Nuclear Tracers in Left Ventricular Hypertrophy

• By: admin
• On: 06/21/2021 10:54:00
• In: Membership

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.

Hypertension
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].

Conclusion
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.


References
1.           Schirmer H, Lunde P, Rasmussen K. Prevalence of left ventricular hypertrophy in a general population; The Tromsø Study. Eur Heart J 1999;20:429-38. https://doi.org/10.1053/euhj.1998.1314
2.           Cuspidi C, Sala C, Negri F, Mancia G, Morganti A, on behalf of the Italian Society of H. Prevalence of left-ventricular hypertrophy in hypertension: an updated review of echocardiographic studies. J Hum Hypertens 2012;26:343-9. https://doi.org/10.1038/jhh.2011.104
3.           Liao Y, Cooper RS, McGee DL, Mensah GA, Ghali JK. The Relative Effects of Left Ventricular Hypertrophy, Coronary Artery Disease, and Ventricular Dysfunction on Survival Among Black Adults. JAMA 1995;273:1592-7. https://doi.org/10.1001/jama.1995.03520440046035
4.           Ghali JK, Liao Y, Simmons B, Castaner A, Cao G, Cooper RS. The prognostic role of left ventricular hypertrophy in patients with or without coronary artery disease. Ann Intern Med 1992;117:831-6. https://doi.org/10.7326/0003-4819-117-10-831
5.           Jaber WA, DiFilippo FP, Cerqueira MD. Left ventricular hypertrophy and SPECT myocardial perfusion imaging: finding the diamonds in the rough. J Nucl Cardiol 2007;14:398-407. https://doi.org/10.1016/j.nuclcard.2007.04.012
6.           Houghton JL, Frank MJ, Carr AA, von Dohlen TW, Prisant LM. Relations among impaired coronary flow reserve, left ventricular hypertrophy and thallium perfusion defects in hypertensive patients without obstructive coronary artery disease. J Am Coll Cardiol 1990;15:43-51. https://doi.org/10.1016/0735-1097(90)90173-m
7.           Vaduganathan P, He Z-X, Mahmarian JJ, Verani MS. Diagnostic Accuracy of Stress Thallium-201 Tomography in Patients With Left Ventricular Hypertrophy. The American Journal of Cardiology 1998;81:1205-7. https://doi.org/https://doi.org/10.1016/S0002-9149(98)00091-5
8.           Schulman DS, Francis CK, Black HR, Wackers FJ. Thallium-201 stress imaging in hypertensive patients. Hypertension 1987;10:16-21. https://doi.org/doi:10.1161/01.HYP.10.1.16
9.           Ammann P, Naegeli B, Rickli H, et al. Characteristics of patients with abnormal stress technetium Tc 99m sestamibi SPECT studies without significant coronary artery diameter stenoses. Clin Cardiol 2003;26:521-4. https://doi.org/10.1002/clc.4960261109
10.         Bartram P, Toft J, Hanel B, et al. False-positive defects in technetium-99m sestamibi myocardial single-photon emission tomography in healthy athletes with left ventricular hypertrophy. Eur J Nucl Med 1998;25:1308-12. https://doi.org/10.1007/s002590050300
11.         Amanullah AM, Berman DS, Kang X, Cohen I, Germano G, Friedman JD. Enhanced prognostic stratification of patients with left ventricular hypertrophy with the use of single-photon emission computed tomography. Am Heart J 2000;140:456-62. https://doi.org/https://doi.org/10.1067/mhj.2000.108833
12.         Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res 2014;114:1804-14. https://doi.org/10.1161/circresaha.114.302524
13.         Raffel DM, Wieland DM. Development of mIBG as a cardiac innervation imaging agent. JACC Cardiovasc Imaging 2010;3:111-6. https://doi.org/10.1016/j.jcmg.2009.09.015
14.         Sakata K, Shirotani M, Yoshida H, Kurata C. Comparison of effects of enalapril and nitrendipine on cardiac sympathetic nervous system in essential hypertension. J Am Coll Cardiol 1998;32:438-43. https://doi.org/10.1016/s0735-1097(98)00261-7
15.         Morimoto S, Terada K, Keira N, et al. Investigation of the relationship between regression of hypertensive cardiac hypertrophy and improvement of cardiac sympathetic nervous dysfunction using iodine-123 metaiodobenzylguanidine myocardial imaging. Eur J Nucl Med 1996;23:756-61. https://doi.org/10.1007/bf00843703
16.         Kjaer A, Meyer C, Wachtell K, et al. Positron Emission Tomographic Evaluation of Regulation of Myocardial Perfusion in Physiological (Elite Athletes) and Pathological (Systemic Hypertension) Left Ventricular Hypertrophy. The American Journal of Cardiology 2005;96:1692-8. https://doi.org/https://doi.org/10.1016/j.amjcard.2005.07.090
17.         Delgado V, Bax JJ. Clinical topic: Nuclear imaging in hypertrophic cardiomyopathy. J Nucl Cardiol 2015;22:408-18. https://doi.org/10.1007/s12350-014-0054-7
18.         Cannon RO, 3rd, Dilsizian V, O'Gara PT, et al. Myocardial metabolic, hemodynamic, and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy. Circulation 1991;83:1660-7. https://doi.org/10.1161/01.cir.83.5.1660
19.         Sorajja P, Chareonthaitawee P, Ommen SR, Miller TD, Hodge DO, Gibbons RJ. Prognostic utility of single-photon emission computed tomography in adult patients with hypertrophic cardiomyopathy. Am Heart J 2006;151:426-35. https://doi.org/10.1016/j.ahj.2005.02.050
20.         Loong CY, Reyes E, Underwood SR. Significant inducible perfusion abnormality in an asymptomatic patient with hypertrophic cardiomyopathy demonstrated by radionuclide myocardial perfusion imaging. Heart 2003;89:989-. https://doi.org/10.1136/heart.89.9.989
21.         Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-79. https://doi.org/10.1093/eurheartj/ehu284
22.         Keng FY, Chang SM, Cwajg E, et al. Gated SPECT in patients with hypertrophic obstructive cardiomyopathy undergoing transcoronary ethanol septal ablation. J Nucl Cardiol 2002;9:594-600. https://doi.org/10.1067/mnc.2002.125997
23.         Lee DC, Johnson NP. Quantification of absolute myocardial blood flow by magnetic resonance perfusion imaging. JACC Cardiovasc Imaging 2009;2:761-70. https://doi.org/10.1016/j.jcmg.2009.04.003
24.         Bravo P, Pinheiro A, Higuchi T, et al. PET/CT Assessment of Symptomatic Individuals with Obstructive and Nonobstructive Hypertrophic Cardiomyopathy. The Journal of Nuclear Medicine 2012;53:407 - 14.
25.         Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary Microvascular Dysfunction and Prognosis in Hypertrophic Cardiomyopathy. N Engl J Med 2003;349:1027-35. https://doi.org/10.1056/NEJMoa025050
26.         Terai H, Shimizu M, Ino H, et al. Cardiac sympathetic nerve activity in patients with hypertrophic cardiomyopathy with malignant ventricular tachyarrhythmias. J Nucl Cardiol 2003;10:304-10. https://doi.org/10.1016/S1071-3581(03)00362-3
27.         PET Tracers in Cardiac Amyloidosis. 2020. at https://www.asnc.org/blog_home.asp?Display=426.)
28.         Spinelli L, Pellegrino T, Pisani A, et al. Relationship between left ventricular diastolic function and myocardial sympathetic denervation measured by (123)I-meta-iodobenzylguanidine imaging in Anderson-Fabry disease. Eur J Nucl Med Mol Imaging 2016;43:729-39. https://doi.org/10.1007/s00259-015-3273-5
29.         Yamamoto S, Suzuki H, Sugimura K, et al. Focal Reduction in Cardiac ¹²³I-Metaiodobenzylguanidine Uptake in Patients With Anderson-Fabry Disease. Circ J 2016;80:2550-1. https://doi.org/10.1253/circj.CJ-16-0690
30.         Naruse H, Arii T, Kondo T, et al. Clinical usefulness of iodine 123-labeled fatty acid imaging in patients with acute myocardial infarction. J Nucl Cardiol 1998;5:275-84. https://doi.org/10.1016/S1071-3581(98)90129-5
31.         Haga T, Okumura T, Isobe S, et al. Potential prognostic implications of myocardial thallium-201 and iodine-123-beta-methylpentadecanoic acid dual scintigraphy in patients with Anderson-Fabry disease. Ann Nucl Med 2019;33:930-6. https://doi.org/10.1007/s12149-019-01406-0
32.         Germain DP, Fouilhoux A, Decramer S, et al. Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients. Clin Genet 2019;96:107-17. https://doi.org/10.1111/cge.13546
 

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)