Molecular Imaging to Monitor Left Ventricular Remodeling in Heart Failure
Purpose of Review
Cardiovascular diseases are the leading cause of deaths worldwide. Many complex cellular and molecular pathways lead to myocardial remodeling after ischemic insults. Anatomy, function, and viability of the myocardium can be assessed by modern medical imaging techniques by both visualizing and quantifying damages. Novel imaging techniques aim for a precise and accurate visualization of the myocardium and for the detection of alternations at the molecular level.
Magnetic resonance imaging assesses anatomy, function, and tissue characterization of the myocardium non-invasively with high spatial resolution, sensitivity, and specificity. Using hyperpolarized magnetic resonance imaging, molecular and metabolic conditions can be assessed non-invasively. Single photon-emission tomography and positron-emission tomography are the most sensitive techniques to detect biological processes in the myocardium. Cardiac perfusion, metabolism, and viability are the most common clinical targets. In addition, molecular-targeted imaging of biological processes involved in heart failure, such as myocardial innervation, inflammation, and extracellular matrix remodeling, is feasible.
Novel imaging techniques can provide a precise and accurate visualization of the myocardium and for the detection of alternations at molecular level.
KeywordsMyocardium Infarction MRI Hyperpolarized MRI PET SPECT
To image heart function, ultrasound and computed tomography (CT) are applied besides the above mentioned techniques [3, 15, 16]. Nuclear medicine imaging techniques, namely PET and SPECT, are used to measure changes in perfusion, metabolism, and molecular pathways at the cellular level during the remodeling . Tracer molecule owing a capability to bind into defined receptor or other molecule steers radionuclide or other compound which enhances image contrast into target tissue . Although tracers have been developed for MRI and SPECT, the most sensitive technique is still PET . To add sensitivity of MRI, novel techniques based on hMRI have been developed which have enabled imaging of the cell cycle and cell metabolism [18•].
Cardiac magnetic resonance imaging (cMRI) contains a wide variety of options to study cardiac anatomy, function, infarct scar, and fibrosis and to characterize the myocardium by relaxation time mapping, perfusion, water diffusion, wall movement, and myocardial stiffness [19, 20]. cMRI is currently the golden standard to assess anatomy and function of the myocardium non-invasively with high spatial resolution and accuracy [3, 15, 16].
The anatomy and functional images from the LV are typically imaged by acquiring rapidly either with multiple 2D- or 3D-cine images that are covering the whole heart during more than 95% of the cardiac cycle . Images allow the accurate determination of end diastolic volume (EDV) and end systolic volume (ESV) which are further used to calculate ejection fraction (EF), stroke volume (SV), and cardiac output (CO) [3, 12, 15, 16, 22]. Reduced EF together with increased EDV and decreased myocardial thickness are the clearest signs of reduced systolic function and remodeling [12, 13, 15, 23, 24]. Additionally, EF and EDV have been shown to increase as a function of time after MI reperfusion in human , swine , and mice . As LV becomes globally thinner, MI scar tissue expands and causes extra workload in the LV, hypertrophy, and expansion of the healthy myocytes to maintain CO [12, 27]. Recently, texture analysis applied on MRI cine images was demonstrated to differentiate nonviable and viable MI areas and remote areas of the myocardium . Texture analysis finds the patterns and relationships among pixels from heterogeneities within the imaging target .
There are also several other methods to study anatomy and function of the heart. Bright-blood technique is used for the detection of hemorrhage in the myocardium  whereas dark-blood technique is used to improve the discrimination of myocardium and adjacent blood pool revealing small areas of MI in the endocardium . Myocardial tagging is an imaging technique which assesses the motion and deformation of LV myocardium with good temporal and spatial resolution . Therefore, myocardial deformation and motion stiffness caused by MI and fibrosis can be detected by myocardial tagging [32, 33]. Feature tracking is a novel image analysis technique for myocardial tagging that was shown to be a feasible and robust technique to detect LV motion where data analysis is faster compared to myocardial tagging .
Contrast Agent Imaging: Late Gadolinium Enhancement and Extracellular Volume
Feasibility of conventional parametric mapping methods in different diseases and tissue characteristics
Conventional Relaxation Times
Visualization of the myocardial tissue and detection of both acute and chronic MI can be done without CA. These techniques offer quantitative assessment of the alternations in the composition of myocardial tissue based on intrinsic water properties, longitudinal T1 [7••, 42, 43] and transversal T2 relaxations [42, 44], to generate contrast within the myocardium . T1-weighted images are typically used for anatomical imaging and T2-weighted images for edema and imaging of transient ischemia (Table 1) . T1 and T2 relaxations can be mapped by acquiring multiple relaxation weighted images and by fitting a curve to signal intensities pixel-by-pixel manner to form relaxation time maps [35, 44, 46]. Both T1 and T2 mapping also allow visualization and quantification of global changes in the myocardium (Table 1) [11, 44, 46].
T1 relaxation time is elevated during MI development [6, 10, 38, 39, 47] and it has been shown to distinguish between reversible and irreversible damages in post ST-elevation MI (STEMI) [22, 48, 49]. In chronic MI, native T1 relaxation times are lower than in acute MI because edematous and necrotic tissues in the acute MI are replaced by smaller amounts of expanded extracellular collagen [7••, 50]. Therefore, T1 mapping can be used for diagnostic purposes to detect different pathological states in the myocardium (Table 1) [6, 39, 40].
T2 relaxation determines edema via increased T2 relaxation time resulting from an increased amount of interstitial free water . Therefore, T2 relaxation time is suitable for the determination of the area at risk in acute MI [6, 28, 40]. However, T2 suffers from a poor contrast-to-noise ratio compared to T1 and longitudinal rotating frame relaxation time (T1ρ) . T2* relaxation time can be chosen when myocardial iron content is used to detect myocardial hemorrhage since T2* relaxation time is more sensitive for magnetic susceptibilities than T2 due to the accumulated iron content (Table 1) [15, 28, 40, 52].
T 1ρ Relaxation Time
Another advanced technique is based on the mapping of a longitudinal rotating frame relaxation time (T1ρ) which measures relaxation during a radiofrequency (RF) pulse [42, 53]. T1ρ relaxation is sensitive to slow molecular motions (range of 0.1 to 10 kHz in vivo compared to fast molecular motions at Larmor frequency at 10–500 MHz which are used in T1 and T2 relaxation time measurements) [7••]. In general, T1ρ relaxation time is always between T1 and T2 relaxation times approaching T2 when spin-lock pulse power nears zero . Increased T1ρ relaxation time associates with increased extracellular volume and fibrotic area in MI [37, 53] and correlates with LGE in mice (Fig. 2) [7••, 54], pigs , and humans  after MI. One limitation of the T1ρ relaxation time mapping in clinics is the relatively high specific absorption rate (SAR) causing tissue heating [7••].
Relaxation Along Fictitious Field
Relaxation along a fictitious field (RAFF) in the nth rotating frame (RAFFn) is a novel MRI relaxation time technique to perform rotating frame relaxation time measurements with less SAR [7••, 56, 57••, 58••]. RAFF takes advantage of the fictitious magnetic field which is produced by a fast sweep of the effective RF field [56, 57••]. Advantages of the low SAR become more evident when RAFF in the higher rank (n) rotating frames (RAFFn), an extension of RAFF, is used. Typically, n varies between 1 and 5 in imaging applications [56, 57••]. The contrast between MI and remote areas has been demonstrated with RAFFn technique in mice and the MI area was equally accurately detected as with T1ρ, LGE, and histology (Fig. 2) [7••]. TRAFFn relaxation times are also elevated and more sensitive than T1ρ in the detection of fibrotic area in the hypertrophic myocardium in mice .
Other MRI Techniques
Myocardial perfusion gives useful information about capillary blood flow in the myocardium. Myocardial perfusion can be measured without CA by techniques of arterial spin labeling  and blood oxygen level-dependent contrast . CA is used in myocardial angiography, where blood flow inside coronary arteries can be measured since the blood flow is alternated in the area of MI compared to the surrounding heart muscle . CA-MRA has also been used to determine microvascular obstruction in swine acute MI model with high accuracy [22, 71]. Increased ECV, loss of cardiomyocytes and therefore loss of orientational structure, increases water diffusion in MI compared to the rest of the myocardium  which can be imaged with the diffusion weighted MRI . Diffusion tractography,  measuring the orientation of cardiomyocytes, has grown in the CMRI field since diffusion tractography was introduced in rat MI model ; MI area is disturbing the normal form of crossing helical fiber architecture of normal myocytes. Bright-blood, which is gradient-echo based and black-blood, which is a spin-echo based, T2-weighted sequence, can be used to assess myocardial structure, acute MI and ischemic areas with good accuracy in patients [15, 75]. Stiffness of MI area and the rest of the myocardium is also studied by MRI elastography where the MI area is discriminated from the rest of the myocardium by the difference between the motion stiffness of those areas (MI, 4.6 ± 0.7 kPA; healthy, 3.0 ± 0.6 kPA) [73, 76]. Moreover, cMRI has an ability to determine with great accuracy mitral valve  and aortic valve  malfunctions, which often occur as MI develops and therefore imaging the function of mitral and aortic valves might give additional information about the heart’s condition .
SPECT and PET
SPECT and PET represent nuclear imaging techniques that enable mapping of radiotracer concentration and kinetics in the myocardium with very high sensitivity . Improvement in PET and SPECT imaging technology has led to the evolution of imaging beyond the isolated assessment of myocardial perfusion, toward molecular-targeted imaging of biological processes involved in heart failure, such as myocardial metabolism, innervation, inflammation, and extracellular matrix remodeling. PET and SPECT scanners are increasingly integrated with either CT or MRI systems into PET-CT or PET-MRI hybrid imaging devices, which facilitate the localization of a molecular signal, by fusion with high resolution morphologic images .
Myocardial perfusion imaging with SPECT or PET enables 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 . In addition to the assessment of relative distribution to the 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 in multi-vessel disease, detect balanced decreases of MBF in all major coronary artery vascular territories, and provide prognostic information beyond regional myocardial ischemia [82, 83]. Reduced CFR is a typical feature of a cardiomyopathic heart as a consequence of microvascular dysfunction even in the absence of epicardial CAD [84, 85]. 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 ischemic and dilated cardiomyopathy [84, 85].
The value of 18F-FDG PET in guiding decisions on revascularization assigned 430 heart failure patients with an ejection fraction below 35% to either management assisted by 18F-FDG PET imaging or standard care . Although the study overall showed only a nonsignificant trend toward reduction in cardiac events for 18F-FDG PET assisted management, 18F-FDG PET assisted management improved outcomes in the subgroup of patients whose treatment adhered to the recommendations by imaging [89, 90], especially in patients with a large amount of hibernating myocardium . Similarly, an observational study evaluating survival benefit from revascularization according to the extent of ischemic, scarred, and viable myocardium found survival benefit from revascularization in patients with hibernating myocardium > 10% of the left ventricle . Current guidelines recommend that myocardial revascularization should be considered in patients with chronic ischemic heart failure with ejection fraction ≤ 35% in the presence of viable myocardium .
In addition to 18F-FDG, there are other PET tracers for the assessment of different aspects of myocardial metabolism [94, 95]. 11C-labeld acetate (11C-acetate) allows robust non-invasive measurement of myocardial oxygen consumption in the left and right ventricles independently of the substrate utilization . 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 cardiomyopathy caused by different etiologies . Myocardial substrate metabolism can be studied in detail by fatty acid analogs, such as 18F-fluoro-6-thia-heptadecanoicacid or 11C-palmitate. The former reflects myocardial fatty acid utilization, whereas the latter reflects the flux of fatty acid metabolism through the cell including lipid pool storage, beta-oxidation, and tricarboxylic acid cycle . Imaging of myocardial metabolism with PET has been used for evaluation of many medical and device therapies on the metabolism of the failing heart [94, 95].
Cardiac Sympathetic Innervation
Cardiac sympathetic imaging provides a non-invasive approach to assess alterations in cardiac sympathetic nerve function in cardiomyopathies [96, 97]. Heart failure is associated with an increased sympathetic tome characterized by increased release and decreased reuptake of norepinephrine by cardiac sympathetic nerve endings. Currently, cardiac sympathetic function is most commonly evaluated by SPECT imaging with 123I-metaiodobenzylguanidine (123I-MIBG), an iodinated neurotransmitter analog . Uptake of 123I-MIBG in the heart is primarily mediated by the norepinephrine transporter (NET), an energy-dependent uptake mechanism. Cardiac uptake is usually measured relative to background mediastinal activity in planar images (heart-to-mediastinum ratio). Many studies have demonstrated that cardiac uptake of 123I-MIBG is reduced in individuals with heart failure and indicate that 123I-MIBG can be used as an independent predictor of heart failure progression and cardiac mortality [96, 97, 98, 99].
11C-Metahydroxyephedrine (11C-HED) is a NET ligand that has been used for PET imaging of cardiac sympathetic function. Compared with SPECT, PET imaging provides a quantitative measure of sympathetic nerve function and identifies regional heterogeneity of innervation. The extent of reduced neural activity assessed with quantitative 11C-HED PET has been shown to be a predictor of sudden cardiac arrest independently of EF, infarct volume, symptoms, and natriuretic peptide levels in CAD patients who were candidates for an implantable cardioverter defibrillator placement for primary prevention of sudden cardiac death . Despite benefits in terms of quantification and assessment of regional distribution, widespread clinical imaging with 11C-HED has been limited by the short radioactive half-life (20 min) and the need for an onsite cyclotron. N-[3-Bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine (LMI1195) is a novel PET tracer that has been recently evaluated for evaluation of cardiac sympathetic neuronal function in man [101, 102]. Like MIBG, this agent is a benzylguanidine analog, but labeled with 18F. 18F has a radioactive half-life of 120 min that would allow distribution to sites without an onsite cyclotron.
New Tracers for MI and Remodeling
New PET and SPECT tracers targeting the molecular mechanisms underlying repair of myocardial injury have been studied as potential markers of functional outcome after an acute MI . Molecular imaging of the cellular mechanisms of myocardial remodeling can potentially provide new biomarkers for early detection, risk stratification, and evaluation of response to therapy in heart failure.
Inflammatory response after MI is another target that has been studied for predicting functional recovery after MI. Studies have shown increased myocardial uptake of metabolic markers 18F-FDG  and 11C-methionine  reflecting inflammatory activity after recent MI. Uptake of 18F-FDG early after an acute MI inversely correlated with the degree of functional recovery . Pentixafor is a novel 68Ga-labeled PET tracer that binds to CXCR4 chemokine receptor mediating leukocytes accumulation at the sites of inflammation [120, 121, 122]. In experimental and human MI, increased pentixafor uptake was detected by PET in the infarcted tissue early after injury. After the initial pro-inflammatory phase, cells that promote tissue repair are the major inflammatory cell population in the infarcted myocardium [123, 124]. Molecular imaging may help to understand time course and contributions of the pro- and anti-inflammatory mechanisms after MI.
Other radionuclide imaging approaches have been evaluated to assess molecular mechanisms underlying myocardial fibrosis, such as activation of matrix metalloproteinases [125, 126, 127] and activation of the renin-angiotensin-aldosterone system [128, 129]. Molecular imaging with a radiolabeled ligand of the angiotensin receptor 1, 11C-KR31173, demonstrated changes in myocardial expression of angiotensin receptor 1 in a pig model of chronic MI and the radiotracer was tolerated also in humans . Although new tracers for imaging MI are in a relatively early stage of development, studies have already shown that molecular imaging of the new targets can clarify pathogenesis of heart failure and be potentially useful to study effects of therapies.
Anatomy, function, and viability of the myocardium can be assessed by modern medical imaging techniques by both visualizing and quantifying damages. Novel imaging techniques are capable of precise and accurate visualization of the myocardium and detection of alternations at molecular level. Magnetic resonance imaging assesses the myocardium non-invasively with high spatial resolution and high contrast between myocardium and blood, cardiac function and tissue characterization of the myocardium. Molecular and metabolic conditions can also be assessed non-invasively with novel hyperpolarized magnetic resonance imaging. Single photon-emission tomography and positron-emission tomography are the most sensitive techniques to detect biological processes, including cardiac perfusion, metabolism, and viability in the myocardium.
This study has been supported by the Finnish Academy Center of Excellence, Instrumentarium Science Foundation, Finnish Foundation for Cardiovascular Research, and Finnish Heart Foundation.
Open access funding provided by University of Eastern Finland (UEF) including Kuopio University Hospital.
Compliance with Ethical Standards
Conflict of Interest
Elias Ylä-Herttuala, Antti Saraste, Juhani Knuuti, Timo Liimatainen, and Seppo Ylä-Herttuala1declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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