Validation of the Diagnostic Criteria for IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis (IgG4PA/RPF) 2018, and Proposal of a Revised 2023 Version for IgG4-Related Cardiovascular/Retroperitoneal Disease.

BACKGROUND: In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version.Methods and Results: Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients ("mimickers") identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts' diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating "radiologic findings of pericarditis", "eosinophilic infiltration or lymphoid follicles", and "probable diagnosis of extra-PA/-RPF lesions", improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively. CONCLUSIONS: Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.

Effect of renal function under left ventricular assist device support on the cardiac function and clinical events after heart transplantation.

AIM: We investigated the effects of pre-transplantation renal dysfunction under left ventricular assisted device (LVAD) support on post-transplantation cardiac function, and patient prognosis after heart transplantation (HTx). METHOD: All patients who were bridged by LVAD and underwent HTx at our hospital between 2007 and 2022 were included in this study. Patients were classified into two groups based on estimated glomerular filtration rate (eGFR) before HTx: renal dysfunction (RD) group (eGFR < 60 mL/min/1.73 m2 ) and non-renal dysfunction (NRD) group. RESULT: A total of 132 patients were analyzed, of whom 48 were classified into the RD group and 84 into the NRD group (RD group, 47.9 ± 10.1 years; NRD group, 38.4 ± 11.9 years, p < .0001). Under LVAD support before HTx, the RD group tended to have a history of right ventricular failure (RD group, nine (19%); NRD group, seven (8%); p = .098). After HTx, the echocardiographic parameters did not differ between the two groups in the long term. Furthermore, more concise hemodynamic parameters, exemplified by right heart catheterization, were not significantly different between the two groups. Regarding graft rejection, no significant differences were found in acute cellular rejection and cardiac allograft vasculopathy following HTx. In contrast, patients with RD before HTx had significantly increased mortality in the chronic phase after HTx and initiation of maintenance dialysis, without any overt changes in cardiac function. CONCLUSION: Pre-transplantation renal dysfunction under LVAD support significantly affected clinical course after HTx without any overt changes in graft cardiac function.

Prophylactic negative pressure wound therapy is not effective for preventing driveline infection following left ventricular assist device implantation.

BACKGROUND: Driveline infection (DLI) following left ventricular assist device (LVAD) implantation remains an unresolved problem. Negative pressure wound therapy (NPWT) promotes wound healing by applying negative pressure on the surface of the wound. Recently, the prophylactic application of NPWT to closed surgical incisions has decreased surgical site infections in various postsurgical settings. Therefore, we evaluated the efficacy and safety of prophylactic NPWT for preventing DLI in patients with LVAD implantation. METHODS: Prophylactic NPWT was provided to 50 patients who received continuous-flow LVADs as bridge-to-transplant therapy at our institution between May 2018 and October 2020 (NPWT group). The negative pressure dressing was applied immediately after surgery and retained on the driveline exit site for 7 days with a continuous application of -125 mm Hg negative pressure. The primary outcome was DLI within 1 year of LVAD implantation. We compared the rate of DLI incidence in the NPWT group with that in the historical control cohort (50 patients) treated with the standard dressing (SD) who received LVAD implantation between July 2015 and April 2018 (SD group). RESULTS: No severe complications were associated with the NPWT. During the follow-up period, DLI was diagnosed in 16 participants (32%) in the NPWT group and 21 participants (42%) in the SD group. The rates of DLI incidence and freedom from DLI did not differ between groups (p = 0.30 and p = 0.63). CONCLUSIONS: Prophylactic NPWT at the driveline exit site was safe following LVAD implantation. However, it did not significantly reduce the risk of DLI.

Successful Treatment with Letermovir in a Heart Transplant Recipient with UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Colitis and Viremia.

Currently available anti-cytomegalovirus (CMV) agents are sometimes poorly tolerated, owing to their side effects. Letermovir is a novel anti-CMV drug that is only approved for CMV prophylaxis in hematopoietic stem cell transplant recipients, with fewer side effects. We report the case of a heart transplant recipient with UL97 mutation (L595F) ganciclovir-resistant cytomegalovirus colitis who was successfully treated with off-label use of letermovir. In treating CMV infection or disease with letermovir, a transient rise or lag in the clearance of CMV-DNA polymerase chain reaction levels has been observed. Our case suggests that CMV-pp65 antigenemia can be an additional marker of treatment efficacy.

Social and environmental risks as contributors to the clinical course of heart failure.

Heart failure is a major contributor to healthcare expenditures. Many clinical risk factors for the development and exacerbation of heart failure had been reported, including diabetes, renal dysfunction, and respiratory disease. In addition to these clinical parameters, the effects of social factors, such as occupation or lifestyle, and environmental factors may have a great impact on disease development and progression of heart failure. However, the current understanding of social and environmental factors as contributors to the clinical course of heart failure is insufficient. To present the knowledge of these factors to date, this comprehensive review of the literature sought to identify the major contributors to heart failure within this context. Social factors for the risk of heart failure included occupation and lifestyle, specifically in terms of the effects of specific occupations, occupational exposure to toxicities, work style, and sleep deprivation. Socioeconomic factors focused on income and education level, social status, the neighborhood environment, and marital status. Environmental factors included traffic and noise, air pollution, and other climate factors. In addition, psychological stress and behavior traits were investigated. The development of heart failure may be closely related to these factors; therefore, these data should be summarized for the context to improve their effects on patients with heart failure. The present study reviews the literature to summarize these influences.

Nonsyndromic arteriopathy and aortopathy and vascular Ehlers-Danlos syndrome causing COL3A1 variants.

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant genetic disorder characterized by soft connective tissue vulnerability due to dysfunction of Type III collagen and caused by the pathogenic variants in COL3A1 gene. In the era of next-generation sequencing, multiple genes including COL3A1 can be simultaneously analyzed, and among patients suffering from aortopathy even without any other clinical features suggestive of vEDS, pathogenic COL3A1 variants have been increasingly identified. Here, we briefly summarize the characteristics of 12 Japanese patients from 11 families with arteriopathy and pathogenic or likely pathogenic COL3A1 variants in our hospital. Five patients did not have any extra-arterial clinical features, however, the multigene panel testing for hereditary thoracic aortic aneurysm and dissection unexpectedly revealed that two had glycine substitutions in the triple-helical region and three had haploinsufficient type variants in the COL3A1 gene, whose pathogenicities were all classified as pathogenic or likely pathogenic. Further genetic screening and identification of pathogenic variants in patients with nonsyndromic arteriopathy and aortopathy will enable us to develop risk-stratification and management based on the genetic diagnosis.

Establishing clinical remission criteria and the framework of a treat-to-target algorithm for Takayasu arteritis: Results of a Delphi exercise carried out by an expert panel of the Japan Research Committee of the Ministry of Health, Labour and Welfare for intractable vasculitis.

OBJECTIVES: To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK). METHODS: A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 paediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over four reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with three patients. RESULTS: Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0-5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including positron emission tomography-computed tomography, and two on treatment intensification. CONCLUSIONS: We developed a T2T algorithm and proposals for standardised remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.

Association between infectious event and de novo malignancy after heart transplantation.

The aim of the study was to investigate the incidence of and risk factors for de novo malignancy after heart transplantation (HTx) in a single center. We assessed 102 consecutive patients who received HTx and were followed-up in our center regularly for > 1 year from June 2006 to May 2018. We investigated the incidence of and risk factors for de novo malignancy. The cumulative incidence of each malignancy type during the follow-up period was one (0.98%) for skin cancer, four (3.92%) for nonskin solid organ cancer, and six (5.88%) for posttransplant lymphoproliferative disorder (PTLD). The percentage of patients with more than one infectious event ≤ 1 year after HTx was higher in the malignancy group than in the non-malignancy group. Furthermore, Kaplan-Meier analysis revealed that the incidence rate of infectious events was higher in patients with malignancies than in those without (log-rank P < 0.001). After dividing malignancies into a PTLD group and a solid organ malignancy group, we found that negative Epstein-Barr virus serostatus, cytomegalovirus-positive antigenemia, and the occurrence of any viral or gastrointestinal infectious event at ≤ 1 year were more frequent in patients with PTLD than in patients without it. The survival rate was significantly lower for patients with solid organ malignancy than for patients without malignancy. In conclusion, there was a correlation between infectious events and de novo malignancy, particularly in patients with PTLD. We should confirm this finding by conducting a larger cohort study.

Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.

Fractional exhaled nitric oxide in adult congenital heart disease.

BACKGROUND: Fractional exhaled nitric oxide levels are related to various clinical diseases. This study investigated the associations between the clinical characteristics and the level of fractional exhaled nitric oxide in patients with adult congenital heart disease. METHODS AND RESULTS: Fractional exhaled nitric oxide values were measured in 30 adult patients with stable congenital heart disease who had undergone right heart catheterization and 17 healthy individuals (controls). There was no significant difference in fractional exhaled nitric oxide values between patients with congenital heart disease and healthy controls. Depending on whether their fractional exhaled nitric oxide values were above or below the median value, patients with congenital heart disease were divided into two groups (low vs. high fractional exhaled nitric oxide groups). The relationship between fractional exhaled nitric oxide values and clinical characteristics was investigated. There was a higher percentage of patients with cyanosis in the low fractional exhaled nitric oxide group (50%) than in the high fractional exhaled nitric oxide group (7.1%). There was no significant difference in right heart catheterization data between the low and high fractional exhaled nitric oxide groups. The fractional exhaled nitric oxide value was correlated to the number of neutrophils in patients with cyanosis (r = 0.84 (N = 8), p = 0.005). CONCLUSIONS: In this cohort of patients with adult congenital heart disease, lower levels of fractional exhaled nitric oxide corresponded to the presence of cyanosis.

Significant impact of left ventricular assist device models on the value of flow-mediated dilation: effects of LVAD on endothelial function.

The precise physiological changes associated with the use of left ventricular assist device (LVAD) are not well characterized. We examined the impact of changes in hemodynamic state using LVAD on endothelial function. We measured flow-mediated vasodilation (FMD) to evaluate endothelial vasodilator function of the brachial artery in 53 patients (dilated cardiomyopathy: 39, ischemic cardiomyopathy: 4, and others: 10) with an implanted LVAD (DuraHeart, EVAHEART, or HeartMate II). We found that FMD value in the HeartMateII LVAD group (9.3% ± 2.9%) was significantly higher than those in the other two groups (EVAHEART: 6.7% ± 2.8% and DuraHeart: 6.2% ± 4.0%). Other factors that affected the FMD value were age (r = - 0.31, p = 0.026), Brinkman index (r = - 0.30, p = 0.029); however, aortic opening, aortic regurgitation, and other hemodynamic parameters such as cardiac index or pulmonary capillary wedge pressure did not correlate with FMD. Multivariate analyses revealed that the difference among the LVAD models most significantly affected the FMD values after adjusting for age and smoking status (t = 2.6, p = 0.014). Event free survival rate of death and cerebral infarction was not significantly different according to the value of FMD. The difference among the LVAD groups most significantly affected the state of endothelial function and it had more impact than other clinical factors.

Characteristics of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis and Anticentriole Autoantibodies.

Anticentriole autoantibodies-positive systemic sclerosis (SSc) has been reported to develop pulmonary arterial hypertension (PAH) at a high rate. In this report, we describe two patients with anticentriole antibodies-positive SSc-PAH who were treated with pulmonary vasodilators. Both cases were elderly women with poor physical conditions and clinical findings of SSc. Case 1 was resistant to combination therapy with pulmonary vasodilators; in Case 2, hemodynamic improvement was obtained by upfront combination therapy at an early stage. Because anticentriole antibodies-positive SSc-PAH rapidly deteriorates, careful hemodynamic observation and timely aggressive use of pulmonary vasodilators should be considered.

Erratum: Characteristics of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis and Anticentriole Autoantibodies.

The errors in the following list appeared in the article titled "Characteristics of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis and Anticentriole Autoantibodies" by Hisataka Maki, Kana Kubota, Masaru Hatano, Shun Minatsuki, Eisuke Amiya, Ayumi Yoshizaki, Yoshihide Asano, Hiroyuki Morita, Shinichi Sato, Issei Komuro (Vol 61, No.2, 413-418, 2020).

The Clinical Efficacy of Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension.

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

BACKGROUND: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. METHODS: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. RESULTS: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group (P<0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; P=0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; P=0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. CONCLUSIONS: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730.

Clinical impact of newly developed atrial fibrillation complicated with longstanding ventricular fibrillation during left ventricular assist device support: A case report.

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) improve survival and morbidity in patients with stage D heart failure. Management of LVADs for longer durations is necessary in some clinical settings, and a better understanding of the hemodynamics of patients using LVADs is warranted. Arrhythmia, including atrial (AA) and ventricular (VAs) arrhythmias, is a modifying factor of hemodynamics that is highly prevalent among patients with LVADs. However, the clinical impact of arrhythmias in various clinical settings in patients with LVAD, in which the hemodynamic load is likely to present as worsening of right heart failure, remains to be completely elucidated. CASE PRESENTATION: We describe the case of a patient under sustained ventricular fibrillation for extraordinarily long duration who was stabilized using LVAD support and in whom newly developed atrial fibrillation led to a significant worsening of right heart failure while using an LVAD. CONCLUSION: This case demonstrates the substantial clinical impact of AAs in the management of right heart failure using an LVAD.

Correction to: The potential of cardiac rehabilitation as a method of suppressing abdominal aortic aneurysm expansion: a pilot study.

In the original publication of the article, under the result section.

The potential of cardiac rehabilitation as a method of suppressing abdominal aortic aneurysm expansion: a pilot study.

This study is a prospective evaluation of the effectiveness of cardiac rehabilitation (CR) in terms of clinical outcomes for small abdominal aortic aneurysms (AAA) that were previously reported in a retrospective cohort study. We conducted a prospective non-randomized trial on patients with small AAA (N = 40; mean age 75.0 ± 6.6 years). Patients were enrolled into one of two groups, rehabilitation (CR) or non-rehabilitation (non-CR) group. Only CR group participated in a supervised-CR program including bicycle ergometer for 150 days. The AAA expansion rate and the risk of AAA repair were compared between two groups. We also researched the relationship between AAA expansion rate and body composition, blood IL-6 and TGFß1 levels. The CR (N = 15) and non-CR groups (N = 25) were comparable in terms their baseline data. The CR group had a significantly smaller change in the maximal AAA size (- 1.3 ± 2.4 mm/years) compared to the non-CR group (2.0 ± 3.6 mm/years) (p < 0.01). The IL-6, and TGFß1 levels were unrelated to the changes in AAA size. There was mild positive correlation between the change in systolic blood pressure from rest to exercise and the AAA expansion rate (p = 0.06). The risk of AAA repair after 12 months was lower in the CR group compared to the non-CR group (0% vs. 28%, respectively). CR in patients with small AAA significantly suppressed AAA expansion and resulted in a lowered risk of AAA repair.Clinical trial Trial name: The study of the profitability and protective effect of cardiac rehabilitation on abdominal aortic aneurysm. Number: UMIN000028237. UTL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R0000323.