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.

Pericarditis-complicated takotsubo cardiomyopathy in a patient with rheumatoid arthritis.

A 64-year-old woman with medication-controlled rheumatoid arthritis (RA) was admitted to our hospital complaining of chest pains. An electrocardiogram showed elevated ST-segments in the inferior leads, and inverted T-waves in the left precordial leads. Left ventriculography demonstrated apical ballooning, and cardiac magnetic resonance imaging demonstrated apical ballooning of the left ventricle, and moderate pericardial effusion. The patient was diagnosed with takotsubo cardiomyopathy (TTC), complicated by pericarditis. In the literature, autoimmune disorders have been associated with TTC. We suggest that this patient's pericardial effusion was caused by TTC, and that her coexisting RA might have played a role in the etiology of the significant pericardial fluid accumulation.

Pericardial Involvement in IgG4-related Disease.

We herein report the case of a 65-year-old man with pericardial involvement associated with autoimmune pancreatitis. Chest CT imaging showed pericardial thickening. The patient responded to corticosteroid therapy, and the pericardial thickening resolved. Multiple organs are involved in immunoglobulin G4 (IgG4)-related disease (IgG4-RD); however, only a few cases of IgG4-related chronic constrictive pericarditis have been reported. To our knowledge, this is the first reported case of IgG4-RD with pericardial involvement at an early stage. This case indicates that recognizing pericardial complications in autoimmune pancreatitis is important and that CT imaging may be useful for obtaining the diagnosis and providing follow-up of pericardial lesions in cases of IgG4-RD.

Left ventricular outflow tract obstruction with abnormal papillary muscles.

A 65-year-old man with a history of hypertension was admitted to our hospital with fainting and syncope. He had experienced recurrent syncope since 20 years of age. On admission, systolic heart murmur was audible at the apex of the heart. Echocardiography revealed anteriorly displaced papillary muscles (PMs), elongation of the anterior mitral valve leaflet (AML), and systolic anterior motion (SAM) of the AML. Color Doppler imaging showed accelerated flow with a pressure gradient (PG) of 56 mmHg at the left ventricular outflow tract (LVOT). Cardiac magnetic resonance imaging revealed mild asymmetric septal hypertrophy and multiple accessory PMs. Cine images clearly demonstrated SAM and LVOT obstruction due to anteriorly displaced PMs. Based on these findings, the patient was diagnosed as having hypertrophic cardiomyopathy and LVOT obstruction due to abnormal PMs. Oral administration of bisoprolol (2.5 mg/day) was initiated, because the patient rejected surgical treatment. Follow-up echocardiography revealed a gradual decrease in the LVOT-PG to 24 mmHg, and no episodes of fainting or syncope have recurred for 2 years after the initiation of bisoprolol. .

Polymorphic ventricular tachycardia in a patient with hypertrophic cardiomyopathy and digitalis intoxication.

We report the case of a 74-year-old woman who presented with recurrent episodes of polymorphic ventricular tachycardia (PVT) with a normal QT interval due to digitalis intoxication (serum digoxin concentration, 5.0 ng/mL) and severe hyperkalemia (serum potassium level, 8.3 mEq/L). In addition, laboratory data showed elevated levels of blood urea nitrogen (54 mg/dL) and serum creatinine (1.57 mg/dL), suggesting dehydration. She had been treated with a combination of digoxin and eplerenone for atrial fibrillation and heart failure. The PVT resolved after treatment for hyperkalemia. Cardiac magnetic resonance imaging and left ventriculography showed left ventricular hypertrophy predominantly in the apex, suggesting apical hypertrophic cardiomyopathy (HCM). We presume that the presence of HCM was related to the occurrence of PVT in this patient with digitalis intoxication and hyperkalemia. .

Coronary arteriovenous fistulas complicated by complete atrioventricular block: A case report.

We report the case of a patient with bilateral coronary arteriovenous fistulas (CAVFs) connecting the right coronary artery and left circumflex coronary artery with the right atrium who had progression of first-degree atrioventricular (AV) block to complete AV block during a 4-year period. The His bundle electrogram revealed that the complete AV block was the result of a block at the level of the AV node. Dipyridamole stress thallium-201 myocardial imaging showed decreased perfusion in the inferoapical wall. Coronary angiography and computed tomography showed fistulas that arose from the AV nodal branch of the right coronary artery and from the distal portion of the circumflex coronary artery and drained into the right atrium. Because the fistulas were small, they were not repaired surgically, and a permanent pacemaker was implanted to treat the complete AV block. We presumed that the complication by complete AV block was due to abnormalities of the arteries feeding the AV node and chronic ischemia resulting from a coronary steal associated with the fistulas. To the best of our knowledge, this is the first report of CAVF complicated by complete AV block.

Rapid progression of coronary artery disease in a patient with retroperitoneal fibrosis.

A 76-year-old woman with a history of hypertension and dyslipidemia was admitted to our hospital because of chest pain. On the basis of an electrocardiogram showing ST elevation in V1-3 leads, the patient was diagnosed with acute anterior myocardial infarction. Coronary angiography (CAG) revealed occlusions of the mid portion of the left anterior descending artery (LAD) and distal portion of the left circumflex artery (LCX). A paclitaxel-eluting stent was implanted in the LAD. Two weeks later, the patient complained of abdominal pain. A computed tomography (CT) scan showed a perivascular cuff around the abdominal aorta and F18-fluorodeoxyglucose positron-emission tomography with CT (FDG-PET/CT) scan showed increased tracer uptake around the abdominal aorta and aortic arch, suggestive of retroperitoneal fibrosis. The second CAG, performed on day 46, revealed occlusion of the posterolateral branch of the LCX and rapidly progressing stenosis of the proximal portion of the LCX. The patient was suspected of coronary arteritis and received oral corticosteroid therapy. The third CAG, performed on day 77, revealed occlusion of the posterior descending branch of the right coronary artery. The corticosteroid therapy was gradually tapered after discharge. The fourth CAG, performed 5 months later, did not show progression of the coronary lesions.

Late onset of cholesterol crystal embolism after thrombolysis for cerebral infarction.

A 73-year-old man was admitted to our hospital because of bilateral foot pain. He was treated with thrombolysis for cerebral infarction about 5 months ago. Anticoagulants had not been used because of hemorrhagic infarction. The pulses of bilateral pedal arteries were palpable, but cyanosis was present in the bilateral toes. Laboratory data indicated azotemia and eosinophilia. Magnetic resonance imaging revealed multiple plaques of the thoracic and abdominal aorta, one of which was ulcerated. Skin biopsy proved the diagnosis of cholesterol crystal embolism (CCE). Because no invasive vascular procedure was performed, we assumed that CCE in this patient was related to thrombolysis. We should be cautious for late onset of CCE after thrombolysis.

Fatal cytomegalovirus infection with CD4+ T-lymphocytopenia during corticosteroid therapy for bronchial asthma.

An 80-year-old woman was admitted with dyspnea. She had been treated with oral prednisolone for bronchial asthma. She was intravenously treated with dexamethasone. On the 9th day, she presented oliguria and thrombocytopenia. She was diagnosed as dehydration and disseminated intravascular coagulation, and was treated with hydration and heparin infusion. On the 12th day, she presented macroscopic hematuria and melena. Cystoscopy revealed hemorrhagic cystitis. Bone marrow aspiration showed hemophagocytosis. Serum antigen of cytomegalovirus (CMV) was positive. CD4+ T cell count was very low (40/microL). She was diagnosed as disseminated CMV infection, and was treated with gancyclovir and immunoglobulin infusion. On the 14th day, she died of pneumonia. This is the first report of fatal CMV infection during corticosteroid therapy for bronchial asthma.

A case of left ventricular diverticulum: Change of characteristics after myocardial infarction and usefulness of cardiac computed tomography.

A 72-year-old man with an old myocardial infarction was admitted to our hospital for cardiac reexamination. He had suffered from an inferior myocardial infarction when he was 60-year-old. The left ventriculogram had then shown a small contractile diverticulum at the apical portion of the left ventricle. Anterior myocardial infarction had recurred when he was 63-year-old. The left ventriculogram performed after the anterior myocardial infarction revealed that the diverticulum had become dilated and non-contractile. On admission, electrocardiography and chest X-ray showed no remarkable changes from the previous studies. Cardiac computed tomography (CT) demonstrated an apical left ventricular diverticulum with narrow communication to the main chamber and myocardial discontinuity of the wall at the site of the diverticulum. Tc-99m tetrofosmin myocardial images showed a perfusion defect in the apex. We presumed that a muscular left ventricular diverticulum had changed to the fibrous type after the anterior myocardial infarction. Cardiac CT imaging provides accurate evaluation of the left ventricular diverticulum and is useful for the differentiation between a left ventricular diverticulum and an aneurysm.

Impact of inflow reduction of arteriovenous fistula on systemic hemodynamics in a patient with high-output heart failure during hemodialysis: A case report.

A 68-year-old woman was admitted with dyspnea. The patient had been treated with hemodialysis for renal failure for 11 years. On admission, chest X-ray showed pulmonary edema. Right-heart catheterization revealed high cardiac output (11.8 l/min) and elevated pulmonary capillary wedge pressure (PCWP). Doppler ultrasonography showed high-flow of an arteriovenous fistula (AVF) for hemodialysis. The patient was diagnosed as having high-output heart failure due to a high-flow AVF. Inflow reduction of the AVF was performed by proximal radial artery ligation. Right-heart catheterization performed 2 weeks after the operation revealed that cardiac output had decreased from 11.8 to 9.5 l/min and PCWP was also reduced from 21 to 9 mmHg. Furthermore, flow of the AVF measured by Doppler ultrasonography was also decreased. To our knowledge, this is the first report that assessed hemodynamics of high-output heart failure before and after inflow reduction of the AVF by repeated right-heart catheterization.

Pilsicainide intoxication presenting as left ventricular dyssynchrony in a patient on hemodialysis.

We report here a case of pilsicainide intoxication presenting as left ventricular dyssynchrony in a patient who had been treated on hemodialysis. This is the first report that assessed cardiac function during pilsicainide intoxication by left ventriculography and right heart catheterization.

Aortoesophageal fistula following nasogastric tube placement.

A 78-year-old woman was admitted to our hospital because of fresh cerebral infarction. She had been diagnosed as having rheumatoid arthritis, but had not been treated for 50 years. She could not take in sufficient food. Upper gastrointestinal endoscopy revealed no esophageal or gastric lesions, but the procedure was difficult because of her stiff neck from severe rheumatoid degenerative changes of the cervical spine. A nasogastric (NG) tube was placed, and enteral nutrition was initiated. On the 15th day from initiation of enteral nutrition, she presented hematemesis, and suddenly went into a state of shock and died. An autopsy revealed two esophageal ulcers, one of which penetrated into the descending thoracic aorta. The patient was diagnosed with hemorrhagic shock due to aortoesophageal fistula. We suspect that the NG tube compressed the esophageal wall, and ischemia caused the ulcers.

Takotsubo cardiomyopathy with marked ST-segment elevation and electrical alternans complicated with hyperglycemic hyperosmolar state.

This is the first report of a case of Takotsubo cardiomyopathy with a hyperglycemic hyperosmolar state (HHS). This case presented with marked ST-segment elevation and electrical alternans, uncommon findings in Takotsubo cardiomyopathy. We believe that hyperosmolarity-induced myocardial dehydration and consequent increase in intracellular calcium concentration may be the mechanism of Takotsubo cardiomyopathy and electrical alternans in HHS.

Syncope due to paroxysmal atrioventricular block in a patient with systemic sclerosis: a case report.

A 79-year-old woman with systemic sclerosis was admitted to our hospital because of syncope. On admission, electrocardiogram showed progression of intraventricular conduction defect. Chest radiograph showed marked cardiomegaly. Echocardiogram revealed deterioration of left ventricular systolic function. We suspected progressive myocardial disease with Stokes-Adams attack. When we were preparing a temporary pacemaker, paroxysmal atrioventricular block with asystole for 15 seconds and convulsion occurred. Electrophysiological study showed His-ventricular block and sinus node dysfunction. A permanent pacemaker was implanted. In systemic sclerosis, progression of ventricular conduction defect may warrant prompt electrophysiological study and prophylactic pacemaker implantation.

Ruptured aneurysm of the sinus of Valsalva with Wildervanck syndrome (cervico-oculo-acoustic syndrome), blepharoptosis and short stature: case report.

A 62-year-old woman was admitted to hospital because of nausea. A grade 5/6 continuous murmur was audible near the left sternal border at the second intercostal space. Chest X-ray showed cardiomegaly and bilateral pleural effusion. She was diagnosed as heart failure and a diuretic was prescribed. After remission of the heart failure, echocardiography showed shunt flow from the right coronary cusp to the right ventricle. Aortography revealed that an aneurysm of the right coronary sinus of Valsalva had ruptured into the right ventricle. Coronary angiography revealed a single coronary artery. Chest computed tomography revealed persistent left superior vena cava. Surgical repair was carried out and the patient made an uneventful recovery. In addition to these cardiovascular abnormalities, she had Wildervanck syndrome (Klippel-Feil syndrome, Duane syndrome and sensorineural hearing disturbance), blepharoptosis and short stature. This rare combination has not been reported previously.

Acute myocardial infarction following hormone replacement in hypothyroidism.

Patients with hypothyroidism have an increased risk of coronary artery disease because of significant changes in lipid metabolism and arterial hypertension. We report a 67-year-old man who developed acute myocardial infarction following hormone replacement in hypothyroidism in spite of no previous cardiac symptoms and no ischemia in intravenous dipyridamole myocardial perfusion imaging. Careful examination for ischemic heart disease should be performed before hormone replacement in hypothyroidism.