related to the pathophysiology of aspects of this illness.     

Soluble Angiotensin-Converting Enzyme 2 in Human Heart Failure: Relation With Myocardial Function and Clinical Outcomes

BackgroundAngiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established.Methods and ResultsWe measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF] ≤35%, New York Heart Association Class II-IV). Comprehensive echocardiography was performed at the time of blood sampling. We prospectively examined adverse clinical events (death, cardiac transplant, and heart failure hospitalizations) over 34 ± 17 months. Patients who had higher sACE2 plasma activity were more likely to have a lower LVEF (Spearman's r = –0.36, P < .001), greater right ventricular systolic dysfunction (r = 0.33, P < .001), higher estimated pulmonary artery systolic pressure (r = 0.35, P = .002), larger left ventricular end-diastolic diameter (r = 0.23, P = .02), and higher plasma NT-proBNP levels (r = 0.35, P < .001). sACE2 was less associated with diastolic dysfunction (r = 0.19, P = .05), and was similar between patients with ischemic and nonischemic cardiomyopathies. There was no relationship between sACE2 activity and markers of systemic inflammation. After adjusting for NT-proBNP and LVEF, sACE2 activity remained an independent predictor of adverse clinical events (HR = 1.7 [95% CI: 1.1–2.6], P = .018).ConclusionsElevated plasma sACE2 activity was associated with greater severity of myocardial dysfunction and was an independent predictor of adverse clinical events.     

Dysfunction of brain pericytes in chronic neuroinflammation

Brain pericytes are uniquely positioned within the neurovascular unit to provide support to blood brain barrier (BBB) maintenance. Neurologic conditions, such as HIV-1-associated neurocognitive disorder, are associated with BBB compromise due to chronic inflammation. Little is known about pericyte dysfunction during HIV-1 infection. We found decreased expression of pericyte markers in human brains from HIV-1-infected patients (even those on antiretroviral therapy). Using primary human brain pericytes, we assessed expression of pericyte markers (α1-integrin, α-smooth muscle actin, platelet-derived growth factor-B receptor β, CX-43) and found their downregulation after treatment with tumor necrosis factor-α (TNFα) or interleukin-1 β (IL-1β). Pericyte exposure to virus or cytokines resulted in decreased secretion of factors promoting BBB formation (angiopoietin-1, transforming growth factor-β1) and mRNA for basement membrane components. TNFα and IL-1β enhanced expression of adhesion molecules in pericytes paralleling increased monocyte adhesion to pericytes. Monocyte migration across BBB models composed of human brain endothelial cells and pericytes demonstrated a diminished rate in baseline migration compared to constructs composed only of brain endothelial cells. However, exposure to the relevant chemokine, CCL2, enhanced the magnitude of monocyte migration when compared to BBB models composed of brain endothelial cells only. These data suggest an important role of pericytes in BBB regulation in neuroinflammation.     

Abnormal P‐Wave Morphology Is a Predictor of Atrial Fibrillation Development and Cardiac Death in MADIT II Patients

Background: Several ECG‐based approaches have been shown to add value when risk‐stratifying patients with congestive heart failure, but little attention has been paid to the prognostic value of abnormal atrial depolarization in this context. The aim of this study was to noninvasively analyze the atrial depolarization phase to identify markers associated with increased risk of mortality, deterioration of heart failure, and development of atrial fibrillation (AF) in a high‐risk population with advanced congestive heart failure and a history of acute myocardial infarction. Methods: Patients included in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) with sinus rhythm at baseline were studied (n = 802). Unfiltered and band‐pass filtered signal‐averaged P waves were analyzed to determine orthogonal P‐wave morphology (prespecified types 1, 2, and 3/atypical), P‐wave duration, and RMS20. The association between P‐wave parameters and data on the clinical course and cardiac events during a mean follow‐up of 20 months was analyzed. Results: P‐wave duration was 139 ± 23 ms and the RMS20 was 1.9 ± 1.1 μV. None of these parameters was significantly associated with poor cardiac outcome or AF development. After adjustment for clinical covariates, abnormal P‐wave morphology was found to be independently predictive of nonsudden cardiac death (HR 2.66; 95% CI 1.41–5.04, P = 0.0027) and AF development (HR 1.75; 95% CI 1.10–2.79, P = 0.019). Conclusion: Abnormalities in P‐wave morphology recorded from orthogonal leads in surface ECG are independently predictive of increased risk of nonsudden cardiac death and AF development in MADIT II patients. Ann Noninvasive Electrocardiol 2010;15(1):63–72     

Flamingo cadherin: a putative host receptor for Streptococcus pneumoniae

Streptococcus pneumoniae fructose bisphosphate aldolase (FBA) is a cell wall-localized lectin. We demonstrate that recombinant (r) FBA and anti-rFBA antibodies inhibit encapsulated and unencapsulated S. pneumoniae serotype 3 adherence to A549 type II lung carcinoma epithelial cells. A random combinatorial peptide library expressed by filamentous phage was screened with rFBA. Eleven of 30 rFBA-binding phages inhibited 90% of S. pneumoniae adhesion to A549 cells. The insert peptide sequence of 9 of these phages matched the Flamingo cadherin receptor (FCR) when aligned against the human genome. A peptide comprising a putative FBA-binding region of FCR (FCRP) inhibited 2 genetically and capsularly unrelated pairs of encapsulated and unencapsulated S. pneumoniae strains from binding to A549 cells. Moreover, FCRP inhibited S. pneumoniae nasopharyngeal and lung colonization and, possibly, pneumonia development in the mouse intranasal inoculation model system. These data indicate that FBA is an S. pneumoniae adhesin and that FCR is its host receptor.     

Communication in the Heart: the Role of the Innate Immune System in Coordinating Cellular Responses to Ischemic Injury

Ischemic cardiac injury is the leading cause of heart failure and mortality in the USA and is a major expense to health-care systems. Once the heart is injured, a highly dynamic and coordinated immune response is initiated, which is dependent on both resident and recruited leukocytes. The goal of the inflammatory response is to remove ischemic and necrotic material and to promote infarct healing. If this system is perturbed, the myocardium heals poorly, leading to significant left ventricular dysfunction. Understanding how inflammatory cells coordinate and interact with each other is required prior to designing therapeutic interventions that target pathological processes at play and leave untouched those processes that are protective. This review will discuss the intercellular cross talk between cells of the innate immune system following myocardial ischemic injury and how that response is coordinated over time.