Yoko Horibata

Long-Term Prognosis of Patients With Type A Aortic Intramural Hematoma

Background—The long-term clinical course of patients with type B aortic intramural hematoma (IMH) and predictors for progression remains unknown. The difference of aortic pathology may have a different impact on clinical course compared with classic aortic dissection (AD). The purpose of this study was to investigate long-term clinical course and predictors of progression in patients with type B IMH. Methods and Results—Clinical data were compared retrospectively between 53 patients with acute type B IMH (IMH group) and 57 patients with acute type B AD (AD group). All patients were treated initially with medical therapy. Two patients in IMH group and 14 patients in AD group underwent surgical repair because of aortic enlargement. The in-hospital mortality rate in IMH group was significantly lower than that in AD group (0% and 14%, P =0.006). Mean follow-up periods were 53±43 months, which revealed 3 and 5 late deaths, respectively. Eleven patients with IMH showed progression (development of aortic dissection or aortic enlargement) in follow-up imaging study. The actuarial survival rates in IMH group were 100%, 97%, and 97% at 1, 2, and 5 years, which were significantly higher than those in AD group (83%, 79%, and 79%) (P =0.009). Multivariate analysis identified age >70 years and new appearance of an ulcerlike projection as the strongest predictors of progression in patients with IMH. Conclusions—Patients with type B IMH have better long-term prognosis than patients with AD. Older age and appearance of an ulcerlike projection are predictive for progression in patients with type B IMH.

Clinicopathological features of senile systemic amyloidosis: an ante- and post-mortem study

Senile systemic amyloidosis is a common age-related amyloidosis that involves accumulation of wild-type transthyretin, with cardiac dysfunction being a predominant result. The importance of obtaining an accurate diagnosis of senile systemic amyloidosis has been increasingly recognized, so that novel treatments are being developed. However, the clinicopathological features of senile systemic amyloidosis remain to be completely understood. Here, we evaluated cardiac specimens from 181 consecutive post-mortem cases older than 40 years, including 6 cases of senile systemic amyloidosis, and 5 cases of familial amyloidotic polyneuropathy, which is a hereditary systemic amyloidosis caused by mutant forms of transthyretin. Furthermore, we studied ante-mortem clinicopathological findings of 11 senile systemic amyloidosis cases, in which 9 cases underwent gastrointestinal tract biopsy and/or subcutaneous tissue biopsy, at Kumamoto University Hospital. Of the autopsied cases of elderly Japanese (older than 80 years), 12% had senile systemic amyloidosis, with the percentage increasing with age. The occurrence of senile systemic amyloidosis in elderly Japanese patients was lower than that in previous reports, which suggests that a genetic background and/or environmental factor(s) may have important roles in the occurrence of senile systemic amyloidosis. Transthyretin amyloid deposits in familial amyloidotic polyneuropathy cases developed mainly in the pericardium and the surrounding muscle fascicles, whereas in cases with senile systemic amyloidosis the transthyretin amyloid deposits had a patchy plaque-like shape and developed mainly inside the ventricular wall. Biopsies from senile systemic amyloidosis patients evidenced amyloid deposits in 44% (4/9) of gastrointestinal tract and subcutaneous tissue samples combined. As myocardial biopsy may be dangerous for elderly people, the use of a combination of gastrointestinal tract and subcutaneous tissue biopsies may make diagnosis of senile systemic amyloidosis easier.

A homozygote case of familial amyloid polyneuropathy amyloidgenic transthyretin Val30Met in a non-endemic area.

Homozygotic cases of familial amyloid polyneuropathy (FAP) are expected to show late onset and mild clinical manifestations, although a homozygote case of FAP showing extremely early onset and severe manifestations was reported recently. Clinical aspects of homozygotic cases of FAP remain controversial. We report a clinical feature of a homozygotic case of FAP in a non-endemic area. The case presented late onset, slow progression, an initial symptom of visual loss, small fiber neuropathy, and autonomic dysfunction. Serum total transthyretin (TTR) levels were relatively higher than those of heterozygotic cases of FAP. Homozygotic combination of stable tetramer of ATTR may have contributed to late onset and slow progression in this case. Introduction: Familial amyloid polyneuropathy (FAP), a fatal inherited autosomal dominant disorder, is characterized by systemic accumulation of polymerized amyloidogenic transthyretin (ATTR) in the peripheral nerves and systemic organs [1,2]. It has recently been suggested that instability of heterozygotic tetramer of variant transthyretin (TTR) structures causes dissociation of the tetramer and amyloid fibril formation [3–5]. It was reported that homozygotic tetramer of TTR was more stable than heterozygotic. Homozygotic cases of FAP are expected to show late onset and mild clinical manifestations [6– 8]. However, a homozygote case of FAP showing extremely early onset and severe manifestations was reported recently [9]. Clinical aspects of homozygotic cases of FAP remain controversial. We report clinical features of a homozygotic case of familial FAP ATTR Val30Met in a non-endemic area. Case report: A 72-year old Japanese female living in Hiroshima was admitted to Kumamoto University Hospital in June 2009 suffering from bilateral vitreous opacities and polyneuropathy. She suffered from paroxysmal atrial fibrillation at the age of 62 and cystitis at the age of 67. In her familial history, her aunt had complete AV block at the age of 70 and dysesthesia in her lower extremities at the age of 85. Her parents are cousins and did not have any relations in an endemic area of FAP foci. The patient had slow progressive visual loss at the age of 58. She developed vitreous opacities at the age of 59 but dysesthesia only at the age of 68. Upon admission, physical examination revealed normal modified body mass index (mBMI) (836 kg g/l m), mild orthostatic hypotension, and edema in left lower leg. Neurological examinations revealed visual loss, pupil border irregularity, dry eye, distal dominant muscle atrophy, and weakness in her lower extremities, absent Achilles’ tendon reflexes, dysesthesia and decreased pain and light touch sensation under knees and elbow with dissociated sensory loss, alternating constipation and diarrhea, and stress urinary incontinence. Total serum TTR were 21.8 mg/dl; relatively higher than those usually found in FAP ATTR Val30Met patients. The case did not present hypothyroidism. Nerve conduction studies showed normal motor nerve conduction velocity, decreased compound muscle action potential (CMAP), and absent sensory nerve action potential (SNAP) in the left ulnar nerve. CMAPs and SNAPs in the lower limbs were not observed. Holter ECG showed PACs and PVCs. R-R interval analysis revealed decreased CVRR (1.44, normal values42.81). Echocardiography did not show either granular sparkling sign, thickening of the intra ventricular septum, nor dilatation of left atrial diameter. Abdominal echography did not show reverse liver–kidney contrast indicating no renal involvement [1–3]. I-MIBG myocardial scintigraphy showed normal accumulation in the heart (early H/M ratio: 3.38, delayed H/M ratio1⁄4 3.13, washout rate 37.3%). Laser Doppler skin blood flow showed vascular hyper reactivity after deep breathing in especially lower extremities. On ophthalmological examination, visual acuities were decreased (0.05 and 0.02) and ocular tensions were normal (5 mmHg and 16 mmHg). Schirmer’s test (3 mm) revealed decreased tear production. Irregularity and amyloid deposition were observed on the pupillay margins. Funduscopic analysis revealed vitreous opacities caused by amyloid deposition. Histopathological examination revealed slight amyloid deposition on the gastric mucosa with Congo red staining under polarized light, although amyloid deposition was not detected in the duodenum mucosa or abdominal fat. After confirming the immunoreactivity of TTR in the amyloid deposits of gastric mucosa using an anti-TTR polyclonal antibody, surface enhanced laser desorption/ionization time of flight-mass spectrometry (SELDI TOFMS) was used. A single peak corresponding to ATTR Val30Met was detected in the serum. Direct sequence analysis confirmed the homozygotic mutation in the TTR gene presenting one base substitution at codon 30 from GTG (Val) to ATG (Met). Discussion: We report a clinical feature of a homozygotic case of FAP in a non-endemic area. This case showed late onset, slow progression, an initial symptom of visual loss, small fiber neuropathy, 169

Transthyretin-derived amyloid deposition in the heart of an elderly Japanese population.

Although in Western countries the prevalence of senile systemic amyloidosis (SSA) in the elderly (480 years) was found to be about 25% based on examination of autopsy-derived cardiac specimens, prevalence in Asian countries is still unclear. The aim of the study was to identify clinicopathological features in Japanese patients with transthyretin (TTR)-derived amyloid deposition. Autopsy-derived cardiac specimens were examined. Pathological analyses revealed that TTR-derived amyloid deposition was found in 11% of the patients over 80 years of age. Although the prevalence of TTR-derived amyloid deposition was lower in a Japanese population than that in a Western population, we must consider SSA in elderly patients if the clinical manifestations cannot be explained by other pathologies. Introduction: Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from normally soluble proteins. So far, 27 different precursor proteins have been identified in different kinds of amyloidosis [1]. Transthyretin (TTR) is one of the amyloidogenic proteins and causes two types of amyloid diseases. One is familial amyloid polyneuropathy (FAP), which is hereditary amyloidosis caused by mutatedTTR [2]. The other is non-hereditary senile systemic amyloidosis (SSA) in which wild-type (WT) TTR forms amyloid deposits especially in cardiac and pulmonary tissues, and occasionally in other systemic organs in the elderly [3]. Several reports showed that the prevalence of SSA was up to 25% in the elderly over the age of 80, based on examination of autopsy-derived cardiac specimens in the United State and Europe [4–6]. It has been well documented that most patients with SSA show a slowly progressive amyloid cardiomyopathy which causes congestive heart failure and arrhythmia. However, clinicopathological features of SSA in Asian countries have still not been clearly identified. In this report, we examined the frequency of TTRderived amyloid deposition using autopsy specimens of patients who had not been diagnosed with amyloidosis before their death and the incidence was compared to aging. In addition, the relationship between amyloid deposition and clinical manifestations was also discussed. Materials and methods: Materials: We examined autopsy-derived cardiac specimens of 175 consecutive individuals over 40 years of age at Kumamoto University Hospital, Japan between January 2001 and March 2008. FAP patients were excluded by genetic testing and/or clinical findings in medical records. Concerning age, 10 cases were in their forties, 33 in their fifties, 43 in their sixties, 63 in their seventies, 20 in their eighties, and 5 in their nineties; one case was over 100 years old. In cases with TTR amyloid deposits in cardiac specimens, other tissues were also examined. For immunohistochemical staining, an antibody for human TTR was purchased from Dako (Glostrup, Denmark). Other chemicals used in the study were purchased from Nakarai tesque (Kyoto, Japan). Congo red staining: Tissue samples were fixed with 10% formalin, embedded in paraffin, serially sectioned at a thickness of 4 mm, and placed onto microscopic slides. Sections were stained with alkaline Congo red and hematoxylin. Amyloid deposits were confirmed under polarized light for the presence of green birefringence. Immunohistochemical stainings: The specimens with amyloid deposits were used for immunohistochemical staining. The specimens were deparaffinated, dehydrated in a modified alcohol series, and incubated in blocking buffer (1% bovine serum albumin (BSA), and 5% goat serum in PBS). A polyclonal rabbit anti-human TTR antibody diluted 1:100 in blocking buffer was used as the primary antibody. A horseradish peroxidase-conjugated goat anti-rabbit IgG antibody diluted 1:100 in blocking buffer was used as the secondary antibody. Reactivity was visualized with the DAB Liquid System (DAKO), according to the manufacturer’s instructions. Sections were counterstained with hematoxylin. For parallel control sections, primary antibody was replaced by blocking buffer. Other immunohistochemical stainings with antibodies for other amyloid precursor proteins were not examined. Results: Congo red staining for the specimen revealed Congo red positive deposition in 17 of 175 cases (9.7%). In the 17 amyloid positive cases, we found TTR-derived amyloid deposition in 5 (2.9%). Immunohistochemical staining with antiTTR antibody was negative in another 12 cases. The incidence of cardiac amyloidosis increased with aging. The incidence of TTR-derived amyloid deposition increased with age: 2 of 63 cases in their seventies, one of 20 cases in their eighties, one of 5 cases in their nineties, and one of one case aged over 100 (Figure 1). In 175 autopsy cases, TTR-derived amyloid deposition was not detected under the age of 69 years. 180

Age-dependent increase in thiol conjugated forms of transthyretin (TTR) in the elderly: quantitative analyses by the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) protein chip system.

Senile systemic amyloidosis (SSA) caused by wild-type (WT) transthyretin (TTR) is a prevalent disorder in the elderly. However, mechanisms of WT TTR amyloid formation and risk factors for SSA remain to be elucidated. In this study, to determine age-related changes in serum TTR, we investigated TTR concentrations and modifications ratios in sera of the elderly. Neither significant age-related changes nor gender-related distinctions in serum TTR concentrations were observed from the age of 60’s to 90’s. In addition, serum TTR concentrations of SSA patients did not significantly change compared to those in coeval elderly. However, all kinds of thiol conjugated-TTR ratios significantly increased as the age by means of surface-enhanced laser desorption/ ionization time-of-flight mass spectrometry, while those of SSA patients did not significantly differ from those of the coeval elderly. We speculate that those thiol conjugations of TTR are one of the required trigger for SSA in the elderly. Introduction: Senile systemic amyloidosis (SSA) is a sporadic transthyretin (TTR) amyloidosis derived from wild-type TTR [1]. It has been well documented that most of the patients with SSA show slowly progressive amyloid cardiomyopathy, which causes congestive heart failure and arrhythmia [1]. Several reports exhibited that the prevalence of SSA was up to 25% in the elderly older than 80 years of age based on examination of autopsy-derived cardiac specimens in the United States and Europe [2]. However, the pathogenesis of SSA remains to be elucidated. TTR is mainly produced in the liver and is present in plasma normally as a homotetramer. In analysis of serum samples, several conjugated forms of TTR were observed in addition to unconjugated forms of TTR [3]. Cys-10 residue in TTR is generally one of the modification sites, and the cys-conjugated form of TTR is found most frequently in serum [4,5]. In addition, other modifications of TTR, such as Ssulfonation, cysteinylglycylation, and glutathionylation, are also detected. It was reported in in vitro study that those modifications increased amyloidogenicity of TTR. However, age-dependent changes of such TTR modifications in the elderly and SSA patients were not still determined. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) combines chromatography with mass spectrometry and uses arrays with different surface chemistries. Chromatographic surfaces of ProteinChips provide good support for co-crystallization of matrix and target proteins, which results in formation of a homogeneous layer on the spot. SELDI-TOF MS instrument is also especially adapted for quantitative assay of TTR molecule [6]. In this study, to determine age-related changes in serum TTR, we investigated TTR concentrations and thiol conjugations of TTR in sera of the elderly by means of nephelometry and SELDI-TOF MS, respectively. Materials and methods: Serum samples and measurement of serum TTR concentrations: For measuring TTR concentrations, 409 serum samples of elderly patients (60’s: 136, 70’s: 140, 80’s: 114, and 90’s: 19) and 6 serum samples of SSA patients (74.5+ 5.5 years old) were employed. We excluded patients with low albumin concentrations (54.1 g/dl) and/or high C-reactive protein concentrations (40.3 mg/dl) in sera from the study. Serum TTR concentrations were measured by nephelometry. For evaluation of TTR modifications, we used each 10 serum samples of patients in 60’s, 70’s, 80’s and 90’s, respectively. Informed consent was obtained from each subject. All studies using serum samples were in accordance with the current revision of the Helsinki Declaration. Figure 1. Serum TTR concentrations in the elderly and SSA patients. Serum samples of 409 elderly patients and 6 SSA patients (74.5+ 5.5 years) were employed. Serum TTR concentrations were measured by nephelometry. 14

Transthyretin-derived amyloidosis in musculoskeletal systems.

Transthyretin-derived amyloid deposition is commonly found in tenosynovium of senile systemic amyloidosis patients. However, that in ligaments of other organ sites remains to be elucidated. The purpose of this study was to determine the frequency and types of amyloid deposits found in musculoskeletal systems. We investigated patients with carpal tunnel syndrome, rotator cuff tears, and lumbar canal stenosis. We identified 39 cases with TTR amyloid deposits. The mean age in TTR positive cases was higher than non-TTR cases in tenosynovium and yellow ligaments, but not significantly in rotator cuff samples. In the elderly, TTR-derived amyloid deposits were frequently found in ligaments and tendons of various organ sites. Those amyloid deposits may be involved in the pathogenesis of the orthopedic disorders. Abbreviations: FAP1⁄4 familial amyloidotic polyneuropathy; SSA1⁄4 senile systemic amyloidosis; TTR1⁄4 transthyretin Introduction: Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded normally soluble protein [1]. So far, 27 different precursor proteins have been identified in different kinds of amyloidosis [1,2]. It has been well documented that mutated forms of amyloidogenic proteins are more prone to form amyloid fibrils [3]. Transthyretin (TTR) is one of amyloidogenic proteins causing two types of amyloid diseases because TTR itself has b-sheet rich structure and is highly amyloidogenic [1,4]. One is familial amyloid polyneuropathy (FAP), which is hereditary amyloidosis mainly derived from mutated-TTR [5] and the other is senile systemic amyloidosis (SSA). Recently, SSA has been focused in the recent attention [6]. SSA, non-hereditary form of amyloidosis in which wild-type (WT) TTR generates amyloid deposits especially in cardiac and plumonary tissues and occasionally in other systemic organs in the elderly [7]. It has been well documented that most of patients with SSA show a slowly progressive, infiltrative amyloid cardiomyopathy [7]. This disease is believed to be associated with the aging process. In addition, localized type of TTR amyloid has been sometimes reported [8]. However, it was not well known whether it became the pathogenesis of the disease. Accompanied with orthopedic disorders, amyloid deposition in the ligament and tendon has been reported [9], the relationship with disease and the pathogenesis remains to be elucidated. In this report, we examined the frequency of amyloid deposition in tissues resected by operations because of orthopedic disorders. In addition, relationship between amyloid deposition and clinical manifestations were also discussed. Patients and methods: Patients: We investigated 111 specimens of patients with carpal tunnel syndrome (54 specimens), rotator cuff tears (21 specimens), and lumbar canal stenosis (36 specimens). Those patients were diagnosed at the Department of Orthopaedic Surgery in Kumamoto University Hospital and its associated faculties based on clinical finding and radiological examinations from 2008 to 2009. Congo red staining and immunohistochemistry: Formalin-fixed, paraffin-embedded specimens were stained with hematoxylin–eosin and Congo red, as described previously [3]. Elucidation of FAP: To exclude TTR-related FAP, we performed genetic testing, such as a real time PCR or sequencing. Mass spectrometry using surface-enhanced laser desorption/ionization time-offlight mass spectrometry (SELDI/TOF MS) [10] was performed to confirm the patients who did not posses variant TTR in serum. Ethics: The study protocol was approved by Human Ethics Review Committee of Kumamoto University and a signed consent form was obtained from the family of subjects. All patients’ family members gave their informed consent for performing an autopsy. Results: The presence of amyloid deposits was determined by a positive reaction in paraffin sections with Congo red staining, and by an apple green birefringence in the same sections in polarized light. Histochemical analysis with Congo red staining revealed 47 (39%) amyloid positive samples (Figure 1A). Immunohistochemical examination was performed using anti-amyloid precursor proteins as mentioned in section ‘Materials and method’. AntiTTR antibody reacted with the lesions where amyloid deposition was positive in 39 cases (Figure 1B): 18 cases in flexor tenosynovium, 5 cases in rotator cuff tendons, and 16 cases in the yellow ligaments. In eight samples, any antibodies 163

Effect of cyclodextrins on transthyretin amyloid formation in transthyretin-related amyloidosis.

Transthyretin (TTR), a beta-sheet rich protein, is a precursor protein of familial amyloidotic polyneuropathy (FAP). Although it has been widely accepted that protein misfolding of monomeric form of TTR is rate limiting for amyloid formation, no effective therapy targeting this misfolding step is available. In this study, we focused on cyclodextrins (CyDs), cyclic oligosaccharides composed of glucose units, and reported the inhibitory effect of CyDs on TTR amyloid formation. Of various b-CyDs, GUGb-CyD showed potent inhibition of TTR amyloid formation. In the presence of GUG-b-CyD, no significant TTR amyloid fibrils were detected by electron microscopic analysis. Moreover, far-UV circular dichroism spectra analysis showed that GUG-b-CyD reduced the conformational change of TTR in the process of amyloid formation. Taken together, these data suggest that GUG-b-CyD may modify the stability of TTR conformation, which, in turn, leads to the suppression of TTR amyloid formation. Introduction: Transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP), which is induced by amyloidogenic TTR (ATTR), is characterized by systemic accumulation of amyloid fibrils [1]. It has been proposed that tetrameric TTR is not itself amyloidogenic, but dissociation of the tetramer into a non-native monomer with low conformational stability can lead to amyloid fibril formation [2]. Previous works have also shown that further structural change within the monomer caused by protein misfolding is a rate-limiting step to form TTR amyloid fibril aggregation [3]. However, no effective therapy targeting this misfolding step is available as of this moment. Cyclodextrins (CyDs), cyclic oligosaccharides composed of 6–8 glucose units, are widely used as prospective drug carriers in the pharmaceutical field [4]. There are three common types of natural CyDs depending on how many glucose units are present: aCyD (6), b-CyD (7), and g-CyD (8). Since CyD contains a central hydrophobic cavity and this cavity can serve as an inclusion site for hydrophobic molecules, CyDs are mainly used as multi-functional drug carriers by enhancing the bioavailability of lipophilic drugs, improving efficacy of drugs, and reducing side effects [5]. In addition, it has been proposed that b-CyDs improve the bioavailability of protein drug formulation. Recent studies revealed that b-CyDs bound to a hydrophobic part of the protein surface and increased its stability, which, in turn, led to prevent the protein misfolding and aggregation [6–8]. Because it is well documented that multiple hydrophobic regions of TTR are exposed in the process of TTR amyloid formation, these evidences suggest that b-CyDs may have potential to prevent TTR amyloid formation by inhibiting the misfolding of monomeric form of TTR. In this study, we elucidated the inhibitory effect of CyDs on TTR amyloid formation. Materials and methods: Both WT-TTR and ATTR-V30M were purified from serum samples obtained from healthy volunteers and homozygotic FAP ATTR V30M patients, respectively. b-CyD, hydroxpropyl-b-CyD (HP-b-CyD), 6-O-a-(4-O-a-DGlucuronyl)-D-glucosyl-b-CyD (GUG-b-CyD), and 6-O-a-maltosyl-b-CyD (G2-b-CyD) were examined in this study. To assess the effect of CyDs on TTR amyloid formation in vitro, thioflavin T-based fluorimetric assay was performed. The presence of TTR amyloid fibril was confirmed by electron microscopic analysis as described previously [9]. To evaluate the effect of CyDs on the conformational change of TTR, far-UV circular dichroism spectra analysis and fluorescent spectrum analysis were performed [10]. Results and discussion: Thioflavin T-based fluorimetric assay was first performed to assess the effect of possible b-CyDs on TTR amyloid formation. Of various b-CyDs, GUG-b-CyD showed potent inhibition of TTR amyloid formation, compared with b-CyD, HP-b-CyD, and G2-b-CyD. The amyloid formation of both WT-TTR and ATTR-V30M was suppressed by GUG-b-CyD in a dose-dependent manner. The effect of GUG-b-CyD was sustained and increased in a time-dependent manner, and the significant inhibition of TTR amyloid formation was observed even at 14 days after GUG-b-CyD administration. To confirm the inhibitory effect of GUG-bCyD further, electron microscopic analysis was performed. In agreement with the results described above, TTR amyloid formation was significantly suppressed in the presence of GUG-b-CyD. From these data, it is suggested that GUG-b-CyD indeed has potential to suppress TTR amyloid formation. To investigate the precise mechanism to how GUG-b-CyD inhibits TTR amyloid formation, the conformational change of TTR by GUG-b-CyD treatment was examined by far-UV CD spectra analysis. CD spectra of TTR were shifted and 58

Two-step approach to avoid obstruction of the coronary ostium during transcatheter aortic valve implantation with the SAPIEN 3

Coronary obstruction during transcatheter aortic valve implantation (TAVI) is a rare complication, but it can be serious and is associated with a high mortality rate. This adverse event can be related to procedural factors or anatomic features [1]. Most commonly, the left main coronary artery is involved; however, obstruction of the ostium of the right coronary artery (RCA) might occur if a calcified leaflet is displaced over the ostium [2, 3]. In this case report, we describe a patient who had RCA obstruction during TAVI. The case was a 90-year-old female with symptomatic critical aortic stenosis (peak velocity of 5.9 m/s, aortic valve area of 0.35 cm2 and a mean gradient of 88 mmHg), a reduced left ventricular ejection fraction (42%), no significant coronary artery disease and a Society of Thoracic Surgeons score of 7.3%. The following measurements were obtained from preoperative computed tomography (CT): aortic valve annulus diameters of 26 mm (major) and 20 mm (minor); leaflet lengths of 11.2 mm (right), 11.2 mm (noncoronary) and 13.7 mm (left); very small sinus of valsalva (SOV) diameter (23 mm) (Fig. 1b) for the RCA and 27.4 mm for the left coronary; and severe bulky calcification (Fig. 1a, c, d) at the edge of the right coronary cusp. The ratio of leaflet length/coronary height at the right coronary cusp was 0.99. We used a 2-step approach to protect the RCA, because of the bulky calcified leaflet at the right coronary cusp and the small SOV. As the first step, we inserted a wire and balloon to the mid-portion of the RCA (Fig. 1e) before balloon aortic valvuloplasty (BAV) with a 20-mm balloon. After that, we performed balloon dilatation at the ostium of the RCA. Fortunately, cusp blockage was not observed immediately after balloon deflation. The first step may not necessarily be needed in all cases. However, we are concerned about cusp blockage after valvuloplasty. Only wire and/or balloon protection might be needed and not balloon dilatation. As the second step, we performed stent-set up (Fig. 1f) before TAVI with a 23-mm SAPIEN 3 (Edwards Lifesciences, Irvine, CA, USA). Immediately after valve deployment, there were no ST-segment changes; however, she had ventricular fibrillation that required two defibrillation shocks. A repeat aortogram showed no flow in the RCA secondary to ostial occlusion (Fig. 1g). Percutaneous coronary intervention (PCI) was performed immediately at the ostium of the RCA using the set-up stent with high radial force (BMX-J 3.5 × 18 mm, Terumo, Tokyo, Japan) (Fig. 1h), and the obstruction was eliminated. We performed CT on postoperative day 9, and it showed that the bulky calcification (dotted red circle) between the coronary stent and THV (blue asterisks) was sealed (Fig. 1i). Blue arrow indicates the site of coronary ostium. She was discharged 14 days after the procedure. At 1 year of follow-up, the patient had no symptoms of ischemia, and her functional status and cardiac performance had improved significantly. In conclusion, in this case at very high risk of coronary obstruction, coronary protection using a 2-step approach was helpful and effective to avoid a catastrophic complication.

Letter by Murakami et al Regarding Article, “Unrestrictive Aortopulmonary Window: Extreme Presentation as Non-Eisenmenger in a 30-Year-Old Patient”

We read with great interest the article by Myers and colleagues1 that reported a case without Eisenmenger syndrome in a 30-year-old patient with aortopulmonary window. It is a thought-provoking case; however, the evaluation of her hemodynamics deserves comment. The title of the article is “Unrestrictive Aortopulmonary Window.” However, the preoperative systolic pressure of pulmonary artery was 40% of systemic pressure. It means the defect is “restrictive,” we think. It can be one of the causes of non-Eisenmenger. Pulmonary vascular resistance (PVR) is obtained by dividing the pulmonary driving pressure (mean pulmonary artery pressure minus mean left …