Nuclear Tracers in Left Ventricular Hypertrophy

Guest Bloggers: 

Pranav Chandrashekar, MD

Ahmad Masri, MD MS

Radionuclide imaging with single photon emission computed tomography (SPECT) or positron emission tomography (PET) is widely used in cardiovascular disease, most commonly in the diagnosis and management of coronary artery disease (CAD), but the unique properties of certain tracers have expanded the utility of these tracers in other applications. The presence of left ventricular hypertrophy (LVH) is common in the general population and can be due to a variety of conditions ranging from hypertension and physiologic hypertrophy secondary to exercise, to other complex conditions such as hypertrophic cardiomyopathy (HCM) and cardiac amyloidosis (CA) [1,2]. LVH is associated with an increased risk of death regardless of the presence of CAD, particularly in those of African descent in whom LVH is more commonly identified [3,4]. Although commonly encountered, the effect of LVH on the performance of radionuclide imaging as well as the use of nuclear tracers in other conditions that present as LVH is not well described. Here we review radionuclide tracers and imaging in LVH.
Myocardial Perfusion in LVH
Relative myocardial blood flow distribution measured by SPECT are affected by attenuation and poor depth-dependent spatial resolution [5]. The heterogeneity of wall thickness in LVH can affect observed myocardial counts as the partial-volume effect causes thicker segments to appear more intense. There may also be perfusion defects due to decreased coronary vasodilator reserve in those with LVH but without obstructive epicardial CAD [6]. For these reasons interpretation can be difficult and could lead to diagnostic inaccuracies. This is reflected in the literature with conflicting evidence. In a study of 200 patients, half with LVH, Vaduganathan et al concluded that LVH does not impact 201Thallium (201Tl) stress SPECT results[7]. However, the applicability of these findings to other populations with significant LVH is unclear given the mean wall thickness was only 13 mm and the authors excluded patients with HCM, left bundle branch block, prior infarct or revascularization, and those with an LV ejection fraction less than 50%. This is in contrast to Schulman et al who noted that 29% of patients with hypertension with a low likelihood for CAD had an abnormal 201Tl scan, compared to 7% of normotensive patients [8]. More recently Ammann et al noted that out of 270 patients those with a positive 99mTechnetium-sestamibi (99mTc-MIBI) SPECT study and no obstructive epicardial CAD were more likely to have LVH [9]. In smaller studies of healthy young athletes with LVH, these false positives on SPECT were also present [10,11]. These issues with false positives were also attributed to microvascular dysfunction as well as conduction abnormalities associated with LVH in addition to technical issues mentioned above.

It has been shown that the sympathetic nervous system plays a role in the development of hypertension and subsequent LVH[12]. 123I-metaiodobenzylguanidine (MIBG) is a norepinephrine analogue that mimics its activity and location at with norepinephrine, which has translated non-invasive cardiac sympathetic imaging into the clinical field using SPECT [13]. Predominantly studied in Japan and Europe, abnormal uptake has been noted consistently in hypertensive patients irrespective of the presence of LVH, but also uptake correlates with degree of LVH using LV mass index[14,15]. There is also evidence that anti-hypertensive treatment can improve MIBG uptake, cardiac sympathetic activity, and may provide prognostic value[14]. PET tracers such as 11C-meta-hydroxyephedrine (11C-HED), 11C-epinephrine, or S-[11C]CGP 12177 may have a role, but they have not been studied in a rigorous fashion and more studies are needed to elucidate their role in clinical practice. Molecular imaging can also be used to study the underlying patho-biological basis of LVH in different scenarios. For example, Kjaer et al used N-13 ammonia (13N-NH3) PET imaging to show that patients with hypertension had higher baseline LV perfusion at rest, while athletes had a higher perfusion reserve suggesting LVH secondary to hypertension adapts for increased baseline workload [16].
Hypertrophic Cardiomyopathy
HCM is the most common inherited cardiomyopathy . Nuclear imaging is clinically applicable for the detection of ischemia (both epicardial CAD and microvascular dysfunction) as well as evaluation of abnormal sympathetic myocardial activity[17]. Chest pain is a frequent symptom among HCM patients, but it is not always clear whether the etiology is worsening LVOT obstruction, epicardial obstructive CAD, decreased coronary vasodilator reserve due to increased LV diastolic pressure, or reduced capillary density relative to regional myocardial hypertrophy. MPI can be used with SPECT or PET with or without cardiac magnetic resonance imaging (CMR). Reversible abnormalities on MPI do represent areas of myocardial ischemia in HCM and abnormal SPECT MPI despite normal coronary angiography can help identify HCM patients at increased risk of death [18,19]. However, myocardial perfusion SPECT imaging in HCM may have unique artifacts that should be kept in mind during interpretation. Care should be taken in reviewing both rest and stress images as the septal hypertrophy might mask regional hypoperfusion during stress if one does not take into account the changing septum:lateral walls count ratio between rest and stress [20]. Conversely one should be cautious of “hot spots”, which are localized areas of increased activity frequently seen in the septum of HCM patients. Areas adjacent to this may appear relatively less intense after normalization, creating spurious perfusion defects. These issues are why some have suggested CT coronary angiography as the preferred first modality for epicardial CAD assessment in HCM [21]. SPECT imaging may also be used to identify the location and extent of myocardial infarction after alcohol septal ablation [22]. PET tracers such as 13N-NH3 or 15O-H2O with CMR imaging are useful as it is able to quantify myocardial blood flow, a surrogate for microvascular health and function[23]. Studies suggest that myocardial blood flow is not affected by LVOT gradient[24,25]. Assessment of microvascular dysfunction with PET can be prognostic in HCM as demonstrated by Cecchi et al who noted that reduced myocardial blood flow is highly associated with risk of cardiovascular death[25].
Finally, abnormal sympathetic activity measured with 123I-MIBG SPECT uptake in HCM has been associated with an increased rate of ventricular tachyarrhythmias [26], suggesting a role for risk stratification for primary prevention with an internal cardioverter-defibrillator These repeated observations reveal the complex interplay between autonomic dysfunction and different cardiac diseases.

Cardiac Amyloidosis
Nuclear tracers in cardiac amyloidosis were covered in a previous ASNC blog post [27].

Fabry Disease
Fabry Disease (FD) is an X-linked inborn error of the glycosphingolipid metabolic pathway that leads to the most prevalent lysosomal storage disorder. The predominant cardiac manifestation is LVH due to lipid accumulation. Interestingly it was noted that 123I-MIBG SPECT uptake is reduced in the inferolateral LV wall, prior to the onset of LVH and fibrosis [28]. A possible explanation might be the predominant innervation of the inferior wall by parasympathetic nerves and less by sympathetic nerves, as compared to the antero-septal wall. Thus, it is possible that sympathetic nerves in the inferior wall are more easily depleted in the early stages of FD [29]. Myocardial fatty acid metabolism is a major energy-producing mechanism in the myocardium during fasting. 123I-β-methyl 15-para-iodophenyl 3(R,S)-methyl pentadecanoic acid (123I-BMIPP) is a single-photon branching free fatty acid compound with slow metabolism that has the potential to allow early detection of myocardial energy alterations and the assessment of tissue viability[30]. In 18 FD patients it was found that 123I-BMIPP was a better prognostic determinant of major cardiovascular events compared to 201Thallium SPECT imaging[31]. This demonstrated that the severity of impairment of myocardial fatty acid metabolism, rather than of myocardial perfusion, was associated with a poor prognosis. However comprehensive CMR assessment with parametric mapping is the cornerstone of evaluation of FD nowadays [32].

LVH is commonly encountered in cardiovascular practice and requires a thorough evaluation for both accurate diagnosis and optimal subsequent management. Molecular imaging holds promise in understanding disease patho-biology which can be useful in clinical practice. However, in LVH, molecular imaging has largely been under-investigated and under-utilized. Perhaps the recent example of the imaging revolution that has occurred with cardiac amyloidosis represents a window into the opportunities and the massive return on investment in these new areas.

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Author Biographies 
Dr. Chandrashekar is a PGY-4 cardiac amyloidosis fellow at the Knight Cardiovascular Institute, Oregon Health and Science University in Portland, Oregon. @pranavc91

Dr. Masri is the Director of the Hypertrophic Cardiomyopathy Center, Oregon Health and Science University in Portland, OR. (@masriahmadmd