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.

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.

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.

Possible Association Between Body Temperature and B-Type Natriuretic Peptide in Patients With Cardiovascular Diseases.

BACKGROUND: In addition to various biological effects of natriuretic peptides (NP) on cardiovascular systems, we recently reported that NP raises intracellular temperature in cultured adipocytes. We herein examined the possible thermogenic action of NP in consideration of hemodynamic parameters and inflammatory reaction by proposing structural equation models. METHODS AND RESULTS: The study population consisted of 1985 consecutive patients who underwent cardiac catheterization. Covariance structure analyses were performed to clarify the direct contribution of plasma B-type NP (BNP) to body temperature (BT) by excluding other confounding factors. A hierarchical path model showed increase in BNP, increase in C-reactive protein and decrease in left ventricular ejection fraction were mutually associated. As expected, C-reactive protein was positively correlated with BT. Importantly, despite a negative correlation between BNP and left ventricular ejection fraction, a decrease in the left ventricular ejection fraction was associated with BT decrease, whereas elevation in BNP level was associated with BT increase independently of C-reactive protein level (P = .007). CONCLUSIONS: Patients with LV dysfunction tend to manifest a decrease in BT, whereas BNP elevation is associated with an increase in BT independently of inflammatory response. These findings suggest the adaptive heat-retaining property of NP (and/or NP-associated factors) when BT falls owing to unfavorable hemodynamic conditions in a state of impaired cardiac function.

Diagnosis of cardiac sarcoidosis despite negative findings on serial late gadolinium enhancement with cardiac magnetic resonance imaging/18F-fluorodeoxyglucose positron emission tomography examinations.

We present a case of a 42-year-old Japanese man with ocular and pulmonary sarcoidosis who eventually led to a diagnosis with cardiac sarcoidosis (CS) through endomyocardial biopsy (EMB), despite negative findings on both late gadolinium enhancement with cardiac magnetic resonance (LGE-CMR) imaging and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Cardiac sarcoidosis (CS) develops in only 5% of patients with systemic sarcoidosis. Previous studies have reported that CS was found in up to 50% of autopsy series with fatal sarcoidosis, implying that CS is frequently underdiagnosed with potentially life-threatening consequences. Therefore, the diagnostic accuracy and prognostic value of CS are important. Currently, LGE-CMR and FDG-PET play an important role in establishing a diagnosis of CS with high sensitivity. In the presented case, regardless of serial examinations with LGE-CMR and FDG-PET, confirmed diagnosis of CS could not be achieved; ultimately, a definitive diagnosis of CS was obtained through EMB. To the best of our knowledge, this is the first reported case showing the diagnosis of CS despite negative findings on serial LGE-CMR and FDG-PET examinations.

Cardiac ischemia-reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity.

BACKGROUND: Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium-glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. METHODS AND RESULTS: The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. CONCLUSIONS: Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.

Predictors of oxygenation impairment in medical treatment for type B acute aortic dissection.

Lung oxygenation impairment often occurs in patients with type B acute aortic dissection (AAD), necessitating mechanical ventilation. Patients receiving mechanical ventilation are at risk of complications, so a low-oxygen condition requiring mechanical ventilation should be avoided. We explored the predictors of oxygenation impairment. We enrolled 46 patients with type B AAD who had been medically treated and underwent computed tomography. Blood was sampled to measure markers of inflammation, such as the C-reactive protein (CRP) levels and white blood cell count. The arterial partial pressure of oxygen/fraction of inspired oxygen ratio (PaO2/FiO2) was calculated to quantify the severity of respiratory failure. Spearman's rank correlation analysis revealed that the minimum PaO2/FiO2 ratio was significantly correlated with gender, age, and current smoker, and the peak CRP, body temperature, and D-dimer values. A multivariate regression analysis revealed that younger age, male sex, and the peak CRP level were significant predictors of the minimum PaO2/FiO2 ratio (P = 0.01, 0.035 and 0.005, respectively). A covariance structure analysis showed that a younger age and the peak CRP level were significant predictors of oxygenation impairment in type B AAD. Oxygenation impairment in type B AAD is correlated with younger age and a higher peak CRP level. This will enable the identification of patients whose respiratory condition is susceptible to worsening and help prevent mechanical ventilation, leading to the provision of appropriate therapy.

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.

Transient decrease in serum potassium level during ischemic attack of acute coronary syndrome: paradoxical contribution of plasma glucose level and glycohemoglobin.

BACKGROUND: Although a decrease in serum potassium level has been suggested to be a fairly common observation in acute coronary syndrome (ACS), there have so far been no definitive reports directly demonstrating the transient potassium decrease (the potassium dip) during ischemic attack of ACS compared to stable phase in individual patients. To understand the pathophysiological significance of the potassium dip, we examined the changes in serum potassium level throughout ischemic attack and evaluated the clinical factors affecting it. METHODS: The degree of the potassium dip during ischemic attack (as indicated by ΔK, ΔK = K at discharge - K on admission) was examined in 311 consecutive patients with ACS who required urgent hospitalization in our institution. RESULTS: Serum potassium level during ischemic attack was significantly decreased compared to that during stable phase (P < 0.001). Multiple regression analysis revealed that plasma glucose level during attack was the sole factor which was positively correlated with ΔK (P < 0.01), while HbA1c level was negatively correlated (P < 0.05). The medication profiles and renal function had no impact on ΔK. A longer hospitalization period, higher incidence of myocardial infarction and higher peak creatine kinase level were observed in patients with a larger ΔK. CONCLUSIONS: We have clearly demonstrated that there is a transient decrease in serum potassium level during ischemic attack of ACS compared to stable phase. The degree of the potassium dip was tightly correlated with glucose level, which overwhelmed the diabetic condition, and it also indicates the disease severity. The present study therefore promotes awareness of the significance of monitoring potassium level in parallel with glucose level in patients with ACS.

Cardiac tamponade as an independent condition affecting the relationship between the plasma B-type natriuretic peptide levels and cardiac function.

Plasma B-type natriuretic peptide (BNP) is finely regulated by the cardiac function and several extracardiac factors. Therefore, the relationship between the plasma BNP levels and the severity of heart failure sometimes seems inconsistent. The purpose of the present study was to investigate the plasma BNP levels in patients with cardiac tamponade and their changes after pericardial drainage. This study included 14 patients with cardiac tamponade who underwent pericardiocentesis. The cardiac tamponade was due to malignant diseases in 13 patients and uremia in 1 patient. The plasma BNP levels were measured before and 24-48 h after drainage. Although the patients reported severe symptoms of heart failure, their plasma BNP levels were only 71.2 ± 11.1 pg/ml before drainage. After appropriate drainage, the plasma BNP levels increased to 186.0 ± 22.5 pg/ml, which was significantly higher than that before drainage (P = 0.0002). In patients with cardiac tamponade, the plasma BNP levels were low, probably because of impaired ventricular stretching, and the levels significantly increased in response to the primary condition after drainage. This study demonstrates an additional condition that affects the relationship between the plasma BNP levels and cardiac function. If inconsistency is seen in the relationship between the plasma BNP levels and clinical signs of heart failure, the presence of cardiac tamponade should therefore be considered.

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.

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.

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.

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.

The role of Na+/H+ exchanger in Ca2+ overload and ischemic myocardial damage in hearts from type 2 diabetic db/db mice.

BACKGROUND: A higher increase in intracellular Na(+) via Na(+)/H(+) exchanger (NHE) during ischemia has been reported in type 2 diabetic mouse hearts. We investigated the role of NHE in inducing changes in cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) and alterations in ventricular function during ischemia-reperfusion in type 2 diabetic mouse hearts. METHODS: Hearts from male type 2 diabetic db/db (12-15 weeks old) and age-matched control db/+ mice were subjected to Langendorff perfusion and loaded with 4 µM of the Ca(2+) indicator fura-2. The hearts were exposed to no-flow ischemia for 15 minutes and then reperfused. [Ca(2+)](i) was measured by monitoring fura-2 fluorescence at 500 nm (excitation wavelengths of 340 and 380 nm), while left ventricular (LV) pressure was simultaneously measured. RESULTS: db/db hearts exhibited a lower recovery of LV developed pressure than db/+ hearts during reperfusion following ischemia. Diastolic [Ca(2+)](i) was increased to a greater level in diabetic hearts than in the control hearts during ischemia and reperfusion. Such an increase in cytoplasmic Ca(2+) overload during ischemia-reperfusion in diabetic hearts was markedly reduced in the presence of the NHE inhibitor cariporide. This was accompanied by a significantly improved recovery of ventricular function on reperfusion, as shown by a lower increase in diastolic pressure and increased recovery of developed pressure. CONCLUSION: NHE plays a key role in enhancing cytoplasmic Ca(2+) overload during ischemia-reperfusion and severely impairing post-ischemic cardiac function in hearts from type 2 diabetic db/db mice.