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Histological Diagnosis of Coronary Amyloidosis Using Percutaneous Transluminal Directional Atherectomy

Open AccessPublished:November 14, 2022DOI:https://doi.org/10.1016/j.cjco.2022.11.009
      Cardiac amyloidosis (CA) is a cardiomyopathy that results from deposition of amyloid fibrils in cardiac tissue, causing progressive heart failure
      • Zhang K.W.
      • Stockerl-Goldstein K.E.
      • Lenihan D.J.
      Emerging Therapeutics for the Treatment of Light Chain and Transthyretin Amyloidosis.
      . Two types of amyloid protein are major causes of CA: light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR).
      • Zhang K.W.
      • Stockerl-Goldstein K.E.
      • Lenihan D.J.
      Emerging Therapeutics for the Treatment of Light Chain and Transthyretin Amyloidosis.
      In ATTR amyloidosis, dissociation of transthyretin (TTR) tetramer into misfolded monomers leads to self-assembly and formation of insoluble cross-β-sheet-rich amyloid fibrils.
      • Zhang K.W.
      • Stockerl-Goldstein K.E.
      • Lenihan D.J.
      Emerging Therapeutics for the Treatment of Light Chain and Transthyretin Amyloidosis.
      Ischemic heart disease is among comorbidities associated with ATTR-CA. Amyloid accumulation in intramural coronary arterioles associated with microvascular dysfunction has been known;
      • Dorbala S.
      • Vangala D.
      • Bruyere Jr., J.
      • et al.
      Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis.
      however, amyloid vasculopathy in epicardial coronary primary arteries causing myocardial ischemia has not been reported.
      An 81-year-old man was referred to our hospital for symptomatic heart failure of New York Heart Association functional class III. He underwent surgery for bilateral carpal tunnel syndrome 7 years ago. He had been prescribed diuretics for lower leg edema for 5 years. His leg edema and dyspnea on exertion gradually progressed. At presentation to our hospital, his blood pressure was 105/80 mmHg and heart rate was 73 beats per minute. Physical examination revealed normal heart sounds, clear respiratory sounds, and bilateral leg edema. Chest X-ray showed a normal cardiac silhouette without pleural effusion. Electrocardiography showed sinus rhythm with poor R wave progression in leads V1 through V3. B-type natriuretic peptide level was 68.5 pg/mL (normal range 0-18.4 pg/mL) and troponin T level was 0.053 ng/mL (normal <0.014 pg/mL). Immunoelectrophoresis of serum and urine proteins were negative for M-protein and Bence-Jones protein. Serum kappa: lambda free light chain ratio was within normal range at 1.58. Echocardiography demonstrated hypertrophy of left ventricle (interventriular septum 12 mm, posterior wall 13 mm), right ventricle, and interatrial septum, with myocardial granular sparkling (Supplemental Figure S1). 2D-speckle tracking demonstrated decreased global longitudinal strain with apical sparing. Wall motion abnormality was also observed at left ventricular anteroseptal region with left ventricular ejection fraction of 55%. Cardiac magnetic resonance imaging showed diffuse late gadolinium enhancement with subendocardial predominance (Supplemental Figure S2). 99mTechnetium-pyrophosphate scintigraphy imaging showed enhanced myocardial uptake (Supplemental Figure S3). Endomyocardial biopsy demonstrated amyloid accumulation in the myocardial tissue, that was positive for TTR and negative for amyloid A, kappa chain, or lambda chain (Figure 1A-1D and supplemental Figure S4). He did not have TTR gene mutation. Based on these findings, he was diagnosed with wild-type ATTR-CA. Even though he did not experience angina-like episode, LV regional wall motion abnormality suggested ischemic heart disease comorbidity. Coronary angiography revealed a severely stenotic lesion in the proximal LAD artery with resting full-cycle ratio (RFR, a non-hyperemic index assessing functional myocardial ischemia) of 0.83, suggesting significant myocardial ischemia (Figure 1E). Considering the coronary flow-based ischemic finding and left ventricular hypokinesia at the LAD territory, we performed percutaneous coronary intervention. Intravascular ultrasound and optical coherence tomography demonstrated a homogenous fibrotic or fibrofatty-like plaque (Figure 1F and 1G). It was not a typical atheromatous plaque pattern. We resected the coronary artery plaque using directional coronary atherectomy (DCA) catheter so as to avoid plaque shift and subsequent side branch occlusion,
      • Habara M.
      • Tsuchikane E.
      • Nasu K.
      • et al.
      The first clinical experience with a novel directional coronary atherectomy catheter: Preliminary Japanese multicenter experience.
      and deployed a drug-eluting stent (Figure 1H, and Supplemental Figure S5). Histopathological examination of the resected plaque showed an intimal tissue with fibrosis and hyalinization (Figure 2A, and Supplemental Figure S6). Masson’s trichrome staining showed brilliant blue fibrosis and amorphous bluish gray components suggestive of amyloid (Figure 2B). Direct fast scarlet (DFS) staining failed to show clear red amyloid deposition under ordinary light microscopy (Figure 2C); however, polarized light microscopy demonstrated apple-green birefringence indicating amyloid infiltration in the coronary plaque (Figure 2D). Furthermore, electron microscopy detected an accumulation of 10-nm-thick amyloid fibrils in the coronary artery plaque (Figure 2E). Thus, the diagnosis of coronary amyloidosis was established.
      Figure thumbnail gr1
      Figure 1Histopathological findings of myocardial tissue, and coronary angiographic and intravascular modality images. Right ventricular tissues were obtained by endomyocardial biopsy. A, Hematoxylin-eosin staining. Eosinophilic amorphous substances suggesting amyloid were accumulated in the myocardial interstitium. B, Direct fast scarlet (DFS) staining detected diffuse amyloid deposition in the myocardium. C, Immunostaining against transthyretin. D, Electron microscopy detected infiltration of amyloid fibrils surrounding cardiomyocytes (arrows). E, Coronary angiography demonstrated severe stenosis in the proximal left anterior descending artery (arrows). F, Intravascular ultrasound imaging of the coronary artery plaque. Mild calcification was observed (arrowheads). G, Optical coherence tomography imaging showed a plaque mainly composed fibrous tissue with low signal-intensity region (arrowheads) suggesting fibro-fatty plaque. H, Coronary artery plaque was resected using directional coronary atherectomy catheter (arrowheads) before stenting.
      Figure thumbnail gr2
      Figure 2Coronary histological finding of the resected plaque tissue. A, Hematoxylin-eosin staining of the resected plaque tissue. The plaque was composed of fibrous tissue without typical finding of much cholesterol accumulation and foam cell formation. B, Masson’s trichrome staining of the plaque tissue. C, DFS staining of the coronary plaque tissue. D, Polarized light microscopy of the DFS staining specimen detected apple-green birefringence indicating of amyloid deposition in the coronary plaque. E, Electron microscopic finding of the resected plaque tissue. Greyish amorphous fibrillar substances were observed. The fiber thickness are approximately 10 nm, compatible with amyloid fibrils.
      He was discharged well, and disease-modifying therapy with tafamidis was commenced at our outpatient clinic.

      Discussion

      Infiltration of amyloid protein in CA primarily occurs in the myocardial interstitium and conduction system, causing cardiac hypertrophy and arrhythmia. Previous reports of coronary amyloidosis have shown the deposition of amyloid fibrils in intramural small arteries, causing so called intramural coronary amyloidosis.
      • Dorbala S.
      • Vangala D.
      • Bruyere Jr., J.
      • et al.
      Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis.
      ,
      • Mueller P.S.
      • Edwards W.D.
      • Gertz M.A.
      Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis.
      Such amyloid microangiopathy leads to wall thickening and luminal occlusion causing coronary microvascular dysfunction and myocardial ischemia.
      • Dorbala S.
      • Vangala D.
      • Bruyere Jr., J.
      • et al.
      Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis.
      The degree of vascular involvement is reportedly much greater in AL-CA than ATTR-CA. Amyloid deposition in the epicardial coronary arteries has also been demonstrated in a study based on pathological specimens collected at autopsy and heart transplantation, with highly frequent involvement of adventitial vasa vasorum (up to 91-97%), but no substantial luminal stenosis was observed in the epicardial coronary arteries.
      • Wittich C.M.
      • Neben-Wittich M.A.
      • Mueller P.S.
      • et al.
      Deposition of amyloid proteins in the epicardial coronary arteries of 58 patients with primary systemic amyloidosis.
      Our case was the first demonstrating the accumulation of amyloid fibrils in a severely stenotic coronary lesion obstructing epicardial primary vessel. We successfully established a diagnosis of coronary amyloidosis based on biopsy of the coronary plaque using DCA catheter, while an antemortem diagnosis of coronary amyloidosis is quite difficult. It remains unclear whether the coronary artery disease was attributable to coronary amyloid accumulation or amyloid deposition occurred in a pre-existing atherosclerotic plaque in the present case. However, it is reasonable to speculate that amyloid depositions might have accelerated arteriosclerosis through amyloid-triggered inflammation, taking into account a study demonstrating that plasma levels of proinflammatory interleukin-6 (IL-6) were elevated in patients with ATTR-CA and a clinical evidence showing that IL-6 independently predicts future cardiovascular events.
      • Hein S.J.
      • Knoll M.
      Aus dem Siepen F, et al. Elevated interleukin-6 levels are associated with impaired outcome in cardiac transthyretin amyloidosis.
      There has been a case report of ATTR amyloid accumulation in eccentric intimal thickening of a saphenous vein graft harvested for coronary artery bypass grafting surgery.
      • Farci F.
      • De Martino A.
      • Pratali S.
      • et al.
      Transthyretin-related amyloid in a saphenous vein. Histological diagnosis in a patient undergoing coronary artery bypass surgery.
      This observation reinforces our hypothesis that amyloid toxicity plays a role in the development of vascular disease including arteriosclerosis and vasculopathy. Further longitudinal investigations are needed to determine the pathophysiological role of transthyretin amyloid in the development of coronary artery disease and to demonstrate the effect of ATTR-targeting therapies on plaque regression.
      In conclusion, we report a case of ATTR-CA accompanied by stenotic coronary artery plaque with accumulation of amyloid fibrils in the major branch of coronary arteries. DCA catheter-based biopsy of the coronary plaque contributed to the accurate diagnosis, otherwise the antemortem diagnosis was impossible.

      Novel Teaching Points

      i. It has been reported that coronary amyloidosis occurs in the intramural small arterioles as microangiopathy. This case was the first demonstrating the accumulation of amyloid fibrils in coronary arteriosclerosis causing luminal stenosis in epicardial primary coronary arteries. Pathophysiological relevance of amyloid accumulation in the development of arteriosclerosis associated with cardiac amyloidosis was suggested.
      ii. Antemortem diagnosis of coronary amyloidosis in primary vessels is quite difficult. Biopsy using percutaneous directional coronary atherectomy enables histological diagnosis of coronary amyloidosis in patients with cardiac amyloidosis.

      References

        • Zhang K.W.
        • Stockerl-Goldstein K.E.
        • Lenihan D.J.
        Emerging Therapeutics for the Treatment of Light Chain and Transthyretin Amyloidosis.
        JACC Basic Transl Sci. 2019; 4: 438-448
        • Dorbala S.
        • Vangala D.
        • Bruyere Jr., J.
        • et al.
        Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis.
        JACC Heart Fail. 2014; 2: 358-367
        • Habara M.
        • Tsuchikane E.
        • Nasu K.
        • et al.
        The first clinical experience with a novel directional coronary atherectomy catheter: Preliminary Japanese multicenter experience.
        Catheter Cardiovasc Interv. 2017; 89: 880-887
        • Mueller P.S.
        • Edwards W.D.
        • Gertz M.A.
        Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis.
        Am J Med. 2000; 109: 181-188
        • Wittich C.M.
        • Neben-Wittich M.A.
        • Mueller P.S.
        • et al.
        Deposition of amyloid proteins in the epicardial coronary arteries of 58 patients with primary systemic amyloidosis.
        Cardiovasc Pathol. 2007; 16: 75-78
        • Hein S.J.
        • Knoll M.
        Aus dem Siepen F, et al. Elevated interleukin-6 levels are associated with impaired outcome in cardiac transthyretin amyloidosis.
        World J Cardiol. 2021; 13: 55-67
        • Farci F.
        • De Martino A.
        • Pratali S.
        • et al.
        Transthyretin-related amyloid in a saphenous vein. Histological diagnosis in a patient undergoing coronary artery bypass surgery.
        Cardiovasc Pathol. 2019; 41: 21-23