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Abstract Background We examined whether the pharmacodynamic drug–drug interaction between esaxerenone and trimethoprim enhances the hyperkalemic effect. Methods A retrospective observational study was conducted to identify patients >18 years undertaking esaxerenone alone or esaxerenone plus trimethoprim at Mie University Hospital from May 2019 to December 2022. We performed propensity score-matching (1:1) to compare between-group differences in the maximum change in serum potassium levels (ΔK) using the Mann–Whitney U test. For esaxerenone plus trimethoprim, Spearman's correlation coefficients were used to examine correlations between ΔK and variables, including changes in blood urea nitrogen (ΔBUN), serum creatinine levels (ΔCr), and weekly trimethoprim cumulative dose. Results Out of propensity score-matched groups (n=8 each), serum potassium levels significantly increased after administration of esaxerenone alone (4.4 [4.2 to 4.7] meq/L to 5.2 [4.7 to 5.4] meq/L, p=0.008) and esaxerenone plus trimethoprim (4.2 [4.0 to 5.1] meq/L to 5.4 [4.7 to 5.5] meq/L, p=0.023). ΔK did not significantly differ between the groups (esaxerenone alone; 0.6 [0.3 to 0.9] meq/L vs. esaxerenone plus trimethoprim; 1.0 [0.4 to 1.3] meq/L, p=0.342). ΔK positively correlated with ΔBUN (r=0.988, p

Background: Limited evidence exists regarding the incidence of recurrent venous thromboembolism (VTE) in patients diagnosed with isolated distal deep vein thrombosis (DVT) who are at risk of thrombosis extension whether they receive anticoagulation therapy or not. Objectives: The study aimed to investigate the incidence of recurrent VTE and the impact of rivaroxaban in this patient population. Methods: This open-label, exploratory, and randomized controlled trial was conducted at 7 centers in Japan between April 2019 and April 2022. Adult patients with isolated distal DVT at risk of thrombosis extension received either rivaroxaban combined with physical therapy or physical therapy alone for 90 days. Whole-leg ultrasound was performed at 14 and 90 days. We assessed a composite outcome of symptomatic or asymptomatic proximal DVT or symptomatic pulmonary embolism as the primary outcome until the end of the treatment period using an intention-to-treat analysis. Major bleeding was evaluated as a key secondary outcome. Results: Out of 90 enrolled patients, 3 were excluded due to withdrawal of consent; therefore, we analyzed 87 participants. The rivaroxaban group (n = 42) reported no primary outcomes (0%; 95% CI, 0.0%-8.4%), whereas the physical therapy group (n = 45) had 2 cases of symptomatic proximal DVT (4.4%; 95% CI, 0.5%-15.1%). Major bleeding events occurred in 4 patients in the rivaroxaban group (9.5%; 95% CI, 2.7%-22.6%), whereas no events occurred in the physical therapy group (0%; 95% CI, 0%-7.9%). Conclusion: Preliminary data suggest that rivaroxaban may reduce the risk of VTE recurrence among this patient subset, albeit with an increased incidence of bleeding events.

Abstract Background Recent studies have focused on immune checkpoint inhibitors. Renal complications associated with the use of immune checkpoint inhibitors are uncommon compared with other immune-related adverse events. Acute interstitial nephritis accounts for most of these renal complications, with nephrotic syndrome quite rare. We herein report a case of nephrotic syndrome associated with immune checkpoint inhibitors that was more severe than that in previous cases. By comparing this case with previous reports, the possible reasons for the particular severity of this case are discussed. Case presentation A 75-year-old man developed nephrotic syndrome with acute kidney injury after the first combination therapy of nivolumab and ipilimumab for malignant pleural mesothelioma. The results of a kidney biopsy indicated minimal change disease with mild atherosclerosis, acute interstitial nephritis, and fusion of nearly all podocyte foot processes. Nivolumab and ipilimumab therapy were stopped, and treatment with corticosteroids was initiated. We investigated previously reported cases of nephrotic syndrome using immune checkpoint inhibitors. Seventeen cases of immune checkpoint inhibitor-related nephrotic syndrome, including ours, have been reported. Two of the 17 patients with immune checkpoint inhibitor-related nephrotic syndrome required hemodialysis treatment for acute kidney injury. Unlike many previously reported cases, the present patient was administered two different immune checkpoint inhibitors, which may be one of the reasons for the development of severe nephrotic syndrome. Conclusions In addition to previously reported risk factors, immune checkpoint inhibitor combination therapy can exacerbate nephrotic syndrome compared to immune checkpoint inhibitor monotherapy.

Background Myosin phosphatase targeting subunit 2 (MYPT2) is an important subunit of cardiac MLC (myosin light chain) phosphatase, which plays a crucial role in regulating the phosphorylation of MLC to phospho‐MLC (p‐MLC). A recent study demonstrated mineralocorticoid receptor‐related hypertension is associated with RhoA/Rho‐associated kinase/MYPT1 signaling upregulation in smooth muscle cells. Our purpose is to investigate the effect of MYPT2 on cardiac function and fibrosis in mineralocorticoid receptor‐related hypertension. Methods and Results HL‐1 murine cardiomyocytes were incubated with different concentrations or durations of aldosterone. After 24‐hour stimulation, aldosterone increased CTGF (connective tissue growth factor) and MYPT2 and decreased p‐MLC in a dose‐dependent manner. MYPT2 knockdown decreased CTGF. Cardiac‐specific MYPT2‐knockout (c‐MYPT2−/−) mice exhibited decreased type 1 phosphatase catalytic subunit β and increased p‐MLC. A disease model of mouse was induced by subcutaneous aldosterone and 8% NaCl food for 4 weeks after uninephrectomy. Blood pressure elevation and left ventricular hypertrophy were observed in both c‐MYPT2−/− and MYPT2+/+ mice, with no difference in heart weights or nuclear localization of mineralocorticoid receptor in cardiomyocytes. However, c‐MYPT2−/− mice had higher ejection fraction and fractional shortening on echocardiography after aldosterone treatment. Histopathology revealed less fibrosis, reduced CTGF, and increased p‐MLC in c‐MYPT2−/− mice. Basal global radial strain and global longitudinal strain were higher in c‐MYPT2−/− than in MYPT2+/+ mice. After aldosterone treatment, both global radial strain and global longitudinal strain remained higher in c‐MYPT2−/− mice compared with MYPT2+/+ mice. Conclusions Cardiac‐specific MYPT2 knockout leads to decreased myosin light chain phosphatase and increased p‐MLC. MYPT2 deletion prevented cardiac fibrosis and dysfunction in a model of mineralocorticoid receptor‐associated hypertension.

Abstract Background Severe hypocalcemia may lead to life-threatening arrhythmias. Denosumab is an effective treatment for osteoporosis that allows long intervals between doses. However, there is a risk of hypocalcemia in some patients. Due to the long half-life of denosumab, emergency physicians caring for patients presenting with symptoms of hypocalcemia may not be aware of the medication, and adverse effects may last longer. Case presentation A 55-year-old woman with a history of systemic lupus erythematosus (SLE) and anxiety disorder called for an ambulance for symptoms of hyperventilation and muscle cramps. After evaluation at the local hospital, she developed pulseless ventricular tachycardia and was resuscitated by defibrillation by the hospital staff. After conversion to sinus rhythm, she was transported to a tertiary center. Upon arrival, pulseless ventricular tachycardia occurred again, and veno-arterial extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pumping (IABP) were implemented. Laboratory results showed severe hypocalcemia (corrected calcium level of 5.3 mg/dL) whereupon intravenous calcium supplementation was started. She had received the first dose of denosumab (60 mg) by subcutaneous injection 24 days prior to hospitalization. She was eventually weaned from ECMO and IABP support. Conclusion Cardiac arrest due to hypocalcemia is relatively rare but can be fatal. In the present case, hyperventilation may have acutely exacerbated pre-existing hypocalcemia, leading to ventricular tachycardia. The patient had a slightly decreased serum calcium level prior to denosumab. Close monitoring may be preferable after the primary dose of denosumab in selected patients. Emergency physicians caring for patients who may be suffering from symptoms/signs of hypocalcemia must be mindful of medications that have long half-lives and affect electrolyte balance when treating fatal arrhythmia due to hypocalcemia.

Abstract Background Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a disease entity with nonorganized granular glomerular deposition with monoclonal proteins of both heavy and light chains. Dysproteinemia was observed in only 30% of the patients with PGNMID. We herein report a case of PGNMID with discrepancy between serum and glomerular deposits. Case presentation The patient was a 50-year-old man who had been followed at a local clinic due to hypertension, type 2 diabetes, hyperlipidemia, hyperuricemia, fatty liver, and obesity. Proteinuria had been noted five years previously, and he had been referred to a hematology department due to hyperproteinemia, high gamma globulin, and κ Bence-Jones protein (BJP) positivity one year previously. Bone marrow aspiration showed 5% plasma cells, and he was referred to the nephrology department to evaluate persistent proteinuria. He was hypertensive, and his estimated glomerular filtration rate was 54.2 ml/min/1.73 m2. His urinary protein level was 0.84 g/g⋅Cr. Urine and serum immunofixation showed BJP-κ type and IgG-κ type, respectively. Kidney biopsy showed an increase in mesangial cells and matrix without nodular lesions under a light microscope. Immunofluorescence microscopy showed granular deposits of IgG and C3 on the capillary wall and weak positivity for C1q. IgG3 was predominant among the IgG subclasses, and intraglomerular κ and λ staining was negative for κ and positive for λ. Direct fast scarlet staining was negative. Electron microscopy showed lumpy deposits without a fibrillar structure in the subepithelial area. Based on the above findings, a diagnosis of membranous nephropathy-type PGNMID was made. Since proteinuria increased gradually after three years of treatment with valsartan (40 mg, daily), oral prednisolone (30 mg, daily) was initiated, which led to decreased proteinuria. The dose of oral prednisolone was gradually tapered to 10 mg per day. At that time, proteinuria was 0.88 g/g⋅Cr. We found 204 cases in 81 articles in the PubMed database, among which 8 showed discrepancy in the heavy and/or light chains between serum and kidney. Conclusions We experienced a case of membranous nephropathy-type PGNMID with discrepancy in light chains between serum and kidney that was successfully treated with oral prednisolone.

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.

Recurrent in-stent restenosis of the coronary artery is a rare but intractable problem. In this situation, coronary arteritis should be considered as an etiology. This case highlights the use of immunosuppressive drugs, including tocilizumab, and follow-up F-18-fluorodeoxyglucose positron emission tomography/computed tomography to break the vicious circle of recurrent stenosis caused by isolated coronary arteritis of unknown cause.

Most male X-linked Alport syndrome patients with COL4A5 nonsense mutations experience end-stage kidney failure by 30 years old. Although there is no definition of high-flow arteriovenous fistula, access blood flows greater than 2000 mL/min might predict the occurrence of high-output heart failure. A 50-year-old Japanese man had suffered from proteinuria at 4 years old and sensorineural hearing loss and a lenticular lens at 20 years old. He had started to receive hemodialysis treatment due to end-stage kidney disease at 22 years old. A genetic test confirmed a novel hemizygous nonsense variant COL4A5 c.2980G > T (p.Gly994Ter), and he was diagnosed with X-linked Alport syndrome. COL4A5 c.2980G > T was considered “pathogenic” according to the American College of Medical Genetics and Genomics guidelines and in vitro experiments. Shortness of breath on exertion was exaggerated, his brachial artery blood flow was over 4,236–4,353 mL/min, his cardiac output was 5,874 mL/min, and he needed radial artery banding at 51 years old. After radial artery banding surgery, the brachial artery blood flow decreased to 987–1,236 mL/min, and echocardiography showed a cardiac output at 5100 mL/min with improved E’ and E/E’. His shortness of breath on exertion improved gradually. Although rare, high-output heart failure due to high-flow arteriovenous fistula should be kept in mind as a complication in X-linked Alport syndrome patients, and our patient was successfully treated with radial artery banding surgery.

Abstract Background Phase-contrast cine cardiovascular magnetic resonance (CMR) quantifies global coronary flow reserve (CFR) by measuring blood flow in the coronary sinus (CS), allowing assessment of the entire coronary circulation. However, the complementary prognostic value of stress perfusion CMR and global CFR in long-term follow-up has yet to be investigated. This study aimed to investigate the complementary prognostic value of stress myocardial perfusion imaging and global CFR derived from CMR in patients with suspected or known coronary artery disease (CAD) during long-term follow-up. Methods Participants comprised 933 patients with suspected or known CAD who underwent comprehensive CMR. Major adverse cardiac events (MACE) comprised cardiac death, non-fatal myocardial infarction, unstable angina, hospitalization for heart failure, stroke, ventricular arrhythmia, and late revascularization. Results During follow-up (median, 5.3 years), there were 223 MACE. Kaplan–Meier curve analysis revealed a significant difference in event-free survival among tertile groups for global CFR (log-rank, p

Abstract Background Gut pathological microbial imbalance or dysbiosis is closely associated with colorectal cancer. Although there are observable differences in molecular and clinical characteristics between patients with right- and left-sided colon cancer, differences in their gut microbiomes have not been thoroughly investigated. Furthermore, subsequent changes in microbiota status after partial colectomy remain unknown. We examined the human gut microbiota composition to determine its relationship with colon cancer and partial colon resection according to location. Methods Stool samples from forty-one subjects (10 in the control group, 10 in the right-sided colon cancer [RCC] group, 6 in the sigmoid colon cancer [SCC] group, 9 in the right colon resection [RCR] group and 6 in the sigmoid colon resection [SCR] group) were collected, and DNA was extracted. After terminal restriction fragment length polymorphism (T-RFLP) analysis, the samples were subjected to 16S rRNA gene amplicon sequencing, and the metabolic function of the microbiota was predicted using PICRUSt2. Results T-RFLP analysis showed a reduced ratio of clostridial cluster XIVa in the SCC patients and clostridial cluster IX in the RCC patients, although these changes were not evident in the RCR or SCR patients. 16S rRNA gene amplicon sequencing demonstrated that the diversity of the gut microbiota in the RCC group was higher than that in the control group, and the diversity in the SCR group was significantly higher than that in the RCR group. Principal coordinate analysis (PCoA) revealed significant differences according to the group. Analyses of the microbiota revealed that Firmicutes was significantly dominant in the RCC group and that the SCC group had a higher abundance of Verrucomicrobia. At the genus level, linear discriminant analysis effect size (LEfSe) revealed several bacteria, such as Ruminococcaceae, Streptococcaceae, Clostridiaceae, Gemellaceae, and Desulfovibrio, in the RCC group and several oral microbiomes in the SCC group. Metabolic function prediction revealed that cholesterol transport- and metabolism-related enzymes were specifically upregulated in the RCC group and that cobalamin metabolism-related enzymes were downregulated in the SCC group. Conclusion Gut microbial properties differ between RCC and SCC patients and between right hemicolectomy and sigmoidectomy patients and may contribute to clinical manifestations.

Abstract Although cardiac troponin is a highly specific biomarker for myocardial cell injury, it is important to recognize the pitfalls of this test in the diagnosis and management of immune checkpoint inhibitor (ICI) myocarditis. We describe the challenging case of an 81‐year‐old woman with persistently high troponin after undergoing immunotherapy with ipilimumab and nivolumab, and histological evidence of amyloid deposition in the myocardium. The patient received immunosuppressive treatments based on the magnitude of troponin changes because myocarditis was clinically suspected. However, histological examination revealed the deposition of transthyretin amyloid fibrils with only minimal T‐lymphocyte infiltration and no myocyte necrosis, suggesting transthyretin cardiac amyloidosis rather than ICI myocarditis. This case highlights the importance of assessing other causes of persistently high troponin, and the necessity of incorporating comprehensive histological and immunohistochemical examinations of the endomyocardial biopsy, especially when cardiovascular magnetic resonance imaging is inconclusive.

Abstract Background Patients with pulmonary arterial hypertension (PAH) carrying bone morphogenetic protein receptor type 2 (Bmpr2) mutations present earlier with severe hemodynamic compromise and have poorer survival outcomes than those without mutation. The mechanism underlying the worsening clinical phenotype of PAH with Bmpr2 mutations has been largely unaddressed in rat models of pulmonary hypertension (PH) because of the difficulty in reproducing progressive PH in mice and genetic modification in rats. We tested whether a clinically-relevant Bmpr2 mutation affects the progressive features of monocrotaline (MCT) induced-PH in rats. Methods A monoallelic single nucleotide insertion in exon 1 of Bmpr2 (+/44insG) was generated in rats using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9, then PH, pulmonary vascular disease (PVD) and survival after MCT injection with or without a phosphodiesterase type 5 inhibitor, tadalafil, administration were assessed. Results The +/44insG rats had reduced BMPR2 signalling in the lungs compared with wild-type. PH and PVD assessed at 3-weeks after MCT injection were similar in wild-type and +/44insG rats. However, survival at 4-weeks after MCT injection was significantly reduced in +/44insG rats. Among the rats surviving at 4-weeks after MCT administration, +/44insG rats had increased weight ratio of right ventricle to left ventricle plus septum (RV/[LV + S]) and % medial wall thickness (MWT) in pulmonary arteries (PAs). Immunohistochemical analysis showed increased vessels with Ki67-positive cells in the lungs, decreased mature and increased immature smooth muscle cell phenotype markers in the PAs in +/44insG rats compared with wild-type at 3-weeks after MCT injection. Contraction of PA in response to prostaglandin-F2α and endothelin-1 were significantly reduced in the +/44insG rats. The +/44insG rats that had received tadalafil had a worse survival with a significant increase in RV/(LV + S), %MWT in distal PAs and RV myocardial fibrosis compared with wild-type. Conclusions The present study demonstrates that the Bmpr2 mutation promotes dedifferentiation of PA smooth muscle cells, late PVD and RV myocardial fibrosis and adversely impacts both the natural and post-treatment courses of MCT-PH in rats with significant effects only in the late stages and warrants preclinical studies using this new genetic model to optimize treatment outcomes of heritable PAH.

The aim was to investigate the clinical characteristics of coronavirus disease 2019 (COVID-19) patients who were admitted to a designated hotel, and to clarify the risk factors for hospitalization of such patients with clinical deterioration. The medical records of COVID-19 patients who were admitted to the designated hotel in Mie Prefecture, Japan, between August 2020 and September 2021 were reviewed retrospectively. Of the 1,087 COVID-19 patients who were admitted to the designated hotel, 936 patients (32.1± 12.8 years, 61.3% male) were recruited after excluding patients under the age of 15 years (n = 33), those admitted from the hospital (n = 111, 10.2%), COVID-19 vaccinated patients (n = 4, 0.4%), and those who were discharged to their own home due to social disorders (n = 3). During the study period, 884 patients (94.4%) were discharged to their own home with improving symptoms, whereas 52 patients (5.6%) were hospitalized for a deteriorating clinical condition. The logistic regression analyses showed that older age (≥ 40 years), higher body mass index (≥ 25 kg/m2), hypertension were the risk factors for hospitalization. As the new risk scale score based on the results of the odds ratios increased, the hospitalization rate increased significantly: 2.0% at 0-1 points, 9.7% at 2-3 points, and 28.8% at 4-5 points (p < 0.001). None of the 52 hospitalized patients died, and none developed serious complications from COVID-19 after hospitalization. In conclusion, the designated accommodation program for COVID-19 patients was safe, especially for those with a low risk for hospitalization.

Abstract Background Nutcracker syndrome (NCS) is characterized by compression of the left renal vein (LRV) between the aorta and the superior mesenteric artery. While rare, NCS was reported to be accompanied by double inferior vena cava (IVC). We herein report a case of Noonan syndrome (NS) with double IVC who presented with macrohematuria and proteinuria. Case presentation The patient was a 23-year-old man, who had been diagnosed with NS due to RIT1 mutation, after showing foamy macrohematuria 3 weeks previously. A physical examination revealed low-set ears and a webbed neck. A urinalysis showed hematuria and proteinuria, and urinary sediments showed more than 100 isomorphic red blood cells per high-power field. His proteinuria and albuminuria concentrations were 7.1 and 4.5 g/g⋅Cr, respectively. Three-dimensional contrast-enhanced computed tomography (CT) showed double IVC and narrowing of the LRV after interflow of the left IVC. The aortomesenteric angle on a sagittal reconstruction of the CT image was 14.7°. Cystoscopy revealed a flow of macrohematuria from the left ureteral opening. On Doppler ultrasonography, there was scant evidence to raise the suspicion of the nutcracker phenomenon. Since severe albuminuria continued, a left kidney biopsy was performed. Light microscopy showed red blood cells in Bowman’s space and the tubular lumen. Electron microscopy revealed disruption of the glomerular basement membrane (GBM). Vulnerability of the GBM was suspected and a genetic analysis revealed a heterozygous mutation at c.4793 T > G (p.L1598R) in the COL4A3 gene. Screening for coagulation disorders revealed the factor VIII and von Willebrand factor (vWF) values were low, at 47.6 and 23%, respectively. A multimer analysis of vWF showed a normal multimer pattern and he was diagnosed with von Willebrand disease type 1. As the bleeding tendency was mild, replacement of factor VIII was not performed. His macrohematuria and proteinuria improved gradually without treatment, and his urinalysis results have been normal for more than 6 months. Conclusions The present case showed macrohematuria and proteinuria due to NCS in NS with double IVC and von Willebrand disease type 1. The macrohematuria and proteinuria originated from glomerular hemorrhage because of vulnerability of the GBM due to COL4A3 mutation.

Abstract Aims Isometric handgrip (IHG) training reduces the blood pressure in patients with hypertension. It is unclear how IHG exercise affects the haemodynamics and cardiovascular function through the muscle reflex in patients with heart failure (HF) with reduced (HFrEF) and preserved ejection fraction (HFpEF). Methods and results Twenty patients (HFrEF: n = 10, HFpEF: n = 10) underwent left ventricular (LV) pressure–volume assessments using a conductance catheter and microtip manometer to evaluate haemodynamics, LV and arterial function, and LV‐arterial coupling during 3 min of IHG at 30% of maximal voluntary contraction (MVC), followed by 3 min of post‐exercise circulatory arrest (PECA). Three minutes of IHG exercise produced significant and modest increases in the heart rate (HR) and LV end‐systolic pressure (LVESP), respectively, in both HFpEF and HFrEF groups. In HFrEF, the increase in LVESP was caused by the variable increase in effective arterial elastance (Ea), which was counterbalanced by the increase in LV end‐systolic elastance (Ees), resulting in a maintained Ees/Ea. In HFpEF, the increase in LVESP was not accompanied by changes in Ea, Ees, Ees/Ea, or LV end‐diastolic pressure. LVESP during PECA was not maintained in HFpEF, suggesting smaller metabo‐reflex activity in HFpEF. Conclusions The IHG exercise used in this study may increase the LVESP and LVEDP without detrimental effects on cardiac function or ventricular‐arterial coupling, especially in HFpEF patients. The effects of IHG exercise on haemodynamics and ventricular‐arterial coupling may be affected by the patient background and the type and intensity of the exercise.

Abstract Crb2 is a cell polarity-related type I transmembrane protein expressed in the apical membrane of podocytes. Knockdown of crb2 causes glomerular permeability defects in zebrafish, and its complete knockout causes embryonic lethality in mice. There are also reports of Crb2 mutations in patients with steroid-resistant nephrotic syndrome, although the precise mechanism is unclear. The present study demonstrated that podocyte-specific Crb2 knockout mice develop massive albuminuria and microhematuria 2-month after birth and focal segmental glomerulosclerosis and tubulointerstitial fibrosis with hemosiderin-laden macrophages at 6-month of age. Transmission and scanning electron microscopic studies demonstrated injury and foot process effacement of podocytes in 6-month aged podocyte-specific Crb2 knockout mice. The number of glomerular Wt1-positive cells and the expressions of Nphs2, Podxl, and Nphs1 were reduced in podocyte-specific Crb2 knockout mice compared to negative control mice. Human podocytes lacking CRB2 had significantly decreased F-actin positive area and were more susceptible to apoptosis than their wild-type counterparts. Overall, this study's results suggest that the specific deprivation of Crb2 in podocytes induces altered actin cytoskeleton reorganization associated with dysfunction and accelerated apoptosis of podocytes that ultimately cause focal segmental glomerulosclerosis.

Abstract Background Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. Methods Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. Results The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89–1.08) in the canagliflozin group and 1.07 (95% CI 0.97–1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82–1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e′) showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e′

Abstract Amyloid transthyretin (ATTR) depositions cause left ventricular (LV) hypertrophy, diastolic dysfunction, and heart failure. The time course of changes in LV geometry and diastolic dysfunction has not been fully reported in patients with ATTR cardiomyopathy. A 79‐year‐old woman with previous myocardial infraction presented with shortness of breath on exertion, and progressive bilateral lower extremity weakness and polyneuropathy. She was diagnosed with Val30Met hereditary ATTR cardiomyopathy by cardiac biopsy and genetic testing. During the past 5 year period, significant LV concentric remodelling with small LV cavity occurred, resulting in an increased LV stiffness and prolonged LV relaxation. This case report highlights the time course of changes in LV geometry and diastolic function and the importance of early diagnosis of ATTR cardiomyopathy.

Proteinuria is known to be associated with all-cause and cardiovascular mortality, and nephrotic syndrome is defined by the level of proteinuria and hypoalbuminemia. With advances in medicine, new causative genes for genetic kidney diseases are being discovered increasingly frequently. We reviewed articles on proteinuria/nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, diabetic kidney disease/nephropathy, hypertension/nephrosclerosis, Alport syndrome, and rare diseases, which have been studied in mouse models. Significant progress has been made in understanding the genetics and pathophysiology of kidney diseases thanks to advances in science, but research in this area is ongoing. In the future, genetic analyses of patients with proteinuric kidney disease/nephrotic syndrome may ultimately lead to personalized treatment options.

Abstract Background Multicentric Castleman’s disease is a life-threatening disorder involving a systemic inflammatory response and multiple organ failure caused by the overproduction of interleukin-6. Although renal complications of Castleman’s disease include AA amyloidosis, thrombotic microangiopathy, and membranoproliferative glomerulonephritis, membranous nephropathy is relatively rare. We experienced a case of secondary membranous nephropathy associated with Castleman’s disease. Case presentation The patient was a 43-year-old Japanese man who had shown a high zinc sulfate value in turbidity test, polyclonal hypergammaglobulinemia, anemia, and proteinuria. A physical examination revealed diffuse lymphadenopathy, an enlarged spleen and papulae of the body trunk. A skin biopsy of a papule on the patient’s back showed plasma cells in the perivascular area and he was diagnosed with multicentric Castleman’s disease, plasma cell variant. Kidney biopsy showed the appearance of bubbling in the glomerular basement membranes in Periodic acid methenamine silver stain and electron microscopy revealed electron dense deposits within and outside the glomerular basement membranes. Since immunofluorescence study showed predominant granular deposition of IgG1 and IgG2, he was diagnosed with secondary membranous nephropathy associated with Castleman’s disease. He was initially treated with prednisolone alone, however his biochemical abnormalities did not improve. After intravenous tocilizumab (700 mg every 2 weeks) was started, his C-reactive protein elevation, anemia, and polyclonal gammopathy improved. Furthermore, his urinary protein level declined from 1.58 g/gCr to 0.13 g/gCr. The prednisolone dose was gradually tapered, then discontinued. He has been stable without a recurrence of proteinuria for more than 6 months. Conclusions Tocilizumab might be a treatment option for secondary membranous nephropathy associated with Castleman’s disease.

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic kidney disease and polycystic liver disease is its major extrarenal manifestation, however biliary peritonitis due to a liver cyst rupture is extremely rare. Case presentation The patient was a 71-year-old Japanese woman who was diagnosed with ADPKD 3 years previously and developed right abdominal pain suddenly 1 month previously. As abdominal computed tomography (CT) showed a ruptured liver cyst in the right lobe, she was admitted to our hospital. Her symptoms improved with conservative management and she was discharged from the hospital after 1 week. Although she was asymptomatic for a while, she noticed abdominal distension and general malaise at 1 month after hospital discharge. Since abdominal CT showed massive ascites, she was admitted to our hospital again. A physical examination revealed abdominal distention without tenderness. Her serum creatinine, alkaline phosphatase, γ-glutamyl transpeptidase, total bilirubin, and CA19-9 were elevated. Abdominal paracentesis revealed amber transparent ascites and the bilirubin and CA19-9 concentrations were high. She was diagnosed with biliary peritonitis due to a ruptured liver cyst. Hemodialysis treatment was initiated with drainage of the ascites. The outflow of the ascites was no tendency to decrease and drip infusion cholangiography (DIC)-CT revealed a communication between the ruptured cyst and an intrahepatic bile duct. On day 31, she was transferred to a university hospital and abdominal surgery was performed. After removing the necrotic roof of the ruptured cyst on the right liver lobe, the orifice of the bile leakage was sutured. Cholecystectomy was performed and cholangiography showed no stones in the common bile duct. Abdominal CT one month after the operation showed no recurrence of ascites and she was discharged on day 49. Hemodialysis treatment was discontinued immediately after discharge because urine volume increased and her creatinine level decreased. There has been no recurrence of ascites since then. Conclusions While rare, biliary peritonitis can occur in association with the rupture of a liver cyst in ADPKD patients due to communication between the cyst and the intrahepatic bile duct, and DIC-CT should be recommended when biliary cyst rupture is suspected.

Abstract Background Coronary magnetic resonance angiography (CMRA) allows non-ionizing visualization of luminal narrowing in coronary artery disease (CAD). Although a prior study showed the usefulness of CMRA for risk stratification in short-term follow-up, the long-term prognostic value of CMRA remains unclear. The purpose of this study was to evaluate the long-term prognostic value of CMRA. Methods A total of 506 patients without history of myocardial infarction or prior coronary artery revascularization underwent free-breathing whole-heart CMRA between 2009 and 2015. Images were acquired using a 1.5 T or 3 T scanner and visually evaluated as the consensus decisions of two observers. Obstructive CAD on CMRA was defined as luminal narrowing of ≥ 50% in at least one coronary artery. Major adverse cardiac events (MACE) comprised cardiac death, nonfatal myocardial infarction, and unstable angina. Results Obstructive CAD on CMRA was observed in 214 patients (42%). During follow-up (median, 5.6 years), 31 MACE occurred. Kaplan–Meier curve analysis revealed a significant difference in event-free survival between patients with and without obstructive CAD for MACE (log-rank, p = 0.003) and cardiac death (p = 0.012). Annualized event rates for MACE in patients with no obstructive CAD, 1-vessel disease, 2-vessel disease, and left-main or 3-vessel disease were 0.6%, 1.5%, 2.3%, and 3.6%, respectively (log-rank, p = 0.003). Cox proportional hazard regression analysis showed that, among obstructive CAD on CMRA and clinical risk factors (age, sex, hypertension, diabetes, dyslipidemia, smoking, and family history of CAD), obstructive CAD and diabetes were significant predictors of MACE (hazard ratios, 2.9 [p = 0.005] and 2.2 [p = 0.034], respectively). In multivariate analysis, obstructive CAD remained an independent predictor (adjusted hazard ratio, 2.6 [p = 0.010]) after adjusting for diabetes. Addition of obstructive CAD to clinical risk factors significantly increased the global chi-square result from 8.3 to 13.8 (p = 0.022). Conclusions In long-term follow-up, free breathing whole heart CMRA allows non-invasive risk stratification for MACE and cardiac death and provides incremental prognostic value over conventional risk factors in patients without a history of myocardial infarction or prior coronary artery revascularization. The presence and severity of obstructive CAD detected by CMRA were associated with worse prognosis. Importantly, patients without obstructive CAD on CMRA displayed favorable prognosis.

This case highlights the diagnostic challenge associated with myocarditis, especially when accompanied by coronary spasm. Any coronary spasm with hemodynamic instability and/or an inexplicable widespread electrocardiogram should alert the clinician to the possibility of fulminant myocarditis and the necessity of endomyocardial biopsy for treatment decisions. (Level of Difficulty: Beginner.)

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by bilateral kidney cysts that ultimately lead to end-stage kidney disease. While the major causative genes of ADPKD are PKD1 and PKD2, other genes are also thought to be involved. Fifty ADPKD patients were analyzed by exome sequencing or multiplex ligation-dependent probe amplification (MLPA), followed by long polymerase chain reaction and Sanger sequencing. Variants in PKD1 or PKD2 or GANAB were detected in 35 patients (70%). Exome sequencing identified 24, 7, and 1 variants in PKD1, PKD2, and GANAB, respectively, in 30 patients. MLPA analyses identified large deletions in PKD1 in three patients and PKD2 in two patients. We searched 90 cyst-associated genes in 15 patients who were negative by exome sequencing and MLPA analyses, and identified 17 rare variants. Four of them were considered “likely pathogenic” or “pathogenic” variants according to the American College of Medical Genetics and Genomics guidelines. Of the 11 patients without a family history, four, two, and four variants were found in PKD1, PKD2, and other genes, respectively, while no causative gene was identified in one patient. While the pathogenicity of each variant in these genes should be carefully assessed, a comprehensive genetic analysis may be useful in cases of atypical ADPKD.

BackgroundThe prevalence of cerebral microbleeds (CMBs) is significantly higher in patients with atrial fibrillation (AF) than in those without AF. CMBs in patients with AF have been reported to be primarily of the lobar type, but the exact cause of this remains unknown. We investigated the possibility that hemorrhagic transformation of embolic microinfarction can account for de novo lobar CMBs.MethodsA total of 101 patients who underwent ablation therapy for AF were prospectively registered, and 72 patients completed the assessment with MRI 6 months after catheter ablation. Brain MRI, including diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI), were examined at 1–3 days (baseline) and 6 months after catheter ablation. We quantitatively evaluated the spatial and temporal distribution of embolic microinfarctions and de novo CMBs.ResultsOf the 101 patients, 68 were enrolled in this study. Fifty-nine patients (86.8%) showed embolic microinfarctions on baseline DWI immediately after catheter ablation. There were 137 CMBs in SWI, and 96 CMBs were of the lobar type. Six months later, there were 208 CMBs, including 71 de novo CMBs, and 60 of 71 (84.5%) were of the lobar type. Of the 71 de novo CMBs, 56 (78.9%) corresponded to the location of previous embolic microinfarctions found on baseline DWI. The platelet count was significantly lower and hematocrit/hemoglobin and Fazekas score were higher in the group with de novo CMBs than in the group without de novo CMBs.ConclusionDe novo CMBs frequently appeared after catheter ablation therapy. Our results suggest that embolic microinfarction can cause lobar CMBs.

Background Prognoses and long‐term cardiac function of patients with fulminant myocarditis have not been fully elucidated. Therefore, we clarified the prognoses and long‐term cardiac function according to required percutaneous mechanical circulatory support and histological findings among patients with fulminant myocarditis. Methods and Results We conducted a multicenter retrospective medical record review of 216 patients with fulminant myocarditis requiring percutaneous mechanical circulatory support. Sixty‐one patients were treated with intra‐aortic balloon pump or Impella alone, and 155 patients received veno‐arterial extracorporeal membrane oxygenation and were treated with or without intra‐aortic balloon pump or Impella. Histologically, 107 patients had lymphocytic myocarditis; 34, eosinophilic myocarditis; and 4, giant cell myocarditis. Freedom from composite end point (death, durable left ventricular assist device implantation, and heart transplantation) was 66% at 90 days, 62% at 1 year, and 57% at 6 years. Veno‐arterial extracorporeal membrane oxygenation use was associated with poor prognosis in the multivariable analysis (hazard ratio [HR], 5.27; 95% CI, 1.60–17.36). The eosinophilic myocarditis subgroup showed better prognosis (HR, 0.28; 95% CI, 0.10–0.80) compared with the lymphocytic myocarditis subgroup but not in the multivariable analysis. Ventricular tachycardia/ventricular fibrillation rhythm at admission, high C‐reactive protein level, and no endomyocardial biopsy were also associated with poor prognosis. The left ventricular ejection fraction at 1 year was ≤50% in 16% of patients and was lower in patients with eosinophilic myocarditis (median: 57.9% [48.8–65.0%]) than in those with lymphocytic myocarditis (65.0% [58.6–68.7%]) (P=0.036). Conclusions Patients with fulminant myocarditis who received veno‐arterial extracorporeal membrane oxygenation had a poor prognosis. Long‐term cardiac function was impaired in some patients, especially those with eosinophilic myocarditis.

Abstract Background Left ventricular (LV) diastolic dysfunction is the main cause of heart failure with preserved ejection fraction (HFpEF), and is characterized by LV stiffness and relaxation. Abnormal LV global longitudinal strain (GLS) is frequently observed l in HFpEF, and was shown to be useful in identifying HFpEF patients at high risk for a cardiovascular event. Cardiovascular magnetic resonance (CMR) feature tracking (CMR-FT) enables the reproducible and non-invasive assessment of global strain from cine CMR images. However, the association between GLS and invasively measured parameters of diastolic function has not been investigated. We sought to determine the prevalence and severity of GLS impairment in patients with HFpEF by using CMR-FT, and to evaluate the correlation between GLS measured by CMR-FT and that measured by invasive diastolic functional indices. Methods Eighteen patients with HFpEF and 18 age- and sex-matched healthy control subjects were studied. All subjects underwent cine, pre- and post-contrast T1 mapping and late gadolinium-enhancement CMR. In the HFpEF patients, invasive pressure–volume loops were obtained to evaluate LV diastolic properties. GLS was quantified from cine CMR, and extracellular volume fraction (ECV) was quantified from pre- and post-contrast T1 mapping as a known imaging biomarker for predicting LV stiffness. Results GLS was significantly impaired in patients with HFpEF (− 14.8 ± 3.3 vs.–19.5 ± 2.8%, p

Abstract Background Atrial fibrillation (AF) patients without coronary artery stenosis often show clinical evidence of ischemia. However myocardial perfusion in AF patients has been poorly studied. The purposes of this study were to investigate altered hyperemic myocardial blood flow (MBF) in patients with AF compared with risk‐matched controls in sinus rhythm (SR), and to evaluate hyperemic MBF before and after catheter ablation using dynamic CT perfusion. Methods Hyperemic MBF was quantified in 87 patients with AF (44 paroxysmal, 43 persistent) scheduled for catheter ablation using dynamic CT perfusion, and compared with hyperemic MBF in 87 risk‐matched controls in SR. Follow‐up CT after ablation was performed in 49 AF patients. Results Prior to ablation, hyperemic MBF of patients in AF during the CT (1.29 ± 0.34 ml/mg/min) was significantly lower than in patients in SR (1.49 ± 0.26 ml/g/min, p = 0.002) or matched controls (1.65 ± 0.32 ml/g/min, p

Thin basement membrane nephropathy (TBMN) is characterized by the observation of microhematuria and a thin glomerular basement membrane on kidney biopsy specimens. Its main cause is heterozygous mutations of COL4A3 or COL4A4, which also cause late-onset focal segmental glomerulosclerosis (FSGS) or autosomal dominant Alport syndrome (ADAS). Thirteen TBMN cases were analyzed using Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and exome sequencing. Ten heterozygous variants were detected in COL4A3 or COL4A4 in nine patients via Sanger sequencing, three of which were novel variants. The diagnostic rate of “likely pathogenic” or “pathogenic” under the American College of Medical Genetics and Genomics guidelines was 53.8% (7 out of 13 patients). There were eight single nucleotide variants, seven of which were glycine substitutions in the collagenous domain, one of which was a splice-site single nucleotide variant, and two of which were deletion variants. One patient had digenic variants in COL4A3 and COL4A4. While MLPA analyses showed negative results, exome sequencing identified three heterozygous variants in causative genes of FSGS in four patients with no apparent variants on Sanger sequencing. Since patients with heterozygous mutations of COL4A3 or COL4A4 showed a wide spectrum of disease from TBMN to ADAS, careful follow-up will be necessary for these patients.

Background We aimed to investigate the presence and severity of coronary microvascular dysfunction (CMD) in inflammatory bowel disease (IBD) including Crohn disease and ulcerative colitis and to elucidate the influence of surgical resection of the diseased intestines on CMD by assessing coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography. Methods and Results Thirty‐seven patients with IBD (aged 44±15 years; 22 patients with Crohn disease and 15 patients with ulcerative colitis) and 30 controls (aged 46±12 years) were enrolled. For CFVR measurement, coronary flow velocity was recorded at rest and during hyperemia by ADP infusion using transthoracic Doppler echocardiography, and CFVR

Background: Chronic total occlusion (CTO) in a non-infarct-related artery (IRA) in patients with acute coronary syndrome (ACS) is associated with a poor prognosis. However, whether the prognostic impact of non-IRA CTO differs according to left ventricular ejection fraction (LVEF) is unclear. Methods and results: A total of 2060 consecutive acute myocardial infarction (AMI) patients who underwent primary percutaneous coronary intervention (PCI) were classified into 2 groups according to their LVEF (reduced EF: LVEF < 50%, preserved EF: LVEF ≥ 50%) and further subdivided according to the presence of concomitant non-IRA CTO. In the reduced EF group, patients with CTO had a higher 1-year all-cause death rate (20.3% vs. 34.3%, P = 0.001) and major adverse cardiac event rate (MACE: 19.6% vs. 39.6%, P

Background: Intradialytic hypertension (HTN), which is one of the poor prognostic markers in patients undergoing hemodialysis, may be associated with sympathetic overactivity. The L/N-type calcium channel blocker, cilnidipine, has been reported to suppress sympathetic nerves activity in vivo. Therefore, we hypothesized that cilnidipine could attenuate intradialytic systolic blood pressure (SBP) elevation. Methods: Fifty-one patients on chronic hemodialysis who had intradialytic-HTN (SBP elevation ≥10 mmHg during hemodialysis) and no fluid overload were prospectively randomized into two groups: control and cilnidipine groups. Cilnidipine group patients took cilnidipine (10 mg/day) for 12 weeks. The primary endpoint was the change in the intradialytic SBP elevation before and after the 12-week intervention. Results: Before the intervention, no differences were observed in age, sex or pre-dialytic SBP (148.5 ± 12.9 vs. 148.3 ± 19.3 mmHg) between the two groups. Intradialytic SBP elevation was unchanged in the control group. Cilnidipine significantly lowered the post-dialytic SBP with an attenuation of the intradialytic SBP elevation from 12.0 ± 15.4 mmHg to 4.8 ± 10.1 mmHg. However, the observed difference in the intradialytic SBP elevation by cilnidipine did not reach statistical significance (group×time interaction effect p = 0.25). Cathecolamine levels were unaffected by the intervention in both groups. Conclusion: Cilnidipine lowers both the pre- and post-dialytic SBP and might attenuate intradialytic SBP elevation. Therefore, cilnidipine may be effective in lowering SBP during HD in patients with intradialytic-HTN.

Abstract Background Although the renal toxicity of Deferasirox, an oral iron chelator, has been reported to be mild, there have been reports of acute interstitial nephritis or Fanconi syndrome due to this agent. Thin basement membrane disease (TBMD) is a hereditary disease characterized primarily by hematuria, with gross hematuria also observed in about 7% of cases. We herein report a case of TBMD that presented with acute kidney injury and gross hematuria during treatment with Deferasirox. Case presentation The patient was a 63-year-old man who had been diagnosed with myelodysplastic syndrome 6 years ago. He had started taking Deferasirox at 125 mg due to post-transfusion iron overload 6 months ago. Deferasirox was then increased to 1000 mg three months ago. When the serum creatinine level increased, Deferasirox was reduced to 500 mg three weeks before hospitalization. Although the serum creatinine level decreased once, he developed a fever and macroscopic hematuria one week before hospitalization. The serum creatinine level increased again, and Deferasirox was stopped four days before hospitalization. He was admitted for the evaluation of acute kidney injury and gross hematuria. Treatment with temporary hemodialysis was required, and a kidney biopsy was performed on the eighth day of admission. Although there was no major abnormality in the glomeruli, the leakage of red blood cells into the Bowman’s space was observed. Erythrocyte cast formation was observed in the tubular lumen, which was associated with acute tubular necrosis. The results of an electron microscopic study were compatible with TBMD. Conclusion Although Deferasirox is known to be nephrotoxic, gross hematuria is relatively rare. When we encounter a case of acute kidney injury with gross hematuria during treatment with Deferasirox, TBMD should be considered as a possible cause of gross hematuria.

Pulmonary capillary hemangiomatosis is a rare form of pulmonary artery hypertension; to date, only few descriptions of myocardial pathology in pulmonary capillary hemangiomatosis have been reported in the literature. We report the case of a Japanese female patient who was diagnosed with pulmonary capillary hemangiomatosis combined with acute myocardial inflammation on performing autopsy. She was admitted to our hospital because of acute pneumonia and subsequently suddenly developed severe hypoxemia with breathing difficulty and died 13 days after admission. At autopsy, the histology of the lung was consistent with pulmonary capillary hemangiomatosis. Additionally, a diffuse severe infiltration of inflammatory cells was associated with edema in the myocardium. Myocytolysis was limited and fibrosis was absent. To the best of our knowledge, pulmonary capillary hemangiomatosis with acute myocarditis-like histological findings has been described for the first time through our case.

Brain natriuretic peptide (BNP) levels are increased in both patients with heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF), but the reasons for this remain unclear. Our purpose was to examine whether serum-induced BNP (iBNP) expression partly contributes to increased BNP in patients with HFpEF. BNP reporter cardiomyocytes from pBNP-luc-KI mice were stimulated with serum from patients with HFpEF or HFrEF (n = 114 and n = 82, respectively). Luciferase activity was examined as iBNP and the iBNP-to-BNP ratio was evaluated. Patient characteristics and clinical parameters were compared, and multivariate regression analysis was performed to determine independent predictors of the iBNP-to-BNP ratio. Female sex and frequencies of atrial fibrillation, hypertension and the use of a calcium channel blocker (CCB) were higher in HFpEF. The iBNP-to-BNP ratio was significantly higher in HFpEF (26.9) than in HFrEF (16.1, p < 0.001). Multivariate regression analysis identified the existence of HFpEF as an independent predictor of the iBNP-to-BNP ratio after adjusting for all other measurements (β = 0.154, p = 0.032). Age, hemoglobin, CCB usage and deceleration time were also independent predictors (β = 0.167, p = 0.025; β = 0.203, p = 0.006; β = 0.138, p = 0.049; and β = 0.143, p = 0.049, respectively). These results indicate that the elevated BNP in patients with HFpEF is partly due to iBNP from the heart.

Background: Fractional flow reserve (FFR) is useful for assessing the functional significance of coronary artery stenosis, even in lesions with prior myocardial infarction (pMI). Instantaneous wave-free ratio (iFR) is a vasodilator-free alternative for the physiological assessment of coronary artery stenosis. In addition, iFR shows good diagnostic agreement with FFR and an iFR-guided revascularization strategy was non-inferior to an FFR-guided revascularization strategy. However, the clinical usefulness of iFR for the evaluation of a coronary artery lesions with pMI has not been evaluated. Methods and Results: A total of 200 lesions from 200 patients (44 pMI territories lesions and 156 non-pMI coronary artery lesions) were analyzed retrospectively. Major adverse cardiac events (MACE) were defined as cardiovascular death, non-fatal MI, unstable angina pectoris, fatal arrhythmia and heart failure during 12 months follow-up after the physiological assessment of coronary artery stenosis. iFR was closely correlated with FFR in pMI and non-pMI lesions (r = 0.81 and 0.72; P

AimsGJB4 encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. This study investigated whether GJB4 plays an important role in human heart disease and function.Methods and resultsWe examined a patient and her older brother who both presented with complicated severe hypertrophic cardiomyopathy (HCM) and whose parents are healthy married cousins. The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid changes for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations, the gene for GJB4 was the only identified gene that is possibly associated with cardiac muscle. The resultant E204A substitution exists in the 4th transmembrane domain. GJB4-E204A impaired the binding with gap junction protein A1 (GJA1) compared with GJB4-WT. The expression of GJB4 was induced in rat disease models of left and right ventricle hypertrophy and mouse disease models of adriamycin-induced cardiomyopathy and myocardial infarction, while it was not detected at all in control. An immunohistochemical study was performed for autopsied human hearts and the explanted heart of the patient. GJB4 was expressed and colocalized with GJA1 in intercalated discs in human diseased hearts, which was extensively enhanced in the explanted heart of the patient. The abnormal expression and localization of GJB4 were observed in beating spheres of patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). We generated knockout zebrafish of GJB4 by CRISPR/Cas9 and the endodiastolic volume and the ventricular ejection fraction were significantly lower in GJB4-deficient than in wild-type zebrafish at five days post-fertilization.ConclusionsThese results indicate both that GJB4 is defined as a new connexin in diseased hearts, of which mutation can cause a familial form of HCM, and that GJB4 may be a new target for the treatment of cardiac hypertrophy and dysfunction.

Abstract Background Peripartum cardiomyopathy is a life-threatening condition that occurs during the peripartum period in previously healthy women. Cardiovascular magnetic resonance (CMR) T1 mapping permits sensitive detection of tissue edema and fibrosis, and it may be useful in identifying altered myocardial tissue characteristics in peripartum cardiomyopathy. However, left ventricular (LV) volumes and mass increase considerably even in normal pregnancy, and it is not known whether altered tissue characteristics can be found in normal pregnancy. The aim of this study was to investigate whether the LV remodeling observed in normal pregnancy is associated with altered tissue characteristics determined by CMR. Methods Twelve normal pregnant women and 15 non pregnant women underwent cine CMR and myocardial T1 measurement at 1.5 T. Pregnant women were scanned three times, in the 2nd and 3rd trimesters of pregnancy and at 1 month postpartum. LV volumes, LV mass (LVM), and global longitudinal strain (GLS) were analyzed by cine CMR. Native myocardial T1 was determined using modified Look-Locker inversion recovery (MOLLI) images. Results LV end-diastolic volume (EDV) was significantly greater in the 3rd trimester (126 ± 22 mL) than in non-pregnant women (108 ± 14 mL, p

Abstract Background Both the progression of diabetic kidney disease and increased glycemic variability play important roles in the pathogenesis of coronary plaque formation via inflammatory pathways in patients with type 2 diabetes mellitus (T2DM). Therefore we evaluated the role of renal function in the contributory effects of blood glucose fluctuations and blood levels of inflammatory cytokine concentrations on the tissue characteristics of coronary plaques in patients with T2DM. Methods We prospectively enrolled 71 T2DM patients (mean age: 68 ± 9, male 79%) with 153 coronary artery lesions. Patients were divided into 2 groups according to their estimated glomerular filtration rate (eGFR) levels: Group 1 (≥ 60 mL/min/1.73 m2, n = 40) and Group 2 (

BackgroundRecent studies using stress‐rest perfusion cardiovascular magnetic resonance (CMR) demonstrated a close correlation between myocardial ischemia and reduced fractional flow reserve (FFR). However, its diagnostic concordance may be reduced in patients with multivessel disease. We sought to evaluate the concordance of adenosine stress‐rest perfusion CMR for predicting reduced FFR, and to determine the additive value of measuring global coronary flow reserve (CFR) in the coronary sinus in multivessel disease. Methods and ResultsNinety‐six patients with angiographic luminal narrowing >50% underwent comprehensive CMR study and FFR measurements in 139 coronary vessels. FFR

This article describes data related to a research article titled “Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study”, Kurita et al. (in press) [1]. Myocardial extracellular volume fraction (ECV) is an imaging biomarker that can elevate in various heart diseases. This article describes correlation between CT-derived and MRI-derived ECV in 24 myocardial segments in 8 patients. CT-derived ECV was obtained from pre-contrast and delayed-phase images acquired by using dual-source CT system. MRI-derived ECV was obtained by using modified Look-Locker inversion recovery sequence implemented on a 3 T MRI system.

Cardiac myosin light chain kinase (cMLCK) plays an obligatory role in maintaining the phosphorylation levels of regulatory myosin light chain (MLC2), which is thought to be crucial for regulation of cardiac function. To test this hypothesis, the role played by ventricular MLC2 (MLC2v) phosphorylation was investigated in the phenylephrine-induced increase in twitch tension using the naturally-occurring mouse strain, C57BL/6N, in which cMLCK is down regulated.By Western blot and nanoLC-MS/MS analysis, cMLCKs with molecular mass of 61-kDa (cMLCK-2) and/or 86-kDa were identified in mice heart. Among various mouse strains, C57BL/6N expressed cMLCK-2 alone and the closest relative strain C57BL/6J expressed both cMLCKs. The levels of MLC2v phosphorylation was significantly lower in C57BL/6N than in C57BL/6J. The papillary muscle twitch tension induced by electrical field stimulation was smaller in C57BL/6N than C57BL/6J. Phenylephrine had no effect on MLC2v phosphorylation in either strains but increased the twitch tension more potently in C57BL/6J than in C57BL/6N. Calyculin A increased papillary muscle MLC2v phosphorylation to a similar extent in both strains but increased the phenylephrine-induced inotropic response only in C57BL/6N. There was a significant positive correlation between the phenylephrine-induced inotropic response and the levels of MLC2v phosphorylation within ranges of 15-30%.We identified a new isoform of cMLCK with a molecular mass of 61kDa(cMLCK-2) in mouse heart. In the C57BL/6N strain, only cMLCK-2 was expressed and the basal MLC2v phosphorylation levels and the phenylephrine-induced inotropic response were both smaller. We suggest that a lower phenylephrine-induced inotropic response may be caused by the lower basal MLC2v phosphorylation levels in this strain.

Free-running 5D whole-heart coronary MR angiography (MRA) is gaining in popularity because it reduces scanning complexity by removing the need for specific slice orientations, respiratory gating, or cardiac triggering. At 3T, a gradient echo (GRE) sequence is preferred in combination with contrast injection. However, neither the injection scheme of the gadolinium (Gd) contrast medium, the choice of the RF excitation angle, nor the dedicated image reconstruction parameters have been established for 3T GRE free-running 5D whole-heart coronary MRA. In this study, a Gd injection scheme, RF excitation angles of lipid-insensitive binominal off-resonance RF excitation (LIBRE) pulse for valid fat suppression and continuous data acquisition, and compressed-sensing reconstruction regularization parameters were optimized for contrast-enhanced free-running 5D whole-heart coronary MRA using a GRE sequence at 3T. Using this optimized protocol, contrast-enhanced free-running 5D whole-heart coronary MRA using a GRE sequence is feasible with good image quality at 3T. [ABSTRACT FROM AUTHOR]