Miller, Wayne L.

Abstract The proliferation of cardiac-related biomarkers and advocacy for their use has often come without adequate discussion of limitations in the interpretation of values and their best use in heart failure (HF) patients to provide a balanced assessment of how cardiac biomarkers are advocated for use in HF and areas where we would argue there are no gaps in knowledge. We include suggestions to address these issues. We have focused on peer-reviewed publications over the period 2000 to present. Most studies have used samples at one or at most two points in time to define risk. Although biomarkers might add to the magnitude of risk, it is unclear how often they lead to changes in treatment. We suggest that defining the use of serial biomarker testing over time would be more helpful. To do this, it is necessary to take into account the biomarker's analytical and biological variability in addition to its ability to define and monitor therapy. These factors are often overlooked leading to conclusions that may be statistically significant but not clinically or analytically robust. An appreciation of the value and limitations of biomarker use is important to all clinicians who manage HF patients. If the proper studies are done so that biomarkers are used optimally, they will likely be helpful in defining when and how to intervene. If we continue as we have, we will continue to have ambiguity about the use of these valuable probes in the assessment and management of HF.

Acute decompensated heart failure (ADHF) is a prominent condition whose frequency is increasing, especially in the context of an aging population. The ability to discern the cause of undifferentiated dyspnea in acute presentations is an increasing struggle. In this review, we seek to explore the various biomarkers that have been studied for the diagnosis of ADHF and their respective clinical utilities as the most recent data would suggest. Natriuretic peptides, galectin-3, soluble ST2, adrenomedullin, cardiac troponin-T, neutrophil gelatinase-associated lipocalin, and copeptin are reviewed. Of these biomarkers, natriuretic peptides are the most thoroughly evaluated and show the most promise for diagnosis or exclusion of acute heart failure, though other biomarkers can add significant utility in the form of prognostication.

Abstract Aims Aldosterone activation is central to the sodium–fluid retention that marks the progression of heart failure (HF). The actions of dietary sodium restriction, a mainstay in HF management, on cardiorenal and neuroendocrine adaptations during the progression of HF are poorly understood. The study aim was to assess the role of dietary sodium during the progression of experimental HF. Methods and results Experimental HF was produced in a canine model by rapid right ventricular pacing which evolves from early mild HF to overt, severe HF. Dogs were fed one of three diets: (i) high sodium [250 mEq (5.8 g) per day, n =6]; (ii) standard sodium [58 mEq (1.3 g) per day, n =6]; and (iii) sodium restriction [11 mEq (0.25 g) per day, n =6]. During the 38-day study, haemodynamics, renal function, plasma renin activity (PRA), and aldosterone were measured. Changes in haemodynamics at 38 days were similar in all three groups, as were changes in renal function. Aldosterone activation was demonstrated in all three groups; however, dietary sodium restriction, in contrast to high sodium, resulted in early (10 days) activation of PRA and aldosterone. High sodium demonstrated significant suppression of aldosterone activation over the course of HF progression. Conclusions Excessive dietary sodium restriction particularly in early stage HF results in early aldosterone activation, while normal and excess sodium intake are associated with delayed or suppressed activation. These findings warrant evaluation in humans to determine if dietary sodium manipulation, particularly during early stage HF, may have a significant impact on neuroendocrine disease progression.

Background—Doppler-echocardiography provides quantitative imaging of systolic and diastolic left ventricular (LV) function, functional mitral regurgitation (FMR), and pulmonary hypertension (PH) in patients with LV systolic dysfunction. Whether PH is linked to survival independently of LV features and FMR in symptomatic and asymptomatic patients is unknown.Methods and Results—Patients with LV ejection fraction ≤40% and quantitative Doppler-echocardiography assessment of FMR and PH were studied. Patients were frequency matched for those with Doppler-echocardiography estimated pulmonary systolic pressure ≥45 mm Hg (n=692) and those without PH (n=692; pulmonary systolic pressure, <45 mm Hg) for age, sex, LV ejection fraction, and quantified FMR severity and analyzed for long-term survival after diagnosis. During follow-up (median, 8.9 years), 885 deaths (63.5%) occurred, with PH being associated with higher 5-year mortality: 51±2% versus 37±2%,P<0.001. In multivariate analysis, PH demonstrated increased mortality risk independent of age, sex, severity of diastolic and systolic LV dysfunction, FMR, comorbidities, and symptom (hazard ratio, 1.34; 95% confidence limit, 1.17–1.53;P<0.001). Subgroup analysis, stratified by symptoms, degree of FMR, and severity of LV dysfunction, demonstrated that PH was associated with excess mortality in all subgroups.Conclusions—In this large cohort of patients with LV systolic dysfunction, in whom FMR and LV characteristics were quantified and matched between those with and without PH, the presence of PH was an independent factor for excess mortality and not a surrogate for the severity of LV systolic dysfunction or FMR. In asymptomatic or symptomatic patients with or without FMR, PH is a critical marker for poor outcomes.

The contributions of histamine (H1 or H2) receptor-mediated responses and, therefore, the effects of histamine blocking agents are unclear with regard to regulation of proximal epicardial and distal resistance coronary arteries. This study was designed to evaluate the effects of selective H1- and H2-receptor antagonists on epicardial and resistance vessels in the closed chest dog model. Histamine, diphenhydramine (H1 blocker), and cimetidine (H2 blocker) were infused into the left anterior descending coronary artery (LAD), and responses were studied by quantitative coronary angiography and flow measurements (133Xe washout). Histamine infusion alone produced a significant dilation of the proximal LAD (13% above control) only at the highest dose (45 micrograms/min), while LAD flow was increased by 128%. In the presence of H1 blocker, histamine produced significantly greater epicardial dilation (55% above control). The flow response curve was shifted to the right in the presence of H1 blocker, but the flow attenuation was overcome by the highest histamine dose. In contrast, the H2 blocker attenuated both epicardial dilation (6% below control) and flow response (31% above control) to the highest histamine dose. Results support a differential regulation of proximal epicardial and distal resistance vessels to histamine with epicardial arteries demonstrating H1-mediated vasoconstriction and H2-mediated vasodilation and distal resistance vessels showing H1- and H2-mediated vasodilation. In addition, these findings suggest that H1 blockade may antagonize histamine-related vasoconstriction and vasospasm, while H2 blockers may permit unopposed H1-mediated vasoconstriction of epicardial arteries and also limit resistance vessel vasodilatory responsiveness in the presence of elevated tissue histamine, as may occur in atherosclerotic coronary artery disease.

Background— Multiple B-type natriuretic peptide (BNP) fragments circulate in patients with heart failure (HF) but the types and relative quantities, particularly in relation to bioactive BNP 1-32, remain poorly defined. The purpose of the study was to relate clinically available BNP values with quantitative information on the concentration of pre-secretion and post-processed fragments of BNP detected by mass spectrometry. Methods and Results— Seventy Class I–IV patients were prospectively enrolled with blood drawn into tubes containing a preservative to protect against BNP degradation. Samples were analyzed by quantitative mass spectrometry (MS) immunoassay for intact BNP 1-32 and its fragments. Clinical BNP 1-2 was measured by standard clinical laboratory methods. ProBNP 1-108, corin, and clinically measured BNP levels were elevated, but MS BNP 1-32 levels were low and differed from clinical BNP ( P =0.01). Intact MS BNP 1-32 correlated modestly with clinical BNP ( r =0.46, P <0.001). MS BNP fragments 3-32, 4-32, and 5-32 demonstrated the best associations with clinical BNP; fragment 5-32 with a correlation coefficient of r =0.81 ( P <0.001). Conclusions— ProBNP 1-108 is measured by clinical BNP assays and contributes to the cumulative results of the BNP assay. However, the observation that clinically measured BNP correlates best with MS degradation fragments and relatively poorly with MS BNP 1-32 suggests that a significant component of circulating clinical BNP is composed of such fragments that are known to demonstrate little biological activity. There appear to be multiple pathways involved in the dysregulation of proBNP in HF, and both the processing of proBNP and the downstream degradation to BNP 1-32 appear to be critical.