Life-threatening coronary vasospasm in patients with type 2 diabetes with SGLT2 inhibitor-induced euglycemic ketoacidosis: a report of two consecutive cases.

Euglycemic diabetic ketoacidosis (eDKA) has emerged as an adverse event associated with sodium-glucose transporter-2 inhibitors (SGLT2i). We present two consecutive cases of SGLT2i-induced eDKA, both manifested as life-threatening coronary vasospastic angina (VSA). Case 1: A 64-year-old male overweight patient with type 2 diabetes (BMI 28.2 kg/m2), treated with dapagliflozin 5 mg daily for 6 months and a restricted diet for 2 months, experienced loss of consciousness following severe chest pain while driving, resulting in a traffic accident: plasma glucose, 163 mg/dL; urine ketones, (+++); bicarbonate (HCO3-), 13.2 mmol/L; and total ketone body, 1539 µmol/L. Coronary angiography (CAG) performed on day 5 revealed diffusely spastic coronary arteries with 90% stenosis in the right coronary artery, leading to the diagnosis of VSA in the presence of coronary atherosclerosis. Case 2: A 63-year-old male patient with type 2 diabetes (BMI 22.2 kg/m2) experienced severe chest discomfort and faintness following 2 months of chest pain while on dapagliflozin 10 mg daily for 1 year: plasma glucose, 112 mg/dL; urine ketones, (+++); HCO3-, 15.3 mmol/L; and total ketone body, 10,883 µmol/L. CAG performed on day 10 revealed no organic stenosis but diffusely spastic coronary arteries in response to coronary ergonovine infusion, confirming the diagnosis of VSA. SGLT2i has the potential to inhibit acetylcholine and butyrylcholine esterase activities, leading to reduced scavenging of acetylcholine and possible induction of coronary vasospasm. These cases highlight the association between life-threatening VSA and SGLT2i-induced eDKA.

Plaque rupture and neovascularisation detected with optical coherence tomography in a case of Kounis syndrome.

Kounis syndrome is an allergic acute coronary syndrome (ACS) characterised by coronary artery spasm, plaque erosion/rupture or stent thrombosis caused by mast cell and other interacting cell activation. Although intracoronary imaging modalities can detect those ACS mechanisms, Kounis syndrome due to plaque rupture has rarely been reported using intracoronary imaging. We present the case of a woman in her 70s who developed Kounis syndrome as a result of plaque rupture detected with optical coherence tomography (OCT). She had non-ST-segment elevation ACS as a result of anaphylaxis to cefazolin. Coronary angiography revealed severe stenosis in the left anterior descending artery; angiographically undetectable plaque rupture was detected using OCT. OCT also revealed intraplaque neovascularisation, suggesting that the culprit plaque had been vulnerable. OCT can aid in understanding the underlying mechanisms of Kounis syndrome.

Atypical Aortic Coarctation in a Patient with an Acute Exacerbation of Multiple Organ Failure: Successful Endovascular Therapy and Spontaneous Retroperitoneal Bleeding.

We experienced a case of acute multiple organ ischemia and multiple organ failure due to atypical aortic coarctation (AAC). Since the patient's hemodynamics were too unstable to perform surgical revascularization, we performed urgent endovascular therapy (EVT) with a stent. Eventually, the patient achieved remission from multiple organ failure and a satisfactory clinical outcome. We feel that EVT for AAC is a sufficiently effective treatment option if the purpose of EVT is to save a patient's life in the acute phase. In the present case, spontaneous retroperitoneal bleeding (SRB) occurred after EVT of AAC, but this is a rare incident, although noteworthy in the clinical course.

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases.

AIMS: The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. METHODS AND RESULTS: We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analysed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as 'pathogenic' by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from 'Uncertain significance' to 'Likely pathogenic' in six probands. CONCLUSION: Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD.

Novel use of a stent graft for uncontrollable intraprocedural stent thrombosis in a patient with acute myocardial infarction.

We report the case of a patient who developed uncontrollable intraprocedural stent thrombosis (IPST) during an emergent percutaneous coronary intervention for acute myocardial infarction that was mitigated only by covering the culprit lesion with a stent graft. Although several factors can induce stent thrombosis, IPST was likely a result of intrastent plaque protrusion in this patient. This is the first case report on the use of stent graft implantation as an effective bailout procedure for uncontrolled IPST. The findings described in this case study warrant the adoption of stent grafts for the complete sealing of plaque protrusion in lesions.

Hereditary Hemorrhagic Telangiectasia with SMAD4 Mutations Is Associated with Fatty Degeneration of the Left Ventricle, Coronary Artery Aneurysm, and Abdominal Aortic Aneurysm.

A 52-year-old man with recurrent epistaxis and palpebral conjunctival telangiectasia visited our hospital for a follow-up checkup for gastrointestinal polyposis. At 48 years of age, he underwent Y-graft replacement for an abdominal aortic aneurysm. Arteriovenous malformation was detected in his lungs, and a genetic test revealed an SMAD4 mutation. Eventually, he was diagnosed with juvenile polyposis-hereditary hemorrhagic telangiectasia (JP-HHT) syndrome. In addition, fatty degeneration of the left ventricle and a coronary aneurysm were detected. This is the first report suggesting the possibility of an association between these manifestations and JP-HHT due to SMAD4 mutations. Examining cardiovascular disorders in JP-HHT patients is imperative.

Localized Right Subclavian Artery Dissection Detected by Accident on an Ultrasound Examination: A Case Report and Literature Review.

Right subclavian artery dissection was detected in a 78-year-old female victim of the Kumamoto earthquake during a carotid artery ultrasound examination. She was subsequently taken to hospital and diagnosed with localized subclavian artery dissection (LSAD) by contrast-enhanced computed tomography. There have been no previous reports of LSAD detected at a medical checkup. LSAD may progress and become severe, even in asymptomatic patients or patients with mild symptoms, and careful long-term follow-up is therefore required in all patients diagnosed with LSAD.

Glossopharyngeal Neuralgia with Syncope Caused by Recurrence of Esophageal Squamous Cell Carcinoma.

We herein report a case of glossopharyngeal neuralgia with repeated syncope caused by the recurrence of esophageal carcinoma. The typical symptoms of glossopharyngeal neuralgia are paroxysmal, stabbing, electric shock-like pain in the pharynx and/or base of the tongue on swallowing and talking. In addition, syncope can also be caused by glossopharyngeal neuralgia. The diagnosis of glossopharyngeal neuralgia is not always easy because of its rarity. In the present case, we suspected that repeated syncope was caused by glossopharyngeal neuralgia due to the recurrence of esophageal carcinoma. Concurrent chemoradiation therapy was effective in reducing the tumor size, which resulted in the complete resolution of the symptoms.

Short- and long-term benefits of drug-eluting stents compared to bare metal stents even in treatment for large coronary arteries.

Although drug-eluting stents (DES) for percutaneous coronary intervention (PCI) have dramatically reduced the incidence of in-stent restenosis, their deployment for large-size coronary lesions is still controversial because of problems such as late in-stent thrombosis and late catch-up in DES. We aimed to evaluate the long-term outcome beyond 2 years of bare metal stents (BMS) as compared with DES in large vessels. Consecutive 228 patients who underwent PCI with large-size stents (>3.5 mm in diameter) in our hospital were enrolled in this study. The end points of this study are target lesion revascularization (TLR) and occurrence of major adverse cardiac events (MACE) for subject patients. We analyzed 183 patients (152 men, mean age 65.8 ± 10.5 years) whose outcome could be followed up for at least 2 years. At the first 8-month follow-up, clinically driven TLR rate was significantly higher in patients who received BMS than those who received DES (17.2 vs. 2.2 %, p < 0.05), although the rate of TLR was not different between the 2 groups beyond 8 months. Thus, overall rate of TLR was higher in BMS than in DES (22.7 vs. 5.4 %, p < 0.05). Under these conditions, the higher rate of TLR for BMS was observed in simple as well as complex lesions with or without diabetes, although there were no significant differences in MACE between BMS and DES. Multivariate analysis showed that BMS was an only independent factor of TLR at the 8 month follow-up period [p = 0.004, odds ratio 9.58, 95 % confidence interval (2.10-43.8)]. These results demonstrate that the rate of in-stent restenosis in large-size coronary lesions was transiently higher in the first 8 months for patients implanted with BMS compared with DES in which no in-stent thrombosis and TLR beyond 2 years were observed. We suggest using the DES even in large-size coronary lesions in terms of short- and long-term outcomes.

Life-threatening ventricular arrhythmia due to silent coronary artery spasm: usefulness of I-123 metaiodobenzylguanidine scintigraphy for detecting coronary artery spasm in the era of automated external defibrillators: a case report.

INTRODUCTION: Cardiac arrhythmia is sometimes life-threatening, and automated external defibrillators are presently used in some countries. Coronary artery spasm is one of the primary causes of life-threatening arrhythmia. In general, chest symptoms are key indicators of possible coronary artery spasm; however, if chest symptoms are not present, clinicians may not suspect this disease. We encountered a patient who had recovered from ventricular fibrillation treated by using an automated external defibrillator, and silent coronary artery spasm was considered to be the cause of this life-threatening arrhythmia. In this case, I-123 metaiodobenzylguanidine scintigraphy was a useful screening tool for a silent coronary artery spasm. CASE PRESENTATION: A 72-year-old Japanese man was transferred to our hospital after recovering from ventricular fibrillation treated by using an automated external defibrillator. He had never complained of chest symptoms previously. Decreased uptake of I-123 metaiodobenzylguanidine was observed in the inferolateral and anteroseptal walls of the left ventricle. A spasm provocation test of the coronary artery was performed, and silent coronary artery spasm was diagnosed as the underlying disease. CONCLUSION: Non-invasive I-123 metaiodobenzylguanidine scintigraphy was a useful screening tool for silent coronary artery spasm as a possible cause of cardiopulmonary arrest in a patient with no chest symptoms.

Intra-cardiac thrombus resolution after anti-coagulation therapy with dabigatran in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy: a case report.

INTRODUCTION: Although dabigatran, a novel oral anti-coagulant, has been approved for the prevention of thromboembolism in patients with non-valvular atrial fibrillation, the efficacy of dabigatran for the resolution of established intra-cardiac thrombi has not been validated. Herein is describe a case in which dabigatran was effective for thrombus resolution in a patient with a left ventricular aneurysm. CASE PRESENTATION: A 59-year-old Japanese man with a mid-ventricular obstructive hypertrophic cardiomyopathy-associated apical aneurysm presented with a left ventricular apical thrombus (15.0mm×17.0mm). Anti-coagulation therapy with dabigatran (150mg b.i.d. with meals) was initiated. Following dabigatran administration, weekly echocardiographic examinations demonstrated gradual decreases in thrombus size. After three weeks, no thrombus was detected and no systemic thromboembolic events had occurred. CONCLUSIONS: The left ventricular apical thrombus resolved after dabigatran administration. Hence, dabigatran may represent an alternative to warfarin as a therapeutic option in patients with previously detected intra-cardiac thrombus.

Rapid changes in plaque composition and morphology after intensive lipid lowering therapy: study with serial coronary CT angiography.

Although intensive lipid lowering by statins can enhance plaque stability, few data exist regarding how early statins change plaque composition and morphology in clinical setting. Therefore, to examine early changes in plaque composition and morphology by intensive lipid lowering with statins, we evaluate coronary plaques from acute coronary syndrome (ACS) before and 3 weeks after lipid lowering by coronary CT angiography. We enrolled 110 patients with suspected ACS and underwent coronary CT. We defined plaque as unstable when CT number of plaque< 50HU and remodeling index (lesion diameter/reference diameter) >1.10. Rosuvastatin (5 mg/day) or atorvastatin (20 mg/day) were introduced to reduce low density lipoprotein cholesterol (LDL-C). Then, CT was again performed by the same condition 3 weeks after lipid lowering therapy. Total 10 patients (8 men, mean age 72.0 years), in whom informed consent regarding serial CT examination was obtained, were analyzed. Among them, 4 patients who denied to have intensive lipid lowering were served as controls. In remaining 6 patients, LDL-C reduced from 129.5±26.9 mg/dl to 68.5±11.1 mg/dl after statin treatment. Under these conditions, CT number of the targeted plaque significantly increased from 16.0±15.9 to 50.8±35.0 HU (p<0.05) and remodeling index decreased from 1.22±0.11 to 1.11±0.06 (p<0.05), although these values substantially unchanged in controls. These results demonstrate that MDCT-determined plaque composition as well as volume could be changed within 3 weeks after intensive lipid lowering. This may explain acute effects of statins in treatment of acute coronary syndrome.

Coronary artery stenting in a patient with factor XI deficiency.

Factor XI deficiency is a rare inherited coagulopathy first described in Ashkenazi Jews. In Japanese populations, factor XI deficiency is thought to be very rare. This disorder causes unique problems during percutaneous coronary intervention (PCI). During PCI, prevention of thrombosis is important and heparin is usually used for anticoagulation. However, care must also be taken to avoid serious complications of bleeding. These two situations are contradictory and anticoagulation with heparin might increase severe bleeding in patients with factor XI deficiency. An 84-year-old Japanese woman was admitted to our hospital for the treatment of worsening effort angina pectoris. A coronary angiography revealed severe stenotic lesions at the left main trunk (LMT) and the right coronary artery (RCA). While performing PCI of the LMT, 8,000 U of heparin were used and the patient underwent successful drug-eluting stent implantation. At this point, the patient's activated coagulation time was over 1,500 s and there was a marked decrease of factor XI activity (<3%: normal range 75-145%). After the diagnosis of factor XI deficiency, PCI for the RCA was scheduled without anticoagulation and fresh frozen plasma instead of dual antiplatelet therapy by aspirin and clopidogrel. Two drug-eluting stents were deployed and dilation using the kissing balloon technique was performed. The procedure was uneventful without stent thrombosis or distal embolization or bleeding. Because the literature on stenting for patients with factor XI deficiency is very limited, this case provides additional clinical information.

A case of acute myocardial infarction with repetitive stent thrombosis during emergent percutaneous coronary intervention. Transient decrease in antithrombin III activity and heparin resistance.

A 59-year-old woman was admitted to our hospital for the treatment of an acute anterior myocardial infarction. She had a history of uncontrolled diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking. Coronary angiography revealed 90% stenosis with spontaneous dissection in the proximal portion of the left anterior descending artery. At this time, heparin was initiated for the first time. Although direct stenting (Be-stent, 3.0-18 mm) was performed for the culprit lesion, coronary dissection occurred at the left main trunk and additional stenting (Multi Link ZETA stent 3.5-15mm) was performed for the left main trunk. Soon after stenting, repetitive stent thrombosis occurred. Aspiration of the thrombus using an aspiration catheter was ineffective and repetitive angioplasty and intraaortic balloon pumping were required. Although we used 17,000 units of unfractionated heparin during the intervention, the activated coagulation time (ACT) was not prolonged (157 seconds). In the coronary care unit, the ACT and activated partial prothrombin time (aPTT) were not prolonged despite the use of large amounts of heparin (69,000 units in 2 days). Protein-S, protein-C, and hepaplastin testing were within normal limits and heparin-platelet factor IV complex antibody was not detected. In the acute phase, a decrease in the antithrombin III activity (65%) was noted and with administration of argatroban, prolongation of the aPTT was achieved. In the chronic phase, the decrease in antithrombin III activity and heparin resistance had improved spontaneously. It is important to recognize the existence of transient decreases in antithrombin III activity in the acute phase of myocardial infarction.

Persistent left bundle branch block in a patient with dilated cardiomyopathy that improved with low dose carvedilol therapy.

A 43-year-old Japanese woman with dilated cardiomyopathy had complete left ventricular bundle branch block (CLBBB), which had persisted for at least two years. At the time of admission, the serum brain natriuretic peptide (BNP) concentration was 502 pg/mL (normal range, 0-18 pg/mL), the left ventricular diastolic dimension (LVDd) was 59 mm, the left ventricular systolic dimension (LVDs) was 54 mm, the %fractional shortening (FS) was 8%, and the left ventricular ejection fraction (LVEF) was 19.7% by echocardiography. Low dose carvedilol was initiated for the treatment of heart failure. Adverse effects, such as progression of cardiac conduction disturbances, did not occur after initiation of carvedilol therapy. About one year after initiation of carvedilol therapy, the CLBBB disappeared and a significant improvement in left ventricular function was noted. The LVDd was 44 mm, the LVDs was 30 mm, the %FS was 33%, and the LVEF was 61%, and the serum BNP concentration was decreased to 18.5 pg/mL. We describe a case in which low dose carvedilol was effective for treating both CLBBB and left ventricular function.

Coronary artery multistenting in the treatment of life-threatening refractory coronary spasm after coronary artery bypass grafting.

A 74-year-old man had undergone on-pump coronary artery bypass grafting (CABG) for effort-induced angina pectoris. Soon after CABG using the left internal thoracic artery for the left anterior descending artery and saphenous vein for the left circumflex artery, ST elevation was found in the inferior leads and complete atrioventricular block, ventricular tachycardia, and circulatory collapse occurred. Emergent coronary angiography revealed diffuse severe spasm of the right coronary artery (RCA). Despite the intravenous and intracoronary administration of massive doses of vasodilators and intra-aortic balloon pumping, the coronary spasm did not resolve. Five stents were deployed from the distal to the proximal portion of the RCA. After multistenting, coronary flow was dramatically improved and the ST elevations in the inferior leads were also improved. Coronary artery spasm after CABG is relatively rare, but when it occurs, it can be fatal. Multistenting is a useful treatment for life-threatening refractory coronary spasm after CABG.

Usefulness of fluorine-18-fluorodeoxyglucose positron emission tomography in a patient with Takayasu's arteritis associated with antiphospholipid syndrome.

A 36-year-old woman was admitted for recurring chest pain and hemoptysis. Blood pressure in the right and left arms was equal, and no murmurs or bruits were heard. Body temperature was normal on admission and remained within the normal range during the hospital stay. C-reactive protein was slightly elevated (2.3 mg/dL) and lupus anticoagulant was positive. Angiography showed no abnormality of the aorta or its branches, but the left pulmonary artery showed occlusion at the proximal portion. Computed tomography (CT) revealed segmental wall thickening of the thoracic aorta. Fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG PET) showed high uptake in the proximal portion of the left pulmonary artery and in the thoracic aorta with wall thickening on CT. Based on these findings, a diagnosis of Takayasu's arteritis associated with antiphospholipid syndrome was made and high-dose steroid therapy (prednisolone 30 mg/day) was started. Two months later, the C-reactive protein level had decreased from 2.3 mg/dL to 1.1 mg/dL, and both the focal wall thickening and (18)FDG uptake of the thoracic aorta were decreased. 18FDG PET was useful for evaluating the efficacy of the steroid therapy in addition to making a diagnosis of Takayasu's arteritis associated with antiphospholipid syndrome.

Abnormal sympathetic innervation of the heart in a patient with Emery-Dreifuss muscular dystrophy.

A 33-year-old man was admitted for general malaise and vomiting. An electrocardiogram showed a complete atrioventricular block and an echocardiogram showed right atrial dilatation and normal wall motion of left ventricle (LV). Gene analysis showed nonsense mutation in the STA gene, which codes for emerin, and Emery-Dreifuss muscular dystrophy was diagnosed. An endomyocardial biopsy of right ventricle showed mild hypertrophy of myocytes. Myocardial scintigraphic studies with Tc-99m methoxyisobutylisonitrile (MIBI) and I-123-betamethyl-p-iodophenylpentadecanoic acid (BMIPP) scintigrams showed no abnormalities. In contrast, I-123 metaiodobenzylguanidine (MIBG) scintigrams showed a diffuse and severe decrease in accumulation of MIBG in the heart. Six months later, his LV wall motion on echocardiograms developed diffuse hypokinesis. These results suggest that the abnormality on I-123 MIBG myocardial scintigrams may predict LV dysfunction in Emery-Dreifuss muscular dystrophy.

High incidence of sudden cardiac death with conduction disturbances and atrial cardiomyopathy caused by a nonsense mutation in the STA gene.

BACKGROUND: The STA gene encodes emerin and is one of the genes that is affected in Emery-Dreifuss muscular dystrophy (EDMD). Although it has been reported that EDMD caused by the STA gene mutation is associated with X-linked recessive inheritance, the genotype-phenotype correlations, with special reference to cardiac manifestations, are not well defined. METHODS AND RESULTS: We identified 16 carriers (7 male and 9 female) with a nonsense mutation in exon 6 of the STA gene in 2 EDMD families. Pacemakers were required for treatment of bradyarrhythmias in all 7 male carriers and in 2 of the 9 female carriers. In addition, 2 of the 9 female carriers displayed atrial fibrillation. In these 2 families, 3 males without pacemaker implantation, who were not tested genetically, had died suddenly. In these family members, the majority of carriers with the mutation had not been clinically diagnosed as having EDMD before genetic testing because of extremely mild or nonexistent skeletal myopathy. CONCLUSIONS: EDMD caused by this mutation is characterized by atypical clinical features and incomplete penetrance of the clinical phenotype and may result in serious cardiac complications, including sudden death. Approaches to preventing possible sudden death in carriers with the STA gene mutation require further study.