Statins use and recurrent venous thromboembolism in the direct oral anticoagulant era: insight from the COMMAND VTE Registry-2.

Statins were reported to have a potential effect of primary prevention of venous thromboembolism (VTE), although that of secondary prevention remains uncertain. To investigate the association between statins use and recurrent VTE in the current era. The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive VTE patients among 31 centers in Japan between January 2015 and August 2020. We divided the entire cohort into 2 groups according to statins use at the time of discharge; the statins (N = 865) and no statins groups (N = 4332). The statins group was older (72.9 vs. 66.7 years, P < 0.001), and less often had active cancer (22.0% vs. 30.4%, P < 0.001). The cumulative incidence of discontinuation of anticoagulation was significantly lower in the statins group (60.3% vs. 52.6%, Log-rank P < 0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in the statins group (6.8% vs. 10.1%, Log-rank P = 0.01). Even after adjusting for the confounders, the lower risk of the statins group relative to the no statins group remained significant for recurrent VTE (HR 0.65, 95% CI 0.45-0.91, P = 0.01). The cumulative 5-year incidence of major bleeding was significantly lower in the statins group (12.2% vs. 14.1%, Log-rank P = 0.04), although, after adjusting for the confounders, the risk of the statins group relative to the no statins group turned to be insignificant (HR 0.77, 95% CI 0.59-1.00, P = 0.054). In this large real-world VTE registry, statins use was significantly associated with a lower risk for the recurrent VTE in the current era.

Edoxaban, Rivaroxaban, or Apixaban for Cancer-Associated Venous Thromboembolism in the Real World: Insights from the COMMAND VTE Registry-2.

BACKGROUND: Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking. METHODS: The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (N = 643, 54%), rivaroxaban (N = 297, 25%), and apixaban (N = 257, 22%) groups. RESULTS: The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p = 0.04; and 37.6, 26.8, and 38.3%, p = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group. CONCLUSION: The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.

Subclass phenotypes in patients with unprovoked venous thromboembolisms using a latent class analysis.

BACKGROUND: Patients with unprovoked venous thromboembolisms (VTEs) can be sub-classified based on the different phenotypes using a latent class analysis (LCA), which might be useful for selecting individual management strategies. METHODS: In the COMMAND VTE Registry-2 database enrolling 5197 VTE patients, the current derivation cohort consisted of 1556 patients with unprovoked VTEs. We conducted clustering with an LCA, and the patients were classified into subgroups with the highest probability. We compared the clinical characteristics and outcomes among the developed subgroups. RESULTS: This LCA model proposed 3 subgroups based on 8 clinically relevant variables, and classified 592, 813, and 151 patients as Class I, II, and III, respectively. Based on the clinical features, we named Class I the younger, Class II the older with a few comorbidities, and Class III the older with many comorbidities. The cumulative 3-year anticoagulation discontinuation rate was highest in the older with many comorbidities (Class III) (39.9 %, 36.1 %, and 48.4 %, P = 0.02). There was no significant difference in the cumulative 5-year incidence of recurrent VTEs among the 3 classes (12.8 %, 11.1 %, and 4.0 % P = 0.20), whereas the cumulative 5-year incidence of major bleeding was significantly higher in the older with many comorbidities (Class III) (7.8 %, 12.7 %, and 17.8 %, P = 0.04). CONCLUSION: The current LCA revealed that patients with unprovoked VTEs could be sub-classified into further phenotypes depending on the patient characteristics. Each subclass phenotype could have different clinical outcomes risks especially a bleeding risk, which could have a potential benefit when considering the individual anticoagulation strategies. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm COMMAND VTE Registry-2: Unique identifier, UMIN000044816 COMMAND VTE Registry: Unique identifier, UMIN000021132.

Fragility and long-term clinical outcomes in patients with venous thromboembolism receiving direct oral anticoagulants: From the COMMAND VTE REGISTRY-2.

INTRODUCTION: There is limited data on the safety of direct oral anticoagulants (DOACs) in fragile patients with venous thromboembolism (VTE). MATERIALS AND METHODS: We used the COMMAND VTE Registry-2 enrolling patients with acute symptomatic VTE. The study population consisted of 3928 patients receiving DOACs, who were divided into fragile (2136 patients) and non-fragile groups (1792 patients). Fragility was defined as patients of age ≥ 75 years, creatinine clearance level ≤ 50 ml/min, and/or body weight ≤ 50 kg. RESULTS: The fragile group significantly more often received reduced doses of DOACs compared to the non-fragile group (51 % and 19 %, P < 0.001). The cumulative 5-year incidence of major bleeding was numerically higher in the fragile group than the non-fragile group (15.0 % and 11.1 %, P = 0.052), even with no significant excess risk after adjusting for confounders (HR 1.03, 95%CI 0.81-1.31, P = 0.78). The cumulative 5-year incidence of clinically relevant bleeding was significantly higher in the fragile group than the non-fragile group (28.6 % and 19.6 %, P < 0.001), even after adjusting for confounders (HR 1.28, 95%CI 1.08-1.53, P = 0.005). There was no significant difference in cumulative 5-year incidence of recurrent VTE between the groups (9.6 % and 8.9 %, P = 0.68), which was consistent after adjusting for confounders (HR 1.13, 95%CI 0.84-1.51, P = 0.41). CONCLUSIONS: Among VTE patients receiving DOACs, fragile patients were associated with a numerically higher rate of major bleeding and a significantly increased risk of clinically relevant bleeding, but not an increased risk of recurrent VTE.

Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　- A Predetermined Companion Report From the ONCO PE Trial.

BACKGROUND: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events. CONCLUSIONS: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

Cancer-associated venous thromboembolism in the direct oral anticoagulants era: Insight from the COMMAND VTE Registry-2.

BACKGROUND: There is a paucity of data on real-world management strategies and clinical outcomes of cancer-associated venous thromboembolism (VTE) in the direct oral anticoagulants (DOACs) era. OBJECTIVES: To investigate the status of cancer-associated VTE in the DOAC era. METHODS: This multicenter, retrospective cohort study among 31 centers in Japan between 2015 and 2020 enrolled 5197 consecutive patients with acute symptomatic VTE, who were divided into 1507 patients (29 %) with active cancer and 3690 patients (71 %) without. RESULTS: The cumulative 3-year rate of anticoagulation discontinuation was significantly higher in patients with active cancer than in those without (62.7 % vs. 59.1 %, P < 0.001). The cumulative 5-year incidence of recurrent VTE was higher in patients with active cancer than in those without (10.1 % vs. 9.1 %, P = 0.01), however, after adjusting for the confounders and competing risk of mortality, the excess risk of the active cancer group relative to the no active cancer group was no longer significant (HR: 0.95, 95 % CI: 0.73-1.24). The cumulative 5-year incidence of major bleeding was much higher in the active cancer group (20.4 % vs. 11.6 %, P < 0.001). Even after adjusting for the confounders and competing risk of mortality, the risk of the active cancer group relative to the no active cancer group remained significant (HR: 1.36, 95 % CI: 1.11-1.66). CONCLUSIONS: The current large real-world registry revealed that the risk of major bleeding was still higher in patients with active cancer than in those without, leading to the frequent anticoagulation discontinuation, which has been still a huge challenge to overcome in the DOAC era.

Pyothorax and Constrictive Pericarditis after Chemoradiotherapy for Esophageal Cancer: A Case Report.

A 75-year-old man underwent chemoradiotherapy for advanced esophageal cancer. After nine years, he was hospitalized for left pyothorax. Consequently, the patient underwent drainage and window opening surgery. He experienced cardiopulmonary arrest but was resuscitated. Based on cardiac catheterization data, the patient was diagnosed with constrictive pericarditis. Unfortunately, extracorporeal circulation did not improve his condition, and he ultimately died. An autopsy revealed adhesion between the pericardium and pleura, especially the pericardium in contact with the left thoracic cavity, which was markedly thickened. This suggests that constrictive pericarditis, a latent complication of chemoradiotherapy, is aggravated by pyothorax.

Clinical and molecular delineation of classical-like Ehlers-Danlos syndrome through a comprehensive next-generation sequencing-based screening system.

Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in TNXB. Thus far, 50 patients from 43 families with biallelic TNXB variants have been identified. Accurate detection of TNXB variants is challenging because of the presence of the pseudogene TNXA, which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect TNXB variants and the recombination of TNXA-derived sequences into TNXB. Using this system, we identified biallelic TNXB variants in nine unrelated clEDS patients. TNXA-derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for TNXB variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.

Drug-coated balloons for the treatment of stent edge restenosis.

BACKGROUND: Drug-coated balloon (DCB) is a device for treating patients with in-stent restenosis; however, there are scant data on its efficacy for stent edge restenosis (SER). This study aimed to investigate the clinical outcomes of DCB use for treating SER compared with new-generation drug-eluting stent (DES) implantation. METHOD: From December 2013 to January 2019, patients who underwent DES implantation or DCB for SER were enrolled. Clinical outcomes were analyzed, and propensity score with matching was conducted. The primary outcome was target-vessel revascularization (TVR). The secondary outcomes were the incidence of all-cause mortality, major adverse cardiovascular events (MACE), and target lesion revascularization (TLR). RESULT: A total of 291 patients with SER were included: 160 were treated with DCB, and 131 with new-generation DES. DCB treatment for SER treatment was associated with a lower risk of TVR than DES [hazard ratio, 0.549; 95% confidence interval (CI), 0.339-0.891] at a median follow-up of 1080 days (interquartile range; 729-1080 days). Propensity score matching (PSM) was performed to adjust for baseline clinical and lesion characteristics. After PSM, no significant difference in the risk of TVR was observed (hazard ratio, 0.965; 95% CI, 0.523-1.781). Similarly, the risk for all-cause death (hazard ratio, 0.507; 95% CI, 0.093-2.770), MACE (hazard ratio: 0.812; 95% CI, 0.451-1.462), and TLR (hazard ratio: 0.962; 95% CI, 0.505-1.833) were comparable between the two groups. CONCLUSION: DCB treatment efficacy for SER was similar to that of new-generation DES after PSM. DCB is a significant alternative to obtain comparable results with new-generation DES for the treatment of SER.

Acute pulmonary thromboembolism after messenger RNA vaccination against coronavirus disease 2019: A case report.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is defined as thrombosis after inoculation of adenovirus vector vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VITT rarely occurs with messenger RNA vaccines, and the use of heparin for VITT is also controversial. A 74-year-old female patient with no risk factors for thrombosis was brought to our hospital after loss of consciousness. Nine days before admission, she had received the third vaccine against SARS-CoV-2 (mRNA1273, Moderna). Immediately after transport, cardiopulmonary arrest occurred, prompting extracorporeal membrane oxygenation (ECMO). Pulmonary angiography showed translucent images of both pulmonary arteries, resulting in the diagnosis of acute pulmonary thromboembolism. Unfractionated heparin was administered, but D-dimer subsequently became negative. Pulmonary thrombosis remained in large volume, indicating that heparin was ineffective. Treatment was shifted to anticoagulant therapy using argatroban, which increased D-dimer level and improved respiratory status. The patient was successfully weaned from ECMO and ventilator. Anti-platelet factor 4 antibody examined after treatment initiation showed negative results; however, VITT was considered as an underlying condition because of the time of onset after vaccination, the ineffectiveness of heparin, and the absence of other causes of thrombosis. In case heparin is not effective, argatroban can be an alternative therapy against thrombosis. Learning objective: During the coronavirus disease 2019 pandemic, treatment with vaccine against severe acute respiratory syndrome coronavirus 2 has been widely performed. Vaccine-induced immune thrombotic thrombocytopenia is the most common thrombosis after adenovirus vector vaccines. However, thrombosis can also occur after messenger RNA vaccination. Though commonly used for thrombosis, heparin may be ineffective. Non-heparin anticoagulants should be considered.

Comprehensive genetic screening for vascular Ehlers-Danlos syndrome through an amplification-based next-generation sequencing system.

Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys-Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.

Oozing-type rupture caused by right ventricular intramural hematoma after right ventricular infarction.

An 81-year-old man was admitted to the hospital because of decreased level of consciousness. He had bradycardia (27 beats/min). Electrocardiography showed ST-segment elevation in leads II, III, and aVF and ST-segment depression in leads aVL, V1. Transthoracic echocardiography (TTE) visualized reduced motion of the left ventricular (LV) inferior wall and right ventricular (RV) free wall. Coronary angiography revealed occlusion of the right coronary artery. A primary percutaneous coronary intervention was successfully performed with temporary pacemaker backup. On the third day, the sinus rhythm recovered, and the temporary pacemaker was removed. On the fifth day, a sudden cardiac arrest occurred. Extracorporeal cardiopulmonary resuscitation was performed. TTE showed a high-echoic effusion around the right ventricle, indicating a hematoma. The drainage was ineffective. He died on the eighth day. An autopsy showed the infarcted lesion and an intramural hematoma in the RV. However, no definite perforation of the myocardium was detected. The hematoma extended to the epicardium surface, indicative of oozing-type RV rupture induced by RV infarction. The oozing-type rupture induced by RV infarction might develop asymptomatically without influence on the vital signs of the patient. Frequent echocardiographic evaluation is essential in cases of RV infarction taking care of silent oozing-type rupture. Learning objective: Inferior left ventricular infarction sometimes complicates right ventricular (RV) infarction. The typical manifestations of RV infarction include low blood pressure, low cardiac output, and elevated right atrium pressure. Although the frequency is low, fatal complications of oozing-type RV rupture might progress asymptomatically. Frequent echocardiographic screening is necessary to detect them.

Long-term outcomes of intermediate coronary stenosis in patients undergoing hemodialysis after deferred revascularization based on fractional flow reserve.

OBJECTIVES: This study aimed to assess the long-term outcomes of patients undergoing hemodialysis (HD) after deferred revascularization based on fractional flow reserve (FFR). BACKGROUND: FFR is a practical technique for assessing the functional severity of intermediate coronary stenosis. Prior research has revealed a satisfactory outcome in patients after the deferral of percutaneous coronary intervention for coronary lesions based on FFR measurement. However, little research has been conducted focusing on patients undergoing HD. METHODS: The retrospective study comprised 225 consecutive patients with FFR assessment and deferred revascularization between January 2016 and December 2019. Based on a deferral cutoff FFR value of >0.80, we assessed the differences in all-cause death, major adverse cardiac events (MACEs), and target vessel failure (TVF) between the HD (n = 69) and non-HD groups (n = 156) during a mean ± standard deviation routine follow-up of 32.2 ± 13.4 months. RESULTS: Although the HD group had significantly higher rates of diabetes mellitus than the non-HD group (53.6% vs. 37.2%, p = 0.021), there were no significant differences in sex, left ventricular ejection fraction, or other risk factors between the groups, nor with respect to stenosis diameter or mean FFR. The HD group had a significantly higher incidence of TVF than the non-HD group (34.8% vs. 14.1%, p < 0.001), as well as a significantly higher risk of all-cause death and MACEs. CONCLUSIONS: The study revealed that deferred revascularization in coronary lesions with an FFR value of >0.80 in patients undergoing HD was associated with poor outcomes. Therefore, it is important to carefully monitor patients with intermediate coronary stenosis undergoing HD.

Status of adult outpatients with congenital heart disease in Japan: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease Registry.

BACKGROUND: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease (JNCVD-ACHD) was founded in 2011 for the lifelong care of adult patients with congenital heart disease (ACHD patients). This network maintains the first Japanese ACHD registry. METHODS AND RESULTS: From 2011 to 2019, the JNCVD-ACHD registered 54 institutions providing specialized care for ACHD patients in 32 of the 47 prefectures in Japan. The registry collected data on the disease profile for 24,048 patients from 50 institutions and the patient characteristics for 9743 patients from 24 institutions. The most common ACHDs were atrial septal defect (20.5 %), ventricular septal defect (20.5 %), tetralogy of Fallot (12.9 %), and univentricular heart (UVH)/single ventricle (SV; 6.6 %). ACHD patients without biventricular repair accounted for 37.0 % of the population. Also examined were the serious anatomical and/or pathophysiological disorders such as pulmonary arterial hypertension (3.0 %) including Eisenmenger syndrome (1.2 %), systemic right ventricle under biventricular circulation (sRV-2VC; 2.8 %), and Fontan physiology (6.0 %). The sRV-2VC cases comprised congenitally corrected transposition of the great arteries without anatomical repair (61.9 %) and transposition of the great arteries with atrial switching surgery (38.1 %). The primary etiology (86.4 %) for Fontan physiology was UVH/SV. In addition, developmental/chromosomal/genetic disorders were heterotaxy syndromes (asplenia, 0.9 %; polysplenia, 0.7 %), trisomy 21 (4.0 %), 22q11.2 deletion (0.9 %), Turner syndrome (0.2 %), and Marfan syndrome (1.1 %). CONCLUSIONS: Although the specific management of ACHD has systematically progressed in Japan, this approach is still evolving. For ideal ACHD care, the prospective goals for the JNCVD-ACHD are to create local networks and provide a resource for multicenter clinical trials to support evidence-based practice.

Ketone body and FGF21 coordinately regulate fasting-induced oxidative stress response in the heart.

Ketone body ß-hydroxybutyrate (ßOHB) and fibroblast growth factor-21 (FGF21) have been proposed to mediate systemic metabolic response to fasting. However, it remains elusive about the signaling elicited by ketone and FGF21 in the heart. Stimulation of neonatal rat cardiomyocytes with ßOHB and FGF21 induced peroxisome proliferator-activated receptor α (PPARα) and PGC1α expression along with the phosphorylation of LKB1 and AMPK. ßOHB and FGF21 induced transcription of peroxisome proliferator-activated receptor response element (PPRE)-containing genes through an activation of PPARα. Additionally, ßOHB and FGF21 induced the expression of Nrf2, a master regulator for oxidative stress response, and catalase and Ucp2 genes. We evaluated the oxidative stress response gene expression after 24 h fast in global Fgf21-null (Fgf21-/-) mice, cardiomyocyte-specific FGF21-null (cmFgf21-/-) mice, wild-type (WT), and Fgf21fl/fl littermates. Fgf21-/- mice but not cmFgf21-/- mice had unexpectedly higher serum ßOHB levels, and higher expression levels of PPARα and oxidative stress response genes than WT mice or Fgf21fl/fl littermates. Notably, expression levels of oxidative stress response genes were significantly correlated with serum ßOHB and PGC1α levels in both WT and Fgf21-/- mice. These findings suggest that fasting-induced ßOHB and circulating FGF21 coordinately regulate oxidative stress response gene expression in the heart.

Acute myocarditis associated with COVID-19 vaccination: A case report.

Recently, new vaccine platforms-including mRNA vaccines for coronavirus disease 2019 (COVID-19) have been given emergency use authorization in Japan. Here, we present a rare case of myocarditis following a COVID-19 vaccine. In this case, myocarditis was confirmed by cardiac magnetic resonance imaging, endomyocardial biopsy, and troponin levels. The degree of myocardial inflammation in the endomyocardial biopsy samples was mild and the patient's clinical course was not severe. Although the pathology of myocarditis in this case was mild, further investigation would be needed. .

Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice.

Cardiac dysfunction is induced by multifactorial mechanisms in diabetes. Deranged fatty acid (FA) utilization, known as lipotoxicity, has long been postulated as one of the upstream events in the development of diabetic cardiomyopathy. CD36, a transmembrane glycoprotein, plays a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport with marked enhancement of glucose use. In this study, we explore whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. We found that cardiac contractile dysfunction had deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake was not reduced in CD36KO-STZ hearts, the total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. The isotopomer analysis with 13C6-glucose revealed that accelerated glycolysis, estimated by enrichment of 13C2-citrate and 13C2-malate, was markedly suppressed in CD36KO-STZ hearts. Levels of ceramides, which are cardiotoxic lipids, were not elevated in CD36KO-STZ hearts compared to wild-type-STZ ones. Furthermore, increased energy demand by transverse aortic constriction resulted in synergistic exacerbation of contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis; therefore, the limitation of FA utilization is detrimental to cardiac energetics in this model of diabetic cardiomyopathy.

A case of a middle-aged patient with a ventricular septal defect complicated by severe pulmonary hypertension-stepwise surgical repair with pulmonary vasodilators.

We report a case of ventricular septal defect (VSD) in which we attempted to treat pulmonary arterial hypertension (PAH) with the goal of VSD closure in an adult with suspected Eisenmenger syndrome in childhood. Four years previously (age 41 years), she was referred to our department due to repeated hemoptysis requiring further treatment of PAH. We started combination therapy with several pulmonary vasodilators. Two years later, her pulmonary vascular resistance (PVR) was improved but still not at the level where VSD closure was possible. To control the increased PA flow resulting from intensive PAH treatment and to reduce the risk of hemoptysis, we performed pulmonary artery banding (PAB). As the risk of hemoptysis decreased, a prostacyclin analog was introduced, and the dose was increased. More than 1 year after PAB, active vasoactivity testing became positive, suggesting that the pulmonary vascular lesion was now "reversible". We performed VSD closure and atrial septal defect creation even though her PVR was still high. After the operation, her exercise capacity was remarkably improved. We suggest that stepwise surgical repair with pulmonary vasodilators is an important treatment option for select patients with VSD with severe PAH. .