Introduction

Cardiac imaging is essential for the diagnosis of heart failure (demonstration of cardiac dysfunction and underlying structural heart disease), to determine its mechanisms (heart failure with reduced or preserved systolic function) and studying etiology (presence of myocardial infarction or ischemic heart disease, valvular heart disease, or cardiomyopathy) [1]. Imaging also plays an important role in determining prognosis and tailoring heart failure therapy, including revascularization, medical therapies, and device therapy with cardiac resynchronization pacemaker and/or implantable cardiac defibrillator to improve symptoms and prognosis [1, 2]. It has been increasingly recognized that detailed evaluation of underlying pathophysiology is essential for the successful development and application of new therapies for heart failure [3].

Positron emission tomography (PET) myocardial perfusion imaging is frequently used for detection of ischemic etiology of heart failure and evaluation of the extent of viable ischemic myocardium before revascularization. Improvement in PET imaging technology has led to evolution of PET imaging beyond the isolated assessment of myocardial perfusion, toward characterization of molecular processes at the cardiac tissue level. Molecular imaging aims at visualization of specific molecular targets that precede or underlie changes in morphology, physiology, and function. Nuclear imaging provides very high detection sensitivity for molecular-targeted imaging of biological processes involved in heart failure, such as myocardial metabolism, innervation, inflammation, and extracellular matrix remodeling. This review describes advances in application of new PET tracers in heart failure with discussion on their potential roles.

Technical aspects of PET

PET imaging represents an advanced technique to map radiotracer concentration and kinetics in the myocardium [4, 5]. With the currently applied PET scanners and post-processing algorithms, images can be reconstructed with a spatial resolution of 4–7 mm. Outstanding sensitivity allows for identification of radiotracer at nano- or picomolar concentrations. With the use of validated photon attenuation and scatter correction algorithms, PET imaging can be used to quantify the absolute amount of nuclear tracer within the myocardium. Relatively high temporal resolution of PET allows the development of dynamic images, which can be used to assess tracer kinetics.

Several recent developments have contributed to application cardiac PET for assessment of heart failure [4, 5]. The availability of PET systems and cyclotrons needed to produce tracers has markedly increased due to its increasing use in oncology. New radiotracers have been introduced, which have the potential to improve availability of cardiac PET and extend the current possibilities for molecular imaging [6,7,8] (Table 1). At the same time, several technical advances have been introduced that improved detection sensitivity and image resolution that allow detection of weak signals coming from molecular-targeted tracers. Development of detector technology has resulted in growth in count rate performance of scanners and new reconstruction algorithms have been introduced that decrease noise in the images [4]. Furthermore, addition of cardiac and respiratory gating of PET images has potential to further increase in detection sensitivity in cardiac PET [9]. PET scanners are increasingly integrated with either computed tomography (CT) or cardiac magnetic resonance (MR) systems into PET-CT or PET-MR hybrid imaging devices, which facilitate the localization of a molecular signal, by fusion with high-resolution morphologic images [10].

Table 1 New positron emission tomography tracers and their applications in heart failure
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Myocardial perfusion imaging

Ischemic cardiomyopathy is the most common cause of heart failure. From 24 multicenter heart failure trials, including 443,568 heart failure patients, 62% of patients had an ischemic etiology [11]. Myocardial perfusion imaging represents a well-established imaging modality for the evaluation of location, extent, severity, and reversibility of myocardial perfusion defects in patients with known or suspected coronary artery disease (CAD), contributing to the detection of ischemic etiology of heart failure [12, 13]. PET myocardial perfusion imaging provides good image quality, certainty of interpretation, and diagnostic accuracy for the detection of CAD. In two meta-analyses of diagnostic studies including 1394 to 1692 patients, pooled sensitivity of PET myocardial perfusion imaging varied from 84 to 90% and specificity from 84 to 88% in the detection of obstructive CAD defined as ≥50 or ≥70% stenosis on invasive coronary angiography [12, 13]. Similar to SPECT, the extent and severity of PET perfusion defects have strong incremental prognostic value beyond traditional cardiovascular risk factors [14].

In addition to the assessment of relative distribution of perfusion, PET with radiotracer kinetic modeling can be used to quantify myocardial blood flow (MBF) in absolute terms (mL/g/min) at rest and during vasodilator stress that allows the computation of coronary flow reserve (CFR). Quantification of regional MBF and CFR by PET may identify microvascular dysfunction, better characterize the extent and severity of CAD burden in multi-vessel disease, and detect balanced decreases of MBF in all major coronary artery vascular territories [15,16,17]. Furthermore, several studies have demonstrated that reduced CFR is a powerful predictor of increased risk of future cardiac events and it is incremental to the presence of regional perfusion defects or angiographic stenosis [18,19,20,21]. In heart failure, it has been shown that global CFR is frequently impaired in cardiomyopathic heart as a consequence of microvascular dysfunction in the absence of epicardial CAD [22, 23]. Outcome studies have supported microvascular dysfunction as an independent contributing factor to the symptoms and progression of heart failure and reduced CFR was a predictor of adverse cardiac events in patients with both ischemic cardiomyopathy [23] and idiopathic dilated cardiomyopathy [22, 23]. However, it remains to be seen whether and how quantitative measurements of CFR can direct therapy in patients with heart failure.

The main limitation of PET perfusion imaging is that perfusion tracers that are currently in clinical use have very short radioactive half-lives. This limits their availability, because an on-site cyclotron or a generator, which requires relatively high volume of patients to be cost-effective, is required. Furthermore, short half-lives limits their applicability for exercise stress. In contrast, pharmacologic stress with simultaneous imaging is used. Currently, a generator produced 82Rubidium (82Rb) is the most commonly used perfusion tracer. In addition to 82Rb, 15O water (H2 15O) and 13N ammonia (13NH3) are used in clinical myocardial perfusion PET. Detailed description of specific characteristics of these tracers can be found elsewhere [24].

New 18F-labeled perfusion tracers

To overcome problems related to short radioactive half-life, perfusion tracers labeled with 18F have been studied [24]. Perfusion tracers labeled with 18F have longer half-life (110 min) than 82Rb (76 s), H2 15O (123 s) or 13NH3 (10 min) and therefore, can be distributed to centers that do not have an on-site cyclotron and potentially can be used with exercise. Of the 18F-based PET perfusion radiotracers, 18F-Flurpiridaz (formerly BMS-747158) that was introduced in 2007 is the most thoroughly studied in animal models and is currently undergoing clinical evaluation in phase III studies [6, 24,25,26,27].

18F-Flurpiridaz is derived from pyridazinone and binds avidly to mitochondrial complex-1 [6, 26]. Preclinical experience with 18F-Flurpiridaz demonstrated high and stable myocardial uptake that together with low positron range results in good image quality, defect resolution, and accurate delineation of myocardial infarct size [6, 25,26,27]. A clinical study did not revealed safety concerns regarding the tracer and the results of dosimetry indicate that the radiation exposure of 18F-flurpiridaz injection (approximately 6 mSv) is lower than that of SPECT imaging [28]. In a phase II clinical trial, diagnostic performance of 18F-Flurpiridaz was compared with that of SPECT MPI for the detection of CAD defined as ≥50% stenosis in 143 patients [29]. Image quality and defect resolution were good (Fig. 1). Compared with 99mTc SPECT, 18F-flurpiridaz PET was associated with higher diagnostic certainty of interpretation (defined as percentage of cases with definitively normal or abnormal interpretation) and sensitivity (61.5 vs. 78.8%, p = 0.02) [25]. Additional benefit of 18F-flurpiridaz is that a rest-treadmill exercise protocol was shown to be feasible [28] and has been applied in the phase II and III clinical studies. Myocardial extraction fraction of 18F-flurpiridaz is high (94%) and proportional to myocardial blood that makes 18F-flurpiridaz a good candidate for absolute quantification of MBF [25]. An experimental study showed good agreement between MBF measures obtained with 18F-flurpiridaz and microspheres over a wide range of regional MBF values (0.1–3.0 mL/min/g) in a pig model [30]. More recently, MBF values have been obtained in humans that were at similar level to the commonly accepted values obtained by other methods [31]. Thus, studies with 18F-flurpiridaz have shown encouraging results for implementation of this tracer in clinical PET myocardial perfusion imaging.

Fig. 1
figure 1

Myocardial perfusion images obtained with 18F-Flurpiridaz (FLUR) PET (top) and Tc-99m sestamibi (MIBI) SPECT (bottom). The 18F-Flurpiridaz images show a severe reversible perfusion defect throughout the territory of the occluded proximal left anterior descending coronary artery. The results of the phase II study demonstrated superior image quality, larger defect size, and better diagnostic certainty with 18F-Flurpiridaz PET than SPECT. Image reproduced with permission from ref. 29

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Assessment of viability and metabolism

Assessment of residual myocardial glucose uptake with 18F-fluorodeoxyglucose (18F-FDG) PET can be used to detect ischemic myocardium that is dysfunctional, but viable and has potential for recovery of contractile function after revascularization [2]. Viable myocardium shows preserved 18F-FDG uptake, whereas markedly reduced or absent uptake indicates scar formation. A preserved or increased uptake of 18F-FDG in the presence of reduced myocardial perfusion, known as flow-metabolism mismatch, is the most commonly used marker of hibernating myocardium that is capable of functional recovery after revascularization. 18F-FDG PET is the most sensitive technique to detect viability and it predicts functional recovery upon revascularization. A pooled analysis of 24 studies in 756 patients demonstrated a weighed mean sensitivity and specificity of 92 and 63%, respectively, for regional functional recovery, with positive predictive value of 74% and negative predictive value of 87% [32]. Retrospective studies have also indicated lower annualized mortality rates of those with viable myocardium who underwent revascularization (4%) versus those with viability who did not undergo revascularization (17%) [33].

The value of 18F-FDG PET in guiding decisions on revascularization was studied in a randomized trial that assigned 430 heart failure patients with an ejection fraction below 35% to either management assisted by 18F-FDG PET imaging or standard care [34]. The study overall showed only a nonsignificant trend toward reduction in cardiac events for 18F-FDG PET-assisted management versus standard care. However, the study observed long-lasting survival benefits for 18F-FDG PET-assisted management in the subgroup of patients whose treatment adhered to the recommendations by imaging [34, 35]. In a subsequent sub study of the PARR-2 data showed that the outcome benefit was related to the amount of hibernating myocardium seen [36]. Similarly, an observational study evaluating survival benefit from revascularization according to the extent of ischemic, scarred and viable myocardium found a significant interaction with the extent of hibernating myocardium, with a cutoff of >10% indicating survival benefit from revascularization [37].

The role of myocardial viability testing in clinical practice remains controversial [2, 34, 38]. Therapeutic decision-making is often difficult in patients with advanced CAD and severe left ventricular dysfunction due to high procedure-related risks. Therefore, there remains a role for viability imaging, but it is best utilized as an adjunct to decision making for complex patients (i.e., previous revascularization, multiple comorbidities) where both the risks and potential benefits of revascularization are the highest [2]. Viability testing among comprehensive evaluation of heart failure patients might help predict the response to revascularization in selected patients with CAD and left ventricle dysfunction and be a marker of prognosis. Current guidelines recommend the myocardial revascularization should be considered in patients with chronic ischemic heart failure with ejection fraction ≤35% in the presence of viable myocardium [1].

In addition to 18F-FDG, there are other tracers for the assessment of myocardial metabolism that have been used for evaluation of many medical and device therapies on metabolism of the failing heart [39, 40]. 11C-labeled acetate (11C-Acetate) allows robust non-invasive measurement of myocardial oxygen consumption in the left and right ventricles [39]. This provides the means to estimate the oxygen cost of contractility, the efficiency of myocardial forward work. The finding of decreased efficiency of myocardial forward work is a consistent and early finding in heart failure caused by different etiologies and that can be improved by therapy. 18F-fluoro-6-thia-heptadecanoicacid is a fatty acid analogue, the uptake of which reflects myocardial fatty acid utilization [40], whereas compounds such as 11C-palmitate reflect the flux of fatty acid metabolism through the cell including lipid pool storage, betaoxidation, and tricarboxylicacidcycle flux.

New tracers for myocardial infarction and remodeling

Repair following myocardial infarction is triggered by a complex interaction of neurohormonal activation and upregulation of local paracrine signaling mechanisms that initiate the restoration of capillary network through angiogenesis and extracellular matrix remodeling through macrophage accumulation and fibroblast activation [41,42,43]. The interplay of angiogenesis, inflammation, and fibrosis determines the restoration of myocardial integrity and eventually contributes to the degree of global remodeling and dysfunction of the left ventricle. New PET tracers targeting the molecular mechanisms underlying repair of myocardial injury have been studied as a potential markers of functional outcome after an acute myocardial infarction. Molecular imaging of the biological processes involved in myocardial remodeling can provide new biomarkers for early detection, evaluation of therapy response, and risk stratification of heart failure.

The αvβ3 integrin is a potential target for imaging angiogenesis and repair of myocardial injury. The αvβ3 integrin is a transmembrane cell surface receptor that facilitates interaction of cells with the ECM. Expression of αvβ3 is an essential mediator of angiogenesis and its expression is markedly upregulated during angiogenesis in the myocardium after infarction [44, 45]. In addition to the endothelium, it is expressed by both activated cardiac myofibroblasts and macrophages after myocardial infarction [45, 46]. Molecular imaging of αvβ3 is based on tracers that contain the RGD peptide subunit (the arginine-glycine-aspartate motif) that binds to activated αvβ3 integrin. Several PET tracers targeting αvβ3 integrin have been evaluated in experimental models of myocardial infarction [44, 46,47,48,49,50,51,52,53], some of them also tested in humans [7, 54,55,56,57]. In experimental and human studies of acute myocardial infarction, RGD-based radiotracers accumulate at the site of infarction as early as 3 days, peaking at 1–3 weeks after myocardial infarction and correlating with angiogenesis, infarct scar formation, and adverse remodeling (Fig. 2). A recent study evaluated prospectively αvβ3 integrin expression with 18F-Fluciclatide PET in 21 patients with recent myocardial infarction or chronic total coronary occlusion [7]. 18F-Fluciclatide uptake was increased at the site of acute infarction and the degree of uptake was associated with the probability of functional recovery. Imaging of αvβ3 integrin may be a potential biomarker to assess functional outcome of infarcted tissue after myocardial infarction and the effects of therapies aimed at accelerating repair after myocardial infarction, such as angiogenic gene therapy [3].

Fig. 2
figure 2

Images of myocardial αvβ3 integrin upregulation evaluated by 68Ga-DOTA-RGD PET after experimental myocardial infarction (MI) in rat. Autoradiographs of cross sections of the left ventricle show increased tracer uptake (green and red color) in the infarcted myocardium peaking at 1 week post-MI persisting at 4 weeks post-MI. Infarction is visible in the corresponding section stained with hematoxylin and eosin (HE). Micro-PET-CT images show increased tracer uptake in the anterolateral wall of the left ventricle (arrow) 1 week after infarction. Image adapted with permission from ref. 50

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Inflammatory response after myocardial infarction is another target of interest after myocardial infarction. Inflammatory cell imaging has been tested indirectly with metabolic markers 18F-FDG [58] and 11C-methionine [59] to predict functional recovery after myocardial infarction. Recent studies have used a new 68gallium (68Ga)-labeled PET tracer pentixafor that binds to CXCR4 chemokine receptor [60,61,62]. Paired CXCR4 and its ligand, SDF-1, regulate the migration of hematopoietic stem cells, as well as neutrophils and monocytes from bone marrow and spleen. In experimental and human myocardial infarction, pentixafor uptake was seen in the infarcted region early after the event, was blocked effectively by a CXCR4 inhibitor, and was substantially reduced by neurohumoral antagonists [60]. Pentixafor uptake showed high interindividual variability in patients [61], which may have implications for the response to CXCR4 or other inflammation-targeted therapy, and for subsequent ventricular remodeling.

Myocardial fibrosis is a common feature of left ventricle remodeling after myocardial infarction. Cardiac magnetic resonance (CMR) can provide quantitative measures of myocardial fibrosis, but PET approaches have been assessed to more specifically assess molecular mechanisms underlying fibrosis formation, such as matrix metalloproteinases and neurohormonal activation [42, 63, 64]. The activation of the renin-angiontensin-aldosterone system plays a role in activation of myofibroblasts and is an important mediator of myocardial fibrosis. Molecular imaging approaches targeting angiotensin receptors to measure angiotensin receptor activation have been studied extensively [42]. 11C-KR31173 is a specific and metabolically stable tracer for angiotensin receptor 1 [64]. The feasibility of in vivo imaging myocardial angiotensin receptor 1 with the use of 11C-KR31173 was shown in a pig model of chronic myocardial infarction and the radiotracer was well-tolerated also in humans [64]. Although clinical applications of new tracers for imaging myocardial infarction remain to be determined, studies have shown that molecular imaging of new targets can clarify pathogenesis of heart failure and be potentially useful to study effects of therapies.

New tracers for cardiac sympathetic innervation

Cardiac sympathetic imaging provides a non-invasive approach to risk-stratify patients with heart failure and at risk of sudden cardiac death [65, 66]. Alterations in cardiac sympathetic function occur early in the development of heart failure. Norepinephrine release from cardiac sympathetic nerves is increased and cardiac norepinephrine reuptake is decreased, which lead to elevated cardiac sympathetic tone. Currently, 123I-metaiodobenzylguanidine (123I-MIBG), an iodinated neurotransmitter analog, is commonly used for SPECT imaging of sympathetic function of the heart [66]. The neuronal uptake of 123I-MIBG in the heart is primarily by the norepinephrine transporter (NET), via an energy-dependent uptake 1 mechanism. Many studies have demonstrated that cardiac uptake of 123I-MIBG is lower in individuals with heart failure and indicate that 123I-MIBG can be used as an independent predictor of heart failure progression and cardiac mortality [66,67,68]. However, widespread application of 123I-MIBG imaging has been limited in part by suboptimal target-to-background activity and reliance on planar imaging for quantitation of myocardial activity relative to background mediastinal activity (heart-to-mediastinum ratio) or myocardial washout. Quantification of absolute regional or global myocardial uptake has been limited.

11C-metahydroxyephedrine (11C-HED) is a NET ligand that has been used for PET imaging of cardiac sympathetic function. In the Prediction of ARrhythmic Events with Positron Emission Tomography (PAREPET) trial, the extent of denervation assessed with quantitative 11C-HED PET was predictor of sudden cardiac arrest (arrhythmic death or intracardiac defibrillator shock for ventricular tachycardia >240/min or ventricular fibrillation) independently of ejection fraction, infarct volume, symptoms, and natriuretic peptide level in coronary artery disease patients who were candidates for an implantable cardiovertor defibrillator placement for primary prevention of sudden cardiac death [69]. A method for identifying heart failure patients with higher ejection fraction who are at hidden increased risk for lethal arrhythmias would be extremely useful as the vast majority of arrhythmic sudden cardiac death victims have minimal to no evidence specific to arrhythmic risk, but the absolute number of these patients is high [65, 66, 69]. However, widespread clinical imaging with 11C-HED has been limited by the short radioactive half-life (20 min) and the need for an on-site cyclotron.

N-[3-bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine (LMI1195) is a novel PET tracer developed for evaluation of sympathetic neuronal function in the heart [70]. This agent is a benzylguanidine analog, in the same class as MIBG, but labeled with 18F, a positron emitter having half-life of 120 min. The uptake of 18F-LMI1195 is NET-mediated in both rabbits and nonhuman primates and was decreased in rodent models of HF [7, 70, 71]. Experimental PET imaging studies with 18F-LMI1195 showed a favorable heart-to-liver ratio, compared with 123I-MIBG [70]. The initial first-in-human results of a multicenter single-dose phase I trial indicate that clinical imaging with 18F-LMI1195 is feasible for the assessment of regional myocardial sympathetic activity [72]. 18F-LMI1195 was well-tolerated and yielded a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. Myocardial uptake and adjacent organ activity suggest that good images should be possible with acceptable patient radiation dose. 18F-LMI1195 PET imaging provides a potentially quantitative approach for evaluation of both regional denervation and the heterogeneity of innervation, indices that may be predictive of sudden cardiac death. The tracer may offer advantages over evaluation of heart-to-mediastinal ratios in future studies of patients with heart disease.

Inflammatory cardiomyopathy and cardiac sarcoidosis

It has been estimated that approximately 5% of patients with sarcoidosis will have clinically manifest cardiac involvement presenting with one or more of ventricular arrhythmias, conduction abnormalities, and heart failure. Furthermore, another 20–25% of pulmonary/systemic sarcoidosis patients have asymptomatic cardiac involvement [73]. There has been a marked increase in the detection rate of cardiac sarcoidosis that is very likely due to improved diagnostic methods and their increased use [73, 74]. The diagnosis of cardiac sarcoidosis is confirmed when non-caseating granulomas are identified in cardiac or extracardiac tissue biopsies combined with clinical manifestations and/or findings on cardiac imaging indicative of myocardial involvement [73]. The sensitivity of endomyocardial biopsy is low due to focal nature of lesions in cardiac sarcoidosis [73, 74], but may be improved if sampling is targeted with the help of cardiac imaging [75].

PET imaging for the diagnosis and monitoring of cardiac involvement in sarcoidosis has been investigated and advanced significantly in recent years. Active inflammation in cardiac sarcoidosis is detected as patchy uptake of 18F-FDG that accumulates in inflammatory cells with high glucose uptake (Fig. 3). In a meta-analysis of seven diagnostic studies (164 patients with a prevalence of 50%), 18F-FDG PET had a sensitivity of 89% and a specificity of 78% for cardiac sarcoidosis [77]. The findings of cardiac PET have also prognostic implications in patients with suspected cardiac sarcoidosis. In a series of 118 patients with known or suspected cardiac sarcoidosis who underwent 82Rb perfusion and 18F-FDG PET imaging, abnormal perfusion and 18F-FDG uptake on PET imaging predicted 2.9-times increased risk of ventricular tachycardia and death compared with normal PET results during follow-up [78]. CMR and PET are both valuable in evaluation of sarcoidosis, because they show different aspects of the disease and the relative frequency of positive findings may vary depending on clinical presentation [79]. CMR provides high resolution for identifying the presence and extent of myocardial scar, whereas 18F-FDG PET is a sensitive marker of inflammatory disease activity and whole body distribution.

Fig. 3
figure 3

Imaging of myocardial inflammation in cardiac sarcoidosis with combined 18F-FDG PET (top) or 68Ga-DOTATOC PET (bottom) and delayed-enhancement magnetic resonance (DE-MR). Uptake of PET tracers reflecting inflammatory activity co-localizes with myocardial injury detected with DE-MR (arrows). 68Ga-DOTATOC PET image adapted with permission from ref. 76

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PET imaging for cardiac sarcoidosis requires patient preparation to suppress physiological myocardial glucose uptake since both normal myocytes and inflammatory cells take up glucose, and hence, 18F-FDG. Protocols to suppress physiological myocyte 18F-FDG uptake vary among studies, including prolonged fasting (12 h), high-fat and low-carbohydrate meals, and/or intravenous heparin [80]. The success of these strategies is also variable, and incomplete suppression of physiological myocardial 18F-FDG uptake may significantly impair diagnostic accuracy of PET [80]. Therefore, new tracers are sought to improve specificity of PET imaging for cardiac sarcoidosis [76, 81,82,83].

Normal macrophages and lymphocytes have somatostatin receptors that are overexpressed in granulomatous conditions such as sarcoidosis. In exploratory studies in patients with suspected cardiac sarcoidosis, somatostatin receptor targeted PET imaging with 68Ga-DOTANOC or 68Ga-DOTATOC has shown promising results in the detection of active cardiac lesions as compared with 18F-FDG PET or CMR (Fig. 3) [76, 81]. Since the myocardium does not display any physiologic somatostatin analogue uptake, tracer retention in the heart may be more specific than that of 18F-FDG. However, the value of new tracers for the detection and monitoring treatment response in cardiac sarcoidosis remains to be tested in larger prospective studies.

Conclusions and future directions

New tracers have potential to improve availability of PET myocardial perfusion imaging that is an established tool for evaluation of ischemic etiology and the extent of viable ischemic myocardium before revascularization in heart failure. Tracers targeting αvβ3 integrin, fibrosis, or inflammatory mediators may provide biomarkers to assess functional outcome and effect of therapies on tissue repair after myocardial infarction. Innervation imaging has been shown to predict heart failure progression and risk of lethal arrhythmias. New PET tracers may facilitate adoption of quantitative measures of global and regional sympathetic nerve function. There is a need for new and more specific tracers for the diagnosis of inflammatory cardiomyopathies and cardiac sarcoidosis, which is currently a diagnostic challenge. In addition to the assessment of prognosis and etiology, the value of new PET tracers will depend on studies demonstrating their ability to guide selection of therapies and incorporation into clinical management algorithms in heart failure.