Fully Automated Pixel-Wise Quantitative Magnetic Resonance Stress Myocardial Perfusion Evaluation of Chest Pain in a Patient with Hypertrophic Cardiomyopathy

Seth Klusewitz, MD¹, Marcus Chen, MD² Peter Kellman, PhD³ Edward Hulten, MD MPH⁴

¹Uniformed Services University School of Medicine and Walter Reed National Military Medical Center, Bethesda, MD, USA
²Advanced Cardiovascular Imaging Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
³National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
⁴Division of Cardiology, Department of Medicine, Alpert Medical School of Brown University, Providence, RI, USA

Clinical History

A 66-year-old African American woman with hypertension, hyperlipidemia, and obesity presented to cardiology clinic for the assessment of exertional dyspnea and typical anginal chest pain. She had no significant family history of cardiac disease. Electrocardiogram (ECG) revealed sinus rhythm and left ventricular hypertrophy. An echocardiogram was obtained (Figure 1) that showed diffuse moderate to severe myocardial thickening most prominent at the basal anteroseptum (1.7cm). There was no systolic anterior motion of the mitral leaflet. Exercise echocardiography did not identify resting or inducible left ventricular outflow tract gradient (Figure 2) and no evidence for resting or exercise induced regional wall motion. After additional anginal episodes over time, she underwent exercise 99-Tcm single photon emission computed tomography (SPECT) myocardial perfusion imaging that demonstrated normal myocardial perfusion with no ischemia or infarct and normal left ventricular systolic function. Due to significant exertional limitations and the possibility for false negative SPECT imaging, she underwent coronary computed tomography angiography that demonstrated no identifiable coronary plaque or stenosis. Ambulatory cardiac monitoring excluded arrhythmia.

Recent American College of Cardiology / American Heart Association chest pain guidelines[1] recommend to consider evaluation of quantitative blood flow, thus the possibility of microvascular ischemia secondary to increased myocardial mass and microvascular angiopathy was entertained and she was referred to a research study at the National Institutes of Health for novel dual sequence quantitative regadenoson (Astellas pharmaceuticals, Northbrook, IL) stress perfusion CMR.

Figure 1. Echocardiogram demonstrating diffuse myocardial thickening most prominent at the basal anteroseptum.

Figure 2. Exercise echocardiography demonstrating absence of left ventricular outflow tract gradient.

CMR Findings

CMR was conducted using a 1.5T scanner (Magnetom Aera, Siemens AG, Erlangen, Germany) with an 18-channel receiver coil and 32-channel spinal coil. Short-axis and long-axis cine and late gadolinium enhancement (LGE) imaging were acquired. Given the persisting symptoms of typical angina and clinical potential for angina without obstructive coronary arteries (ANOCA) among patients with suspected hypertrophic cardiomyopathy (HCM), she consented to research acquisition of dual-sequence[2, 3] vasodilator stress
perfusion myocardial imaging at the time of CMR.

Rest CMR demonstrated severe, asymmetric thickening of the basal to mid septal myocardium, measuring up to 2.0cm at the mid-inferoseptum. CMR was normal for LVEDVI 73 ml/m², LVESVI 28 ml/m², LVSV 85 ml, and LVEF 62% with moderately increased global myocardial mass index 79 m/m² (Movie 1). There was diffuse, patchy late gadolinium enhancement (LGE) in a pattern consistent with fibrosis due to HCM. No ventricular outflow acceleration or mitral regurgitation was present. CMR also demonstrated LGE (Figure 3) of 17% myocardial mass by full width half maximum method.

Movie 1. Cine balanced steady state free precession (bSSFP) four chamber showing severe hypertrophy of the basal to mid septal wall with normal left ventricular systolic function. No qualitative left ventricular outflow acceleration or mitral valve dysfunction is appreciated.

Figure 3. Short-axis inversion recovery images demonstrating enhancement of 17% left-ventricular mass.

Rest perfusion was normal (Movie 2). Qualitative evaluation of stress CMR perfusion images demonstrated diffuse subendocardial ischemia potentially consistent with microvascular ischemia (Movie 3). Fully automated pixel-wise quantitative CMR stress myocardial perfusion imaging maps (Figures 4 – 6) demonstrated absolute reduced stress myocardial blood flow (MBF) of 1.21 ml/min/g (normal >2.25, global)[3, 4] and reduced myocardial flow reserve (MFR) 1.64 (normal >2.0), indicative
of diffuse microvascular ischemia. The ratio of endocardial to epicardial stress MBF was 0.66 (normal >1.0, global)[5] versus rest 1.03, also indicative of diffuse microvascular ischemia (Figure 7).

Movie 2. Normal rest short axis stack (basal, mid, apical) first pass myocardial perfusion images using dual sequence with bSSFP readout of the myocardium.

Movie 3. Short axis stack (basal, mid, apical) regadenoson vasodilator stress first pass myocardial perfusion images using dual sequence with bSSFP readout of the myocardium. Diffuse subendocardial perfusion defect is potentially consistent with microvascular ischemia.

Figure 4. Pixel-Wise Quantitative CMR Stress Myocardial Perfusion Imaging maps indicative of diffuse microvascular ischemia.

Figure 5. Reduced absolute stress myocardial blood flow (MBF) of 1.21 ml/min/g (normal >2.25, global).

Figure 6. Reduced myocardial flow reserve (MFR) of 1.64 (1.21/0.74) (normal >2.0).

Figure 7. Maps of the endocardial, epicardial, and ratio of the two stress and rest MBF. The ratio of endocardial to epicardial stress MBF was 0.66 (normal >1.0, global) versus rest of 1.03 indicative of diffuse microvascular ischemia.

Conclusion

The patient was diagnosed with HCM with 17% LGE (>10-15% is a risk marker for sudden cardiac death (SCD))[6] and ANOCA. After shared decision making, she did not desire primary prevention implantable cardiac defibrillator (ICD) at this time but would consider at a later date. The patient requested medical therapy for relief of chronic, refractory angina. Her symptoms improved with titration of anti-anginal medical therapy. She was referred to cardiogenetics for counseling, genotypic assessment and familial analysis. Genetic testing revealed a pathogenic variant MYBPC3 mutation. A variant of uncertain significance in the PPCS gene was also identified.

Perspective

HCM is a common heritable cardiovascular disease caused by a variety of genetic mutations. The MYBPC3 gene is one of the most common pathogenic variants associated with HCM and is the cause in approximately 40% of patients with HCM.[7] Patients have variable forms of presentation, including syncope, heart failure, arrhythmias, angina and sudden cardiac death. Assessment in such patients focuses on identifying causative mutations, ameliorating potential left ventricular outflow obstruction, relieving morbidity, and determining those at highest risk for sudden cardiac death. Interestingly, genetic mutations have been proposed to cause microvascular changes and fibrosis that may potentially predate the development of a hypertrophy phenotype.[8]

Symptoms of angina or anginal equivalents among patients with HCM require thoughtful evaluation. Referral to an expert center is encouraged when possible as part of best practice.[6] Beyond evaluation of chest pain for epicardial coronary artery stenosis, ANOCA, symptomatic mitral valve dysfunction, left ventricular outflow obstruction or arrhythmia may present with indistinguishable symptoms. HCM guidelines provide class I recommendation for use of cardiac MRI, specifically with use of cine sequences to evaluate myocardial thickening, mitral leaflet motion, or apical aneurysm that increase risk of SCD. Phase contrast CMR aids in evaluation of outflow obstruction. LGE aids in SCD prognosis. Qualitative or quantitative stress perfusion exclude ANOCA or regional ischemia from co-morbid coronary artery disease.

Acknowledgement of ANOCA as an important clinical contributor to chest pain syndromes gained particular recognition after the Women’s Ischemic Syndromes Evaluation study, which identified a 47% prevalence of ANOCA among women referred clinically for cardiac catheterization.[9] In addition to lifestyle limiting anginal symptoms, public health estimates have demonstrated a $21 billion dollar annual economic burden of ANOCA in the USA due to less productive work (presenteeism) and missing work (absenteeism).[10] Clinicians may diagnose ANOCA invasively in the catheterization lab using special instrumentation, in accordance with recommendations of the Coronary Vasomotion Disorders International Study Group (COVADIS) though rarely done in the USA.[11] Alternatively, noninvasive diagnosis is safer, cheaper, preferrable for patients and most commonly pursued by quantitative myocardial perfusion positron emission tomography (PET). As with the present case, CMR also may diagnose ischemia qualitatively but qualitative evaluation cannot reliably grade severity of ischemia and has reduced accuracy with multivessel disease due to balanced ischemia as well as reduced accuracy for diagnosis of microvascular ischemia due to limitations such as dark rim artifact. More recently, a variety of strategies using either dual bolus or dual sequence to quantify perfusion have demonstrated good accuracy and reproducibility when validated versus quantitative microspheres or O-15 H2O PET. Peter Kellman has recently developed a free-breathing, motion corrected dual sequence, single gadolinium injection CMR perfusion technique with b-SSFP myocardial readout capable of quantifying MBF within minutes and displaying on scanner perfusion maps. Although not clinically available at this time, this sequence has good validation versus PET and Hughes et al recently demonstrated 100% of patients with apical variant HCM demonstrate apical microvascular ischemia using dual sequence quantitative perfusion CMR.[12]

Unfortunately, due to cost, practice inertia, and limited access to invasive physiology, PET and quantitative CMR, ANOCA remains paradoxically undiagnosed among HCM patients despite the high prevalence and associated prognostic significance for angina, myocardial infarction, heart failure and death. This also holds true for other important demographics with increased ANOCA prevalence: women, patients with obesity, diffuse coronary artery disease, diabetes mellitus, post-radiation, amyloidosis, renal disease, and many other conditions. Improving access to quantitative perfusion CMR, PET and invasive coronary physiologic testing could improve diagnosis and reduce the global burden of undiagnosed ANOCA.

Disclaimer: The views expressed are those of the authors and do not reflect the official policy or endorsement of the Department of Defense or US government. Any products are named for educational purposes.

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References

1. Gulati M, Levy PD, Mukherjee D, Amsterdam E, Bhatt DL, Birtcher KK et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Journal of the American College of Cardiology 2021;78:e187-e285.
2. Kellman P, Hansen MS, Nielles-Vallespin S, Nickander J, Themudo R, Ugander M et al. Myocardial perfusion cardiovascular magnetic resonance: optimized dual sequence and reconstruction for quantification. Journal of Cardiovascular Magnetic Resonance 2017;19:43.
3. Kotecha T, Martinez-Naharro A, Boldrini M, Knight D, Hawkins P, Kalra S et al. Automated pixel-wise quantitative myocardial perfusion mapping by CMR to detect obstructive coronary artery disease and coronary microvascular dysfunction: validation against invasive coronary physiology. JACC: Cardiovascular Imaging 2019;12:1958-69.
4. Kotecha T, Chacko L, Chehab O, O’Reilly N, Martinez-Naharro A, Lazari J et al. Assessment of Multivessel Coronary Artery Disease Using Cardiovascular Magnetic Resonance Pixelwise Quantitative Perfusion Mapping. JACC Cardiovasc Imaging 2020;13:2546-57.
5. Markley R, Del Buono MG, Mihalick V, Pandelidis A, Trankle C, Jordan JH et al. Abnormal left ventricular subendocardial perfusion and diastolic function in women with obesity and heart failure and preserved ejection fraction. The international journal of cardiovascular imaging 2023;39:811-9.
6. Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Journal of the American College of Cardiology 2024;83:2324-405.
7. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003;107:2227-32.
8. Marian AJ, Braunwald E. Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. Circ Res 2017;121:749-70.
9. Reis SE, Holubkov R, Conrad Smith AJ, Kelsey SF, Sharaf BL, Reichek N et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J 2001;141:735-41.
10. Ferreira VM, Berry C. The Health Economics of Ischemia With Nonobstructive Coronary Arteries. JACC Cardiovasc Imaging 2021;14:1380-3.
11. Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U et al. International standardization of diagnostic criteria for microvascular angina. International journal of cardiology 2018;250:16-20.
12. Hughes RK, Augusto JB, Knott K, Davies R, Shiwani H, Seraphim A et al. Apical Ischemia Is a Universal Feature of Apical Hypertrophic Cardiomyopathy. Circ Cardiovasc Imaging 2023;16:e014907.

Case prepared by:
Pranav Bhagirath, MD, PhD
Editorial Team, Cases of SCMR
Department of Cardiology
Amsterdam University Medical Centers
Amsterdam, The Netherlands