Obstructive Intramural Coronary Amyloidosis: Uncommon or Under-Recognized Cause of Microvascular Angina?

Visual Summary The Patient's Clinical History Before and After the Diagnosis of ATTRwt CA, and His Current Health Status After 1 Year of Treatment With Tafamidis 2D TTE = 2-dimensional transthoracic echocardiography; 6MWT = 6-minute walk test; ACS = acute coronary syndrome; Ao = aorta; ATTRwt CA = wild-type transthyretin cardiac amyloidosis; CMR = cardiac magnetic resonance; CV = cardiovascular; ECG = electrocardiogram; EF = ejection fraction; GLS = global longitudinal strain; Hs-cTn = high-sensitivity cardiac troponin; IVS = interventricular septum; LV = left ventricle; MV = mitral valve; MVR = mitral valve regurgitation; NT-proBNP = N-terminal pro–B-type natriuretic peptide; OICA = obstructive intramural coronary amyloidosis; PH = pulmonary hypertension; PW = posterior wall; RV = right ventricle; TTR = transthyretin.

History of Presentation and Past Medical History

An 83-year-old man with a history of arterial hypertension, dyslipidemia, and obesity also had a notable history of bilateral carpal tunnel surgery. He had previously undergone multiple coronary angiographies for suspected exertional angina (in 2018, 2021, and most recently in 2024). However, none of these angiographies revealed significant epicardial coronary artery stenosis, despite a stress/rest myocardial scintigraphy in 2018 that was positive for inducible ischemia in the inferior myocardial segments. Over the years, given the long-lasting hypertension and the possible microvascular, rather than vasospastic, cause of his angina, medical therapy was progressively optimized with ranolazine, transdermal nitrates, and the calcium-channel blocker felodipine, albeit with limited symptomatic relief. In January 2025, the patient presented to our emergency department with progressively worsening chest pain (angina) and exertional dyspnea. Take-Home Messages • Bone scintigraphy may yield negative results in ATTR-CA with predominant OICA, likely reflecting the paucity of interstitial deposits and the possible limited access of tracer to intramural coronary vessels. • A subset of patients presenting with myocardial ischemia, elevated troponin levels, and angiographically normal epicardial coronaries may therefore be underdiagnosed for OICA, highlighting the importance of considering cardiac amyloidosis screening and endomyocardial biopsy in selected cases.

Investigations and Management

Electrocardiography showed sinus rhythm with normal atrioventricular and intraventricular conduction, nonspecific ventricular repolarization abnormalities, and normal QRS voltage amplitudes. An acute coronary syndrome was ruled out. Laboratory results revealed persistently elevated high-sensitivity troponin levels, peaking at 237 ng/L, 74 ng/L at discharge (it was normal 9 months earlier), normal C-reactive protein, and elevated natriuretic peptides (B-type natriuretic peptide: 141 ng/L; N-terminal pro–B-type natriuretic peptide [NT-proBNP]: 1,026 ng/L), which were similar to levels reported in the earlier months. Transthoracic echocardiography showed a left ventricle with normal chamber dimensions but concentric hypertrophy (interventricular septum: 15 mm, posterior wall: 13 mm). Ejection fraction was preserved (60%) without significant regional wall motion abnormalities. However, global longitudinal strain was significantly reduced (−4.3%) with an “apical sparing” pattern. Diastolic dysfunction with elevated filling pressures (E/A: 1.1, deceleration time: 262 ms, E/e′ ratio: 14) was present. The left atrium was markedly dilated (left atrial volume index: 48 mL/m 2 ). Additional findings included thickened mitral valve leaflets with moderate regurgitation, fibrosclerotic aortic valve cusps with mild stenosis, and right ventricular free wall hypertrophy. There were no signs of pulmonary hypertension, venous congestion, or pericardial effusion. Cardiac magnetic resonance (CMR) revealed a subtle strip of late gadolinium enhancement with a nonischemic pattern and elevated T1-mapping values only in the basal inferior-septal region, consistent with interstitial myocardial fibrosis. T2 mapping was normal. Myocardial blood flow (MBF) quantification did not reveal significant abnormalities. Given a high clinical suspicion for infiltrative cardiomyopathy, further investigations were performed. Serum and urine immunofixation, Bence Jones proteinuria testing, and free light chain assays (kappa/lambda ratio and levels) were all negative. Additionally, bone tracer (HDP-Tc99m) myocardial scintigraphy (Perugini score 0), periumbilical fat biopsy, and genetic testing (both TTR and ApoA1 genes) were negative. Clinical traits of systemic amyloidosis, such as periorbital purpura, macroglossia, the shoulder pad sign, and Popeye sign, were absent. Despite negative noninvasive findings, a strong clinical suspicion persisted, and an endomyocardial biopsy (EMB) was performed.

Pathological findings

Seven EMB specimens were entirely serially sectioned and examined to tissue exhaustion. The analysis revealed substantial amyloid deposition, primarily affecting the intramural arterioles in all samples, causing partial to complete luminal occlusion. Small and focal interstitial amyloid deposits were identified in 2 samples, 1 for light microscopy, and 1 for electron microscopy. The paucity of interstitial deposits may explain the negative bone scintigraphy. These findings pointed to a predominantly obstructive intramural coronary amyloidosis (OICA). Amyloid deposits specifically immunostained with anti-TTR antibodies, with no reactivity to anti-kappa or anti-lambda light chain, anti-SAA, and anti-ApoA1 antibodies. These histological findings led to the final diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) with a predominantly OICA involvement ( Figure 1 ). Nonspecific findings included myocyte hypertrophy and interstitial fibrosis. Figure 1 Histological Findings (A to D) Light microscopy study of FFPE samples. (A) The typical features that characterize OICA: heavy infiltration of the small vessel wall by the dense, apparently amorphous material. In these vessels, smooth muscle cells are few or absent (FFPE section; H&E stain). (B) Another sample showing a small vessel with positive anti-TTR immunostain. FFPE sample; immunostain with anti-TTR antibodies (brown). (C) The intramural coronary arteries with positive Congo-red staining seen at polarized light; (D) shows the corresponding immunostain with anti-TTR antibodies. (E to H) Epon-Araldite–embedded samples. (E) Semithin section, toluidine blue stain. The red arrows indicate the small vessels heavily infiltrated by amyloid. (F1 and F2) Semithin section, Anti-TTR immunostain (brown) of sections from the Epon-Araldite blocks. Squared area in F1 shows some interstitial amyloid deposition and is enlarged in F2. (G) The interstitial space between the myocyte and the vessel is free from amyloid, while the small vessel wall is heavily infiltrated by amyloid, which is specifically labeled with anti-TTR antibodies. Postembedding immunoelectron microscopy. Immunoelectron micrograph; low-magnification view, Bar scale = 5 μm. Red-squared area is enlarged in H. (H) Immunoelectron micrograph; higher magnification view of the boxed area in G. Bar scale = 1 μm. FFPE = formalin fixed and paraffin embedded; H&E = hematoxylin and eosin; OICA = obstructive intramural coronary amyloidosis; TTR = transthyretin.

Treatment and Follow-Up

The patient was referred to our amyloidosis outpatient clinic. Functional status was impaired (322 m on the 6-minute walk test; NYHA functional class IIb), with reduced quality of life (Kansas City Cardiomyopathy Questionnaire score: 36). Overall disease staging corresponded to NAC stage II and Columbia stage II (score 2 + 2 + 2). As a result, in February 2025, disease-specific therapy with tafamidis 61 mg daily was initiated, and the non-dihydropyridine calcium-channel blocker was uptitrated. Sodium glucose transporter 2 inhibitor, transdermal nitrate, and ranolazine were already prescribed. At the 1-year follow-up, the patient remained clinically stable and reported no anginal symptoms. Exercise tolerance improved significantly, with an increase in the 6-minute walk distance from 322 to 422 m. Left ventricular ejection fraction remained stable at 60%. Global longitudinal strain showed partial improvement (from −4.8% to −8%), although still markedly reduced. High-sensitivity troponin levels decreased (from 237 to 24 ng/L), while NT-proBNP values remained stable (from 1,026 to 926 ng/L), without clinical or functional deterioration. Overall, although a correlation with tafamidis could only be assumed, the absence of anginal symptoms, improved functional capacity, and stable cardiac function suggested a favorable clinical course under tafamidis therapy.

Discussion

Amyloidosis is a systemic disorder comprising a broad spectrum of clinical phenotypes caused by the extracellular deposition of insoluble, misfolded proteins with a beta-pleated sheet conformation, organized into amyloid fibrils. These deposits infiltrate various tissues, leading to progressive organ dysfunction. 1 The heart is among the most commonly affected organs. Amyloid deposits can involve the myocardium, endocardium, epicardial fat, valves, and both epicardial and intramural vessels. Typically, amyloid infiltrates the myocardial extracellular matrix, resulting in increased wall thickness and myocardial stiffening. 1 , 2 Consequently, cardiac amyloidosis (CA) often presents with heart failure with preserved ejection fraction (HFpEF) and arrhythmias, particularly atrial fibrillation and conduction disturbances.

Although involvement of both epicardial coronary arteries and small intramural vessels is well documented in pathological studies, 3 , 4 ischemic heart disease (IHD) as the initial clinical presentation of CA remains relatively uncommon ( Table 1 ). Nevertheless, myocardial ischemia syndromes occur in a significant proportion of patients with CA, ranging from 25% to as high as 38%. When IHD is the presenting feature, it is often associated with OICA, which may represent either the predominant or sole manifestation of CA or may coexist with typical interstitial myocardial amyloid infiltration. 4 The clinical spectrum of IHD in CA is broad and includes stable angina, acute myocardial infarction, sudden cardiac death, acute heart failure, or cardiogenic shock ( Table 1 ). Table 1 Summary of Studies Reporting Isolated or Predominant OICA First Author (Year) Study Design/CA Diagnosis Population Main Findings Buja (1970) 5 Autopsy series 15 patients affected by CA identified through autopsy findings. Amyloid deposits in the myocardial interstitium, causing significant myocardial stiffness, and in intramural coronary vessels contributing to ischemic phenomena despite minimal or no significant epicardial atherosclerosis. Smith (1979) 6 Autopsy series 108 patients with CA and clinical signs of ischemic myocardial injury who underwent autopsy. Focal subendocardial ischemic injury due to complete or near-complete luminal obliteration by amyloid of the vessels supplying these areas. Saffitz (1983) 7 Autopsy series 54 patients with CA causing cardiac dysfunction. Amyloid was found both in intramural coronary arteries and in the mural endocardium. Jennette (1983) 8 Case report, autopsy 78-year-old woman with multiple myeloma had systemic amyloidosis. Amyloid deposits were confined to the vascular system. Crotty (1995) 9 Retrospective observational EMB 100 patients affected by CA diagnosed by endomyocardial biopsy. Interstitial deposition: 95% to 100% of the cases with AL, senile (AS) and familiar amyloidosis. Vessels involvement was more common in AL-CA Mueller (2000) 10 Retrospective observational, autopsy, explanted hearts 11 patients with CA diagnosed by autopsy or after examination of an explanted heart. Significant amyloid deposits localized in the small intramural vessels in the absence of significant epicardial coronary stenosis. Ogawa (2001) 11 Case report, autopsy 69-year-old woman who presented with exertional angina and heart failure. Severe obstructive alterations of intramural coronary arteries due to large amounts of amyloid deposits in the vessel's walls, with disseminated fresh myocardial necrosis. Yamano (2002) 12 Case report, autopsy 76-year-old woman with systemic amyloidosis, presenting with angina pectoris and heart failure. Diffuse stenoses and obstructions in intramural coronary arteries by amyloid deposits were found, with only mild to moderate atherosclerosis in the epicardial coronary arteries. Miani (2002) 13 Case report, autopsy 65-year-old man with AMI treated with PCI. Post-AMI refractory angina, with impaired coronary flow reserve at Doppler wire velocity. Extensive amyloid deposition in the media and adventitia of the intramural coronary arteries and vasa vasorum with narrowed lumen. Coisne (2003) 14 Case report, papillary muscle sample 76-year-old man with cardiogenic shock due to papillary muscle rupture. Mitral valve replacement with bioprosthetic valve. Intraoperative findings confirmed the papillary muscle rupture caused by focal apical necrosis. Microscopy showed obstructive intramural coronary amyloidosis. Whitaker (2004) 15 Case report, autopsy 65-year-old man; onset with exertional dyspnea and recurrent angina; absence of obstructive CAD. Treated with chemical sympathectomy, complicated by pulmonary edema. Deposits of immunoglobulin light chain–related (AL) amyloid within the walls of the smaller coronary and pulmonary arteries. Neben-Wittich (2005) 16 Retrospective observational, autopsy, explanted hearts 96 patients with systemic amyloidosis and cardiac involvement. Obstructive intramural coronary amyloidosis was common in patients with primary CA, often resulting in symptomatic myocardial ischemia. Pasotti (2006) 17 Case report EMB 66-year-old man presenting with congestive heart failure. Due to nonobstructive CAD, he underwent EMB. Amyloid infiltration of small intramural vessels without interstitial involvement and foci of coagulative necrosis. Soma (2010) 18 Case report EMB 49-year-old man with AL amyloidosis, admitted for AMI. Given nonobstructive CAD and widespread and mainly subendocardial LGE at CMR, he underwent EMB Amyloid deposition in small intramural coronary arteries. Morin (2013) 19 Case report, autopsy 60-year-old woman, sudden cardiac death. Deposition of amyloid protein was seen diffusely in the walls of multiple arterial branches of the heart and other organs, causing multiple foci of luminal stenosis. George (2015) 20 Case report, abdominal fat biopsy 75-year-old man admitted for chest pain. Due to nonobstructive coronary artery disease, he underwent CMR and amyloidosis diagnostic work-up. Laboratory tests on serum and urine, as well as cytology of bone marrow aspirate, were positive for monoclonal kappa restricted plasma cells. Abdominal fat biopsy was positive for amyloid protein, with immune-staining with anti-K antibodies. Ronny (2017) 21 Case report, autopsy 73-year-old woman with end-stage renal disease, admitted with diagnosis of health care–associated pneumonia and heart failure. Severe amyloid deposition in almost all major organs including the intramural coronary vessels. Amyloid characterized as beta 2-microglobulin at mass spectrometry. Ishida (2019) 22 Case report, autopsy 72-year-old woman with exertional angina and heart failure, in absence of obstructive CAD. AL amyloid fibril deposits predominantly in the intramural coronary arteries and partly in the myocardial interstitium. Pidello (2020) 23 Case report, explanted heart 62-year-old woman presenting with heart failure with associated interventricular septum rupture, who underwent heart transplantation. Histopathology showed areas of fibrosis, Congo red staining revealed large amyloid deposits in the myocardium, epicardium and intramyocardial vessels; immunostaining positive for TTR. Vaxman (2023) 24 Case report, bone marrow biopsy 63-year-old man with chest pain; positive test for endothelial-independent and endothelial-dependent microvascular dysfunction. Laboratory tests and bone marrow biopsy were positive for kappa light chain–restricted plasma cells. Amyloid was present focally in small vessels and bone marrow interstitium and was typed by mass spectrometry as AL kappa. De Michieli (2023) 25 Retrospective observational EMB 174 patients with either ATTR-CA or AL-CA, who underwent endomyocardial biopsy. In the subset of patients with CA who experienced chest pain, more frequently involved vascular and perivascular amyloid deposition. Flynn (2025) 26 Case report EMB 63-year-old man presenting with progressive exertional dyspnea and angina. He was affected by a kappa light chain myeloma. Thickened, hyalinized blood vessels; the presence of amyloid was demonstrated by the staining of amorphous material with Congo red and positive immunohistochemistry for kappa light chains. AL = light chain; AMI = acute myocardial infarction; ATTR-CA = transthyretin cardiac amyloidosis; CA = cardiac amyloidosis; CAD = coronary artery disease; CMR = cardiac magnetic resonance; EMB = endomyocardial biopsy; LGE = late gadolinium enhancement; OICA = obstructive intramural coronary amyloidosis; PCI = percutaneous coronary intervention; TTR = transthyretin.

IHD-like manifestations in patients with CA are increasingly recognized, with ischemic symptoms often overlapping with those of HFpEF. In a recent review on chest pain in CA, 10% to 20% of patients reported chest pain as the initial symptom. The prevalence of isolated or predominant OICA is hard to estimate. Current knowledge comes from: 1) large cohorts reporting interstitial amyloid and microvascular involvement with ischemic symptoms despite patent epicardial coronary arteries; 2) autopsy or explanted hearts showing OICA alongside interstitial, endocardial, valvular, and coronary artery amyloid; and 3) case reports or small series where intramural coronary deposition is significant but interstitial amyloid is minimal or absent. Table 1 reports a summary of studies describing isolated or predominant OICA. 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 This latter condition might be underdiagnosed in patients presenting with microvascular angina, patent coronary arteries, and elevated troponin levels, yet without other typical CA features.

Our case raises the question of whether bone scintigraphy can detect isolated OICA when interstitial amyloid is absent or minimal. Whereas imaging has limited EMB indications over time in ATTR-CA diagnosis, 3 EMB remains crucial when bone scintigraphy is negative (scores 0 or 1), and the clinical suspicion is high, as in our patient. A negative bone scintigraphy in OICA suggests the tracers may not adequately reach small intramural vessels, allowing OICA to go undetected. CMR can significantly aid in diagnosing microvascular angina, but cannot determine the specific cause of small-vessel disease; quantitative perfusion CMR shows severe inducible ischemia, but usually in CA patients with interstitial infiltration. 27 In our patient, microvascular angina was suspected based on negative bone scintigraphy and light chain (AL) screening, CMR suggestive of nonischemic interstitial fibrosis, and elevated NT-proBNP and troponin. CMR is currently recommended (class 2A) for diagnosing ischemia with nonobstructive coronary arteries. 28 However, MBF was normal in our patient. Microvascular dysfunction may be present with normal MBF, whereas the coronary flow reserve is more sensitive to it. Additionally, the nonischemic pattern of late gadolinium enhancement on CMR might be explained by the cardiac amyloidosis itself, as the minimal interstitial amyloid deposition observed in our patient likely contributed to the subtle late gadolinium enhancement strip. The unique role of OICA versus OICA plus loss of capillary vessels in inducible myocardial ischemia by CMR stress perfusion mapping 27 remains to be elucidated.

In our patient, EMB was essential for diagnosing OICA. Although amyloid detection in EMB depends on disease extent and sample number, expert pathologists identify and characterize amyloid even when present in minimal amounts. 29 , 30 , 31 Whereas in systemic amyloidosis, tissue biopsy from noncardiac organs may obviate the need for EMB, when the heart is the sole affected organ and imaging is noninformative, EMB is essential. In our case, all EMB samples showed microvascular involvement, whereas interstitial deposits were minimal and observed in only 2 of 7 samples.

Further research is needed to clarify the prevalence and clinical relevance of OICA as a distinct phenotype of ATTR-CA. Future studies should assess how often OICA is missed in patients presenting with ischemic symptoms, patent epicardial coronary arteries, and negative bone scintigraphy. The diagnostic yield of advanced imaging modalities, including quantitative perfusion CMR and novel molecular tracers, requires systematic evaluation. Emerging evidence suggests that positron emission tomography imaging with novel amyloid-binding tracers may offer enhanced sensitivity in detecting myocardial amyloid deposits, including in cases of predominantly vascular involvement where bone scintigraphy may be nondiagnostic. 32 This may be particularly relevant in patients with ATTR-CA presenting with Perugini grade 0 uptake, as in our patient, in whom conventional bone-avid tracers failed to identify amyloid. However, despite these promising features, the available evidence remains limited; ongoing studies, including the PETAL trial ( NCT06048601 ), are expected to clarify the diagnostic role of positron emission tomography imaging in this setting.

In addition, an important future application for EMB may be in elderly patients presenting with microvascular angina, angiographically normal epicardial coronaries, troponin elevation, and particularly when bone scintigraphy is negative. In such cases, multimodal studies integrating histopathology, advanced imaging (including microvascular assessment), and biomarkers are needed to derive noninvasive signatures of OICA and to triage who truly requires EMB.

Ultimately, a better understanding of OICA will improve early diagnosis, risk stratification, and therapeutic management of CA patients with ischemic manifestations.

Conclusions

Isolated or predominant involvement of intramural coronary arteries by amyloid may account for microvascular angina with troponin elevation in patients with patent coronary arteries, where standard diagnostic tools for CA yield negative results. At present, while awaiting imaging modalities capable not only of detecting CA but also of distinguishing interstitial from isolated or predominant microvascular involvement, EMB should be considered when no alternative diagnostic options are available.

Funding Support and Author Disclosures

Research on amyloidosis was supported by the PNC “INNOVA” project PNC-E3–2022–23683266 (to Dr Arbustini). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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