Effects of angiotensin receptor-neprilysin inhibitor on ketone body metabolism in pre-heart failure/heart failure patients.

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] µmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients.

URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease.

We recently reported that the selective inhibition of urate transporter-1 (URAT1), which is primarily expressed in the kidneys, ameliorates insulin resistance by attenuating hepatic steatosis and improving brown adipose tissue function in diet-induced obesity. In this study, we evaluated the effects of dotinurad, a URAT1-selective inhibitor, on the hearts of high-fat diet (HFD)-fed obese mice for 16-20 weeks and on neonatal rat cardiomyocytes (NRCMs) exposed to palmitic acid. Outside the kidneys, URAT1 was also expressed in cardiomyocytes and indeed worked as a uric acid transporter. Dotinurad substantially attenuated HFD-induced cardiac fibrosis, inflammatory responses, and cardiac dysfunction. Intriguingly, among various factors related to the pathophysiology of diet-induced obesity, palmitic acid significantly increased URAT1 expression in NRCMs and subsequently induced apoptosis, oxidative stress, and inflammatory responses via MAPK pathway, all of which were reduced by dotinurad. These results indicate that URAT1 is a potential therapeutic target for metabolic heart disease.

Inhibitory action of B-type natriuretic peptide on adrenocorticotropic hormone in patients with acute coronary syndrome.

In addition to the classical actions of hemodynamic regulation, natriuretic peptides (NPs) interact with various neurohumoral factors that are deeply involved in the pathophysiology of cardiovascular diseases. However, their effects on the hypothalamic-pituitary-adrenal (HPA) axis, which is activated under acute high-stress conditions in acute coronary syndrome (ACS), remain largely unknown. We investigated the impact of plasma B-type NP (BNP) on plasma adrenocorticotropic hormone (ACTH)-cortisol levels during the acute phase of ACS ischemic attacks. The study population included 436 consecutive patients with ACS for whom data were collected during emergency cardiac catheterization. Among them, biochemical data after acute-phase treatment were available in 320 cases, defined as the ACS-remission phase (ACS-rem). Multiple regression analyses revealed that plasma BNP levels were significantly negatively associated with plasma ACTH levels only during ACS attacks (P < 0.001), but not in ACS-rem, whereas plasma BNP levels were not significantly associated with plasma cortisol levels at any point. Accordingly, covariance structure analyses were performed to clarify the direct contribution of BNP to ACTH by excluding other confounding factors, confirming that BNP level was negatively correlated with ACTH level only during ACS attacks (ß = -0.152, P = 0.002), whereas BNP did not significantly affect ACTH in ACS-rem. In conclusion, despite the lack of a significant direct association with cortisol levels, BNP negatively regulated ACTH levels during the acute phase of an ACS attack in which the HPA axis ought to be activated. NP may alleviate the acute stress response induced by severe ischemic attacks in patients with ACS.NEW & NOTEWORTHY BNP negatively regulates ACTH during a severe ischemic attack of ACS in which hypothalamic-pituitary-adrenal axis ought to be activated, indicating an important role of natriuretic peptides as a mechanism of adaptation to acute critical stress conditions in humans.

Time-dependent changes in P2Y12 reaction unit values for predicting the different types of cardiovascular events in patients with ischemic heart disease.

Several studies have investigated the association between P2Y12 reaction unit (PRU) value and major adverse cardiovascular events (MACEs) in patients with ischemic heart disease, but there is no well-established consensus on the utility of PRU value. Furthermore, the optimal PRU cut-off value varied with studies. One reason may be that the endpoints and observation periods differed, depending on the study. This study aimed to investigate the optimal cut-off and predictive ability of the PRU value for predicting cardiovascular events, while considering different endpoints and observation periods. We surveyed a total of 338 patients receiving P2Y12 inhibitors and measured PRU during cardiac catheterization. Using time-dependent receiver operating characteristic analysis, we evaluated the cut-off and area under curve (AUC) of the PRU value for two MACEs (MACE ①: composite of death, myocardial infarction, stent thrombosis, and cerebral infarction; MACE ②: composite of MACE ① and target vessel revascularization) at 6, 12, 24 and 36 months after cardiac catheterization. MACE ① occurred in 18 cases and MACE ② in 32 cases. The PRU cut-off values at 6, 12, 24, and 36 months were 257, 238, 217, and 216, respectively, for MACE ① and 250, 238, 209, and 204, respectively, for MACE ②. The AUCs at 6, 12, 24, and 36 months were 0.753, 0.832, 0.718, and 0.717, respectively, for MACE ① and 0.724, 0.722, 0.664, and 0.682, respectively, for MACE ②. The optimal cut-off and predictive ability of PRU values for cardiovascular events varied depending on different endpoints and duration of the observation periods. A relatively high PRU value is effective for short-term event suppression, but a low value is required for long-term event suppression.

Effects of angiotensin receptor-neprilysin inhibitor on insulin resistance in patients with heart failure.

AIMS: Although the haemodynamic effects of angiotensin receptor-neprilysin inhibitor (ARNI) on patients with heart failure have been demonstrated, the effect on glucose metabolism has not been fully elucidated. We retrospectively investigated the effect of ARNI on abnormal glucose metabolism in patients with stable chronic heart failure using an additional structural equation model (SEM) analysis. METHODS: We analysed 34 patients who regularly visited to the outpatient department of our institute with heart failure from October 2021 and July 2022 and who were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Seventeen patients switched from ACE inhibitors or ARBs to an ARNI (ARNI group), and the other 17 patients continued treatment with ACE inhibitors or ARBs (control group). RESULTS: At baseline, although the ARNI group included fewer patients with heart failure with preserved ejection fraction in comparison with the control group (P = 0.004), patients with heart failure with mildly reduced ejection fraction, and heart failure with reduced ejection fraction were mostly biased towards the ARNI group (although not statistically significant). The baseline insulin resistance in the ARNI group was already significantly higher in comparison with the control group [fasting blood insulin, 9.7 (7.4, 11.6) vs. 7.8 (5.2, 9.2) µU/mL, P = 0.033; homoeostasis model assessment of insulin resistance (HOMA-IR), 3.10 (1.95, 4.19) vs. 2.02 (1.56, 2.42), P = 0.014]. Three months later, the fasting blood insulin and the HOMA-IR levels were both found to have decreased in comparison with the baseline values [baseline to 3 months: insulin, 9.7 (7.4, 11.6) to 7.3 (4.6, 9.4) µU/mL, P < 0.001; HOMA-IR, 3.10 (1.95, 4.19) to 1.96 (1.23, 3.09), P < 0.001]. An additional SEM analysis demonstrated that the initiation of ARNI had caused a reduction in the fasting blood insulin and the HOMA-IR levels at 3 months independently of the baseline fasting blood insulin and HOMA-IR levels, respectively. Similarly, the initiation of ARNI resulted in a significant reduction in serum uric acid levels (6.28 ± 0.35 to 5.80 ± 0.30 mg/dL, P = 0.008). CONCLUSIONS: In conclusion, even in a short period of only 3 months, the administration of ARNI improved insulin resistance and consequently reduced the serum uric acid levels in patients with stable chronic heart failure. Although the ARNI group already had high insulin resistance at baseline, an additional SEM analysis revealed that the decreased insulin resistance was truly due to the effect of ARNI.

Investigation of the small-balloon technique as a method for retrieving dislodged stents.

The small-balloon technique used to retrieve a dislodged coronary stent is less studied. We investigated the small-balloon technique to study the capture force and retrieval rate of dislodged proximal or distal stents. We developed a retrieval model for stent dislodgement and performed bench tests to compare proximal and distal capture. We evaluated capture force by capture site in a fixed stent dislodgement model and capture force and retrieval rate by capture site using a retrieval model of stent dislodgement. Three-dimensional (3D)-micro-computed tomography (CT) was used to scan the captured conditions of the distal (DC) and proximal (PC) groups. Stent, balloon shaft, and guiding catheter (GC) diameters were measured. Retrieval areas within GC were calculated and compared. The force was significantly lower in the PC group than in the DC group (p < 0.01). Successful retrieval was achieved in 100% and 84.8% in the PC and DC groups, respectively. The force required to retrieve the dislodged stent was significantly lower in the PC group than that in the DC group (p < 0.01). The force was significantly lower in the successful cases in the DC group than in the unsuccessful cases (p < 0.01). The retrievable areas in the PC and DC groups were 67.5% and 32.7%, respectively, as calculated from the values measured from the 3D-CT images. The success rate of PC was higher than that of DC using the small-balloon technique. The smaller proximal stent gap in the PC method facilitated the retrieval of the dislodgement stent.

Right-to-left shunt via iatrogenic atrial septal defect requiring emergency surgical repair following cryoballoon atrial fibrillation ablation in a patient with arrhythmogenic right ventricular cardiomyopathy.

An 81-year-old woman with arrhythmogenic right ventricular cardiomyopathy underwent catheter ablation for atrial fibrillation and atrial flutter. Hypoxemia refractory to the administration of oxygen was seen after transseptal puncture. Transthoracic echocardiography revealed right to left shunt via an iatrogenic atrial septal defect (IASD) that was increased by tricuspid regurgitation flow. Her hypoxemia improved after IASD occlusion with the inflation of a venogram balloon catheter. Emergent surgical IASD closure was successfully performed. IASD after transseptal puncture for atrial fibrillation ablation infrequently causes severe complications that require emergent repair. Learning objective: Some cases requiring iatrogenic atrial septal defect (IASD) closure after atrial fibrillation (AF) ablation have been reported. We describe the case of an arrhythmogenic right ventricular cardiomyopathy patient with right to left shunt via an IASD which required emergent surgical repair after AF ablation. Right to left shunt after trans-septal puncture is rare, however it can be an emergent life-threatening complication. IASD occlusion with venogram balloon catheter is helpful for the diagnosis and the short-term solution.

Relationship between haemodynamic indicators and haemogram in patients with heart failure.

AIMS: Pulmonary congestion, reduced cardiac output, neurohumoral factor activation, and decreased renal function associated with decreased cardiac function may have various effects on haemograms. The relationship between these factors and haemograms in patients with heart failure has not been sufficiently investigated. Recently, it was suggested that the lungs are an important site for platelet (Plt) biosynthesis and that it is necessary to study the relationship between pulmonary congestion and Plt count in heart failure in detail. In this study, we examined the relationship between various haemodynamic indicators and haemograms in detail using statistical analyses. METHODS AND RESULTS: A total of 345 patients who underwent cardiac catheterization for the evaluation of cardiac function between 1 January 2015 and 31 December 2020 were included in the study. Haemodynamic indices, including left ventricular end-diastolic pressure (LVEDP) and cardiac index (CI), were measured. Plasma noradrenaline (Nor) concentration, estimated glomerular filtration rate (eGFR), white blood cell (WBC) count, haemoglobin (Hb) level, and Plt count were measured using blood samples collected at the same time. Structural equation modelling (SEM) was used to examine the relationship between LVEDP, CI, plasma Nor concentration, eGFR, WBC count, Hb level, and Plt count. Bayesian inference using SEM was performed for Plt count. A total of 345 patients (mean age: 66.0 ± 13.2 years) were included in this study, and 251 (73%) patients were men. After simple and multiple regression analyses, path diagrams were drawn and analysed using SEM. LVEDP showed a significant negative relationship with Plt count (standardized estimate: -0.129, P = 0.015), and CI showed a significant negative relationship with Hb level (standardized estimate: -0.263, P < 0.001). Plasma Nor concentration showed a significant positive relationship with WBC count (standardized estimate: 0.165, P = 0.003) and Plt count (standardized estimate: 0.198, P < 0.001). The eGFR had a significant positive relationship with Hb level (standardized estimate: 0.274, P < 0.001). Bayesian inference using SEM revealed no relationship between LVEDP and Hb level or WBC count but a significant negative relationship between LVEDP and Plt count. CONCLUSIONS: LVEDP, CI, plasma Nor concentration, and eGFR were related to WBC count, Hb level, and Plt count in patients with heart failure. There was a strong relationship between elevated LVEDP and decreased Plt count, suggesting that pressure overload on the lungs may interfere with the function of the lung as a site of Plt biosynthesis.

Exogenous ANP Treatment Ameliorates Myocardial Insulin Resistance and Protects against Ischemia-Reperfusion Injury in Diet-Induced Obesity.

Increasing evidence suggests natriuretic peptides (NPs) coordinate interorgan metabolic crosstalk. We recently reported exogenous ANP treatment ameliorated systemic insulin resistance by inducing adipose tissue browning and attenuating hepatic steatosis in diet-induced obesity (DIO). We herein investigated whether ANP treatment also ameliorates myocardial insulin resistance, leading to cardioprotection during ischemia-reperfusion injury (IRI) in DIO. Mice fed a high-fat diet (HFD) or normal-fat diet for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. Left ventricular BNP expression was substantially reduced in HFD hearts. Intraperitoneal-insulin-administration-induced Akt phosphorylation was impaired in HFD hearts, which was restored by ANP treatment, suggesting that ANP treatment ameliorated myocardial insulin resistance. After ischemia-reperfusion using the Langendorff model, HFD impaired cardiac functional recovery with a corresponding increased infarct size. However, ANP treatment improved functional recovery and reduced injury while restoring impaired IRI-induced Akt phosphorylation in HFD hearts. Myocardial ultrastructural analyses showed increased peri-mitochondrial lipid droplets with concomitantly decreased ATGL and HSL phosphorylation levels in ANP-treated HFD, suggesting that ANP protects mitochondria from lipid overload by trapping lipids. Accordingly, ANP treatment attenuated mitochondria cristae disruption after IRI in HFD hearts. In summary, exogenous ANP treatment ameliorates myocardial insulin resistance and protects against IRI associated with mitochondrial ultrastructure modifications in DIO. Replenishing biologically active NPs substantially affects HFD hearts in which endogenous NP production is impaired.

Substantial impact of 3-iodothyronamine (T1AM) on the regulations of fluorescent thermoprobe-measured cellular temperature and natriuretic peptide expression in cardiomyocytes.

There is growing interest in 3-iodothyronamine (T1AM), an active thyroid hormone metabolite, that induces negative inotropic and chronotropic actions in the heart and exerts systemic hypothermic action. We explored the direct impact of T1AM on cardiomyocytes with a focus on the regulation of the intracellular temperature and natriuretic peptide (NP) expression. A thermoprobe was successfully introduced into neonatal rat cardiomyocytes, and the temperature-dependent changes in the fluorescence intensity ratio were measured using a fluorescence microscope. After one-hour incubation with T1AM, the degree of change in the fluorescence intensity ratio was significantly lower in T1AM-treated cardiomyocytes than in equivalent solvent-treated controls (P < 0.01), indicating the direct hypothermic action of T1AM on cardiomyocytes. Furthermore, T1AM treatment upregulated B-type NP (BNP) gene expression comparable to treatment with endothelin-1 or phenylephrine. Of note, ERK phosphorylation was markedly increased after T1AM treatment, and inhibition of ERK phosphorylation by an MEK inhibitor completely cancelled both T1AM-induced decrease in thermoprobe-measured temperature and the increase in BNP expression. In summary, T1AM decreases fluorescent thermoprobe-measured temperatures (estimated intracellular temperatures) and increases BNP expression in cardiomyocytes by activating the MEK/ERK pathway. The present findings provide new insight into the direct myocardial cellular actions of T1AM in patients with severe heart failure.

Pulmonary Vein Angioplasty for Pulmonary Vein Stenosis After Ablation Therapy for Atrial Fibrillation　- A Report of 7 Cases.

BACKGROUND: Pulmonary vein (PV) stenosis after atrial fibrillation (AF) ablation is rare; however, it remains a serious complication. PV angioplasty is reportedly an effective therapy; however, a dedicated device for PV angioplasty has not been developed, and the detailed procedural methods remain undetermined. This study describes the symptoms, indications, treatment strategies, and long-term outcomes for PV stenosis after AF ablation.Methods and Results: This study retrospectively analyzed 7 patients with PV stenosis after catheter ablation for AF and who had undergone PV angioplasty at our hospital during 2015-2021. PV stenosis occurred in the left superior (5 patients) and left inferior (2 patients) PV. Six patients had hemoptysis, chest pain, and dyspnea. Seven de novo lesions were treated using balloon angioplasty (BA) (3 patients), a bare metal stent (BMS) (3 patients), and a drug-coated balloon (DCB) (1 patient). The restenosis rate was 42.9% (n=3; 2 patients in the BA group and 1 patient in the DCB group). The repeat treatment rate was 28.6% (2 patients in the BA group). Stenting was performed as repeat treatment. One patient with subsequent repeat restenosis development underwent BA. Ten PV angioplasties were performed; there were no major complications. CONCLUSIONS: Regarding PV angioplasty after ablation therapy for AF, stenting showed superior long-term PV patency than BA alone; therefore, it should be considered as a standard first-line approach.

Heart Failure Treatments Such As Angiotensin Receptor/Neprilysin Inhibitor Improve Heart Failure Status and Glucose Metabolism.

A recent study suggested that angiotensin receptor/neprilysin inhibitor (ARNI; sacubitril/valsartan) can improve functional capacity and cardiac reverse remodeling in patients with heart failure with reduced ejection fraction (HFrEF). Another study suggested that ARNI reduced glycated hemoglobin (HbA1c) in patients with diabetes and HFrEF; however, the details of its efficacy are unknown. We herein report a case of HFrEF with abnormal glucose metabolism in which ARNI was initiated. On the 7th day of admission (before the initiation of ARNI), blood tests showed an abnormal glucose metabolism as follows: fasting blood glucose 134 mg/dL; and fasting blood insulin 11.4 µU/mL (homeostasis model assessment of insulin resistance (HOMA-IR) index 3.77; homeostasis model assessment of ß-cell function (HOMA-ß), 57.8%). On the 23rd day after the initiation of ARNI, even though the patient was not using hypoglycemic drugs, his fasting blood glucose markedly decreased to 70 mg/dL without hypoglycemic symptoms, and his fasting blood insulin decreased to 5.4 µU/mL (HOMA-IR decreased to 0.93, HOMA-ß increased to 277.7%). These results imply that ARNI has the potential to improve insulin resistance and the islet beta-cell function in patients with heart failure, in addition to the original effect of improving the hemodynamics, although the effect of improving the glucose metabolism is also considered to have been influenced by the improvement of the heart failure status and other drugs that the patient was taking.

URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice.

OBJECTIVE: Accumulating evidence indicates that high uric acid (UA) is strongly associated with obesity and metabolic syndrome and drives the development of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidneys, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. We herein investigated the role and functional significance of URAT1 in diet-induced obese mice. METHODS: Mice fed a high-fat diet (HFD) for 16-18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks. RESULTS: We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than the kidneys. Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (chemokine ligand 2 (Ccl2) and tissue necrosis factor α (TNFα)), all of which were attenuated by dotinurad. Similarly, HFD significantly increased URAT1 expression in BAT, resulting in lipid accumulation (whitening of BAT), and increased the production of tissue reactive oxygen species (ROS), which were reduced by dotinurad via UCP1 activation. CONCLUSIONS: In conclusion, a novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD.

Constrictive Pericarditis with Cardiac Ascites Caused Spontaneous Bacterial Peritonitis.

Patients with constrictive pericarditis (CP) typically present with symptoms related to right-sided heart failure, such as cardiac ascites. Spontaneous bacterial peritonitis (SBP) usually arises in association with ascites secondary to hepatic cirrhosis. We herein report a rare case of CP in which SBP developed due to cardiac ascites, even in the absence of cirrhosis. In this case, pericardiectomy improved both the hemodynamics and the ascites, while therapy with diuretics alone was insufficient. It is important to consider SBP in the differential diagnosis when any abdominal symptoms or an inflammatory response is found in patients with heart failure and cardiac ascites.

Unique crosstalk between platelet and leukocyte counts during treatment for acute coronary syndrome: A retrospective observational study.

In the pathophysiology of acute coronary syndrome (ACS), platelet (PLT) and neutrophil (Neu) crosstalk may be important for activating coagulation and inflammation. It has been speculated that PLTs and Neu may affect each other's cell counts; however, few studies have investigated this hypothesis. In this study, we measured changes in blood cell counts in 245 patients with ACS during treatment and investigated the mutual effects of each blood cell type. Path diagrams were drawn using structural equation modeling, and temporal changes in the count of each blood cell type and the relevance of these changes were analyzed. Throughout the treatment period, the numbers of all blood cell types (red blood cells [RBCs], leukocytes, and PLTs) were associated with each other before and after treatment. A detailed examination of the different cell types revealed that the PLT count at admission had a significant positive effect on the leukocyte (especially Neu) count after treatment. Conversely, the leukocyte (especially Neu) count at admission had a significant positive effect on the PLT count after treatment. During ACS, PLTs and leukocytes, especially Neu, stimulate each other to increase their numbers. The formation of a PLT-leukocyte complex may increase coagulation activity and inflammation, which can lead to a further increase in the counts of both blood cell types.

Lung ventilation/perfusion scintigraphy shows the efficacy of anticoagulant therapy and surgical treatment for papillary fibroelastoma originating from the tricuspid valve.

Papillary fibroelastoma (PFE) is a cardiac tumor that is mainly found on the heart valve and the endocardium of the atria and ventricles. Symptoms such as stroke and myocardial infarction are usually caused by embolization of either the tumor itself or associated thrombus. PFE is known to originate mainly from the left side of the heart, and these cases are-in principle-candidates for surgical resection. On the other hand, cases in which PFE originates from the right side of the heart are rare and reports are limited; thus, the surgical indication is unclear. We herein report a case of symptomatic PFE originating from the tricuspid valve of the heart. In this case, contrast enhanced computed tomography did not show pulmonary embolism; however, lung perfusion scintigraphy showed multiple perfusion defects. The patient was treated by anticoagulant therapy followed by surgical resection. Thereafter, the symptoms disappeared and the multiple perfusion defects improved on lung perfusion scintigraphy, demonstrating the efficacy of the anticoagulant therapy and surgical resection for PFE in the right side of the heart. .

Low triiodothyronine levels correlate with high B-type natriuretic peptide levels in patients with heart failure.

Thyroid hormone metabolism can be closely associated with cardiovascular disorders. We examined the relationship between low triiodothyronine (T3) levels and heart failure status, including B-type natriuretic peptide (BNP) levels, in 625 patients with cardiovascular disorders who underwent cardiac catheterization. A multiple regression analysis revealed that the left ventricular ejection fraction (LVEF), hemoglobin (Hb) levels, sex (male), free T3 (FT3) levels, and estimated glomerular filtration rate (eGFR) were significantly negatively associated with the log BNP value, while age was significantly positively associated with the log BNP value (P < 0.001 each). Furthermore, the log BNP and age were significantly negatively associated with the FT3 levels, while the Hb and body mass index (BMI) were significantly positively associated with the FT3 levels (P < 0.001 each). Theoretically constructed structure equation modeling (SEM) revealed an inverse association between FT3 and BNP (ß = -0.125, P = 0.002), and the same relationship remained in the patient group with normal-range BNP values (ß = -0.198, P = 0.008). We demonstrated a significant relationship between high BNP and low serum FT3 levels, and this relationship remained significant in patients with normal BNP levels. These results indicate that low T3 is associated with high plasma BNP levels rather than worsening of hemodynamics.

Treatment with atrial natriuretic peptide induces adipose tissue browning and exerts thermogenic actions in vivo.

Increasing evidence suggests natriuretic peptides (NPs) coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. We recently reported A-type NP (ANP) raises intracellular temperature in cultured adipocytes in a low-temperature-sensitive manner. We herein investigated whether exogenous ANP-treatment exerts a significant impact on adipose tissues in vivo. Mice fed a high-fat-diet (HFD) or normal-fat-diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. ANP-treatment significantly ameliorated HFD-induced insulin resistance. HFD increased brown adipose tissue (BAT) cell size with the accumulation of lipid droplets (whitening), which was suppressed by ANP-treatment (re-browning). Furthermore, HFD induced enlarged lipid droplets in inguinal white adipose tissue (iWAT), crown-like structures in epididymal WAT, and hepatic steatosis, all of which were substantially attenuated by ANP-treatment. Likewise, ANP-treatment markedly increased UCP1 expression, a specific marker of BAT, in iWAT (browning). ANP also further increased UCP1 expression in BAT with NFD. Accordingly, cold tolerance test demonstrated ANP-treated mice were tolerant to cold exposure. In summary, exogenous ANP administration ameliorates HFD-induced insulin resistance by attenuating hepatic steatosis and by inducing adipose tissue browning (activation of the adipose tissue thermogenic program), leading to in vivo thermogenesis during cold exposure.

A Pilot Evaluation Study of Diffuse Coronary Arterial Contraction Causing Ischemia by Double Measurement of Left Ventriculography Before and After Intracoronary Administration of Nitrates.

Background: Abnormal diffuse coronary artery contraction is not easily diagnosed. In order to evaluate its true risk, we performed double left ventriculography (LVG) before and after intracoronary administration of isosorbide dinitrate (ISDN). We also investigated the relationship between changes in coronary lumen area and changes in left ventricular ejection fraction (LVEF) after ISDN. Methods and Results: The study included 53 patients who underwent an acetylcholine (ACh) provocation test after coronary angiogram and LVG. The second LVG was performed after intracoronary ISDN administration. Coronary lumen area was measured by quantitative coronary arteriography (QCA). Simple and multiple regression analyses showed a significant correlation between changes in total QCA area before and after ISDN administration (pre-and post-total QCA area, respectively) and changes in LVEF. Using structural equation modeling, we observed a negative effect of pre-total QCA area and a positive effect of post-total QCA area on LVEF improvement. Importantly, LVEF improvement was similar between the ACh-positive and -negative groups on the coronary artery spasm test. Receiver operating characteristic curves indicated that the cut-off value at which changes in total QCA area affected changes in LVEF was 5%. Conclusions: Performing double LVG tests before and after ISDN administration may detect myocardial ischemia caused by diffuse coronary artery contraction. The addition of this method to the conventional ACh provocation test may detect the presence of local and/or global myocardial ischemia.