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.

Low blood pressure and guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.

BACKGROUND: Patients with heart failure (HF) presenting with low blood pressure (BP) have been underrepresented in large-scale clinical trials. We investigated the characteristics and implementation of conventional guideline-directed medical therapy (GDMT; renin-angiotensin system inhibitors and ß-blockers) in patients with low BP hospitalized for HF with systolic dysfunction. METHODS: Conventional GDMT was evaluated by discharge BP among 2043 consecutive patients with HF and left ventricular ejection fraction (LVEF) < 50% in the WET-HF registry. Among the 708 (34.7%) patients with lower discharge BP (≤ 100 mmHg; the lower tertiles), exploratory subgroups included patients with previous HF hospitalization, inotrope use, New York Heart Association (NYHA) III-IV class, and lower estimated glomerular filtration rate (eGFR) and LVEF (lower than median value). We evaluated the risk-adjusted association between GDMT implementation and 2-year adverse events (all-cause mortality or HF rehospitalization). RESULTS: Among the 2043 patients (age 74 [63-82] years), the median systolic BP was 108 (98-120) mmHg. Among patients with lower BP, GDMT prescription rate was 62.7%, and GDMT use was associated with decreased adverse events (HR:0.74, 95%CI:0.58-0.94). GDMT prescription rates were lower among higher-NYHA class and lower-eGFR subgroups compared with their reference subgroups, and directionally similar outcomes were noted in all subgroups (favoring GDMT use); however, this association was somewhat attenuated in the lower-eGFR group (HR:0.87, 95%CI:0.64-1.17). CONCLUSIONS: Conventional GDMT use was associated with decreased adverse outcomes in most patients with HF compounded by systolic dysfunction and low BP, albeit caution is warranted in patients with renal dysfunction.

Malnutrition in real-world patients hospitalized for heart failure with preserved ejection fraction and its potential impact on generalizability of EMPEROR-Preserved trial.

BACKGROUND: Despite the benefits of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin, its suitability for patients with heart failure (HF) in the real-world setting remains unclear. Considering the unique pharmacological profile of SGLT2i (e.g., glucose excretion leading to calorie loss) and increasingly aging patients with HF, applicability of trials' finding in patients with malnutrition is important. METHODS: We examined 1633 consecutive patients with a preserved left ventricular ejection fraction (LVEF; >40%) enrolled in a multicenter-based acute HF registry. After applying the EMPEROR-Preserved eligibility criteria, we compared the baseline characteristics of trial-eligible and actual trial participants, and patients with and without malnutrition among the trial-eligible group. Malnutrition was assessed by the geriatric nutritional risk index (GNRI). The trial-eligible patients were divided into high (GNRI≥92) and low (GNRI<92) nutritional groups, and a composite endpoint comprising all-cause death and HF rehospitalization was evaluated. RESULTS: Majority (70.2%) of the analyzed patients were eligible for the EMPEROR-Preserved trial (age: 77 ± 12 years and body mass index [BMI]: 22.0 ± 4.1 kg/m2), but were older and had lower BMIs than the actual trial participants. Notably, 51.9% of the eligible patients were at high risk for malnutrition and had a higher rate of the composite endpoint than non-malnourished counterparts (HR 1.27, 95%CI 1.04-1.56, P = 0.020). The difference in outcomes was predominantly due to mortality from non-cardiac causes. CONCLUSIONS: Mostly patients with HF in a real-world setting met the EMPEROR-Preserved criteria; however, approximately half were at high risk for malnutrition with poorer outcomes owing to non-cardiac-related causes.

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.

Conventional medical therapy in heart failure patients eligible for the PARADIGM-HF, DAPA-HF, and SHIFT trials.

BACKGROUND: Recent trials on novel heart failure (HF) treatments (angiotensin receptor-neprilysin inhibitor, sodium-glucose cotransporter 2 inhibitor, and ivabradine) emphasize the use of conventional medical therapy (angiotensin-converting enzyme inhibitors, beta-blockers [BB], and mineral corticosteroid receptor antagonists). We aimed to evaluate the prescription rate of conventional medical therapy and its association with long-term outcomes in patients eligible for recent trials. METHODS: We examined 1295 consecutive patients with HF with reduced ejection fraction (HFrEF) from a multicenter registry (WET-HF registry). We assessed conventional medical therapy implementation among patients meeting the PARADIGM-HF/DAPA-HF and SHIFT enrollment criteria. We also examined the association between conventional medical therapy use and long-term outcomes within each enrollment criterion. RESULTS: Overall, 62.2% and 35.3% of HFrEF patients met the enrollment criteria of the PARADIGM-HF/DAPA-HF and SHIFT trials. Only 33.9% and 31.9% received full conventional medical therapy within each patient subset. Notably, 84.2% of patients who met the SHIFT enrollment criteria were on BB, and only 23.0% and 4.4% were on ≥50% or the full recommended dose, respectively. Implementation of full conventional medical therapy use was associated with lower 2-year mortality and HF readmission rates in the PARADIGM-HF/ DAPA-HF eligible group (HR 0.68, 95% CI 0.50-0.92). The use of BB at ≥50% of the recommended dose was associated with lower 2-year mortality and HF readmission rates in the SHIFT-eligible group (HR 0.50, 95% CI 0.30-0.84). CONCLUSIONS: Conventional medical therapy was underutilized among patients eligible for novel trials within a Japanese HF registry. Further efforts to optimize conventional medical therapy are needed.

A case of cardiac strangulation following epicardial pacemaker implantation in an adult: a case report.

Background: Cardiac strangulation (CS) is a rare but potentially devastating complication caused by the leads of an epicardial pacemaker (EP). Most cases have been reported in paediatric patients, and there has been no report wherein the diagnosis was made in a living, adult patient, and treated successfully. Case summary: A 31-year-old woman with a history of atrial septal defect (ASD) patch closure and EP implantation for congenital atrial stand-still presented with dyspnoea on exertion. The blood investigation of the patient showed liver dysfunction, chest radiography showed pulmonary artery dilatation, and transthoracic echocardiography showed right chambers dysfunction. Right heart catheterization showed haemodynamics similar to those of constrictive pericarditis, eventually leading to the diagnosis of CS due to EP leads. The patient was successfully operated upon. Discussion: We reported the first case where CS was diagnosed in adulthood and successfully treated with surgical intervention. Cardiac strangulation is challenging to diagnose because of the small number of cases reported and the lack of definitive diagnostic algorithms or criteria. Surgical EP lead removal should be performed without hesitation in cases where CS is considered the primary aetiology of critical symptoms or complications because surgical removal is the only fundamental treatment for CS. In addition, paediatric patients undergoing EP implantation need for close follow-up.

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.

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.

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.

Successful treatment of pulmonary hypertension following hematopoietic stem cell transplant with a single oral tadalafil: a case report.

A 46-year-old man who had undergone hematopoietic stem cell transplant twice because of acute lymphoblastic leukemia with recurrence presented with dyspnea, leading to a diagnosis of pulmonary arterial hypertension which was quickly and effectively treated with the phosphodiesterase type 5 inhibitor tadalafil. To our knowledge, pulmonary arterial hypertension related to hematologic malignancies requiring hematopoietic stem cell transplant is rarely reported. Importantly, the present case suggests that early diagnosis and treatment with a pulmonary vasodilator, such as tadalafil, can greatly decrease pulmonary vascular resistance in patients with severe pulmonary arterial hypertension after hematopoietic stem cell transplant and can then improve other symptoms. Accordingly, pulmonary vascular disease should be considered if respiratory symptoms develop following hematopoietic stem cell transplant, because treatment with pulmonary vasodilator may lead to significant improvement in pulmonary arterial hypertension.

A pilot cohort study assessing the feasibility of complete revascularization with balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

Balloon pulmonary angioplasty improves prognosis by alleviating pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension, even with incomplete revascularization. However, hypoxia or the requirement for pulmonary vasodilators often remain even after pulmonary hypertension relief. With this cohort study, we aimed to examine whether complete revascularization by additional balloon pulmonary angioplasty on residual lesions, even after pulmonary hypertension relief, could resolve hypoxia or the requirement for pulmonary vasodilators. During complete revascularization with balloon pulmonary angioplasty in 42 patients with chronic thromboembolic pulmonary hypertension, we investigated therapeutic effects at baseline (T1), pulmonary hypertension relief phase (T2), and at 6 months post-final balloon pulmonary angioplasty (T3). The pulmonary hypertension relief phase was defined as the first time that a mean pulmonary artery pressure ≤ 25 mmHg or pulmonary vascular resistance ≤ 240 dyn-s/cm5 was reached in right heart catheterization before balloon pulmonary angioplasty. The partial pressure of oxygen increased progressively over T1, T2, and T3 (59.2±8.5, 69.0±9.7, and 80.0±9.5 mmHg, respectively; P<0.001 T2 vs. T3). Minimum oxygen saturation levels during the 6-minute walk distance test were 87% (81‒89%), 88% (84‒92%), and 91% (89‒93.3%), respectively (P<0.001 T2 vs. T3), with gradual increase in the 6-minute walk distance (346±125 m, 404±90 m, 454±101 m, respectively; P<0.001 T2 vs. T3). The percentages of patients using pulmonary vasodilators (54.8%, 45.2%, 4.8%, respectively; P<0.001 T2 vs. T3) and requiring oxygen therapy (26%, 26%, 7%, respectively; P = 0.008 T2 vs. T3) decreased significantly without hemodynamic exacerbation or major complications. Despite the discontinuation of pulmonary vasodilators, mean pulmonary artery pressure improved (36.0 [31.0‒41.3], 21.4±4.2, 18.5±3.6 mmHg, respectively; P<0.001 T2 vs. T3). Complete revascularization with balloon pulmonary angioplasty beyond pulmonary hypertension relief benefits patients with chronic thromboembolic pulmonary hypertension; it may improve oxygenation and exercise capacity, and reduce the need for pulmonary vasodilators and oxygen therapy.

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.

Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity in mice.

Accumulating evidence suggests that high serum uric acid (UA) is associated with left ventricular (LV) dysfunction. Although xanthine oxidase (XO) activation is a critical regulatory mechanism of the terminal step in ATP and purine degradation, the pathophysiological role of cardiac tissue XO in LV dysfunction remains unclear. We herein investigated the role and functional significance of tissue XO activity in doxorubicin-induced cardiotoxicity. Either doxorubicin (10 mg/kg) or vehicle was intraperitonially administered in a single injection to mice. Mice were treated with or without oral XO-inhibitors (febuxostat 3 mg/kg/day or topiroxostat 5 mg/kg/day) for 8 days starting 24 h before doxorubicin injection. Cardiac tissue XO activity measured by a highly sensitive assay with liquid chromatography/mass spectrometry and cardiac UA content were significantly increased in doxorubicin-treated mice at day 7 and dramatically reduced by XO-inhibitors. Accordingly, XO-inhibitors substantially improved LV ejection fraction (assessed by echocardiography) and LV developed pressure (assessed by ex vivo Langendorff heart perfusion) impaired by doxorubicin administration. This was associated with an increase in XO-derived hydrogen peroxide production with concomitant upregulation of apoptotic and ferroptotic pathways, all of which were reduced by XO-inhibitors. Furthermore, metabolome analyses revealed enhanced purine metabolism in doxorubicin-treated hearts, and XO-inhibitors suppressed the serial metabolic reaction of hypoxanthine-xanthine-UA, the paths of ATP and purine degradation. In summary, doxorubicin administration induces cardiac tissue XO activation associated with impaired LV function. XO-inhibitors attenuate doxorubicin-induced cardiotoxicity through inhibition of XO-derived oxidative stress and cell death signals as well as the maintenance of cardiac energy metabolism associated with modulation of the purine metabolic pathway.

Evaluation of Enhanced Lipid Oxidation and Compensatory Suppression using Natriuretic Peptide in Patients with Cardiovascular Diseases.

Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is recognized as a surrogate marker of lipid oxidation and is associated with arteriosclerosis. However, there are limited reports on the relationship between heart failure and MDA-LDL. Therefore, we aimed to determine whether MDA-LDL is activated in patients with left ventricular (LV) dysfunction and examine our hypothesis that the B-type natriuretic peptide (BNP) masks the enhancement of MDA-LDL in patients with LV dysfunction by its strong antioxidative action. The study population comprised 2,976 patients with various cardiovascular diseases. Patients were divided into four groups depending on the LV ejection fraction (LVEF) or plasma BNP level. A nonparametric analysis with the Kruskal-Wallis test was used to perform an interquartile comparison. In addition, structural equation modeling and Bayesian estimation were used to compare the effects of LVEF and BNP on MDA-LDL. MDA-LDL levels did not significantly change (P > 0.05) with respect to the degree of LVEF among the four groups. In contrast, MDA-LDL levels were significantly decreased (P < 0.001) with respect to the degree of BNP among the four groups. A path model based on structural equation modeling clearly showed a significant effect of LVEF (standardized regression coefficient; ß: -0.107, P < 0.001) and BNP (ß: -0.114, P < 0.001) on MDA-LDL, with a significant inverse association between LVEF and BNP (correlation coefficient -0.436, P < 0.001). MDA-LDL should be activated in patients with LV dysfunction; however, BNP is thought to exert a strong compensatory suppression on lipid oxidation, masking the relationship between heart failure and lipid oxidation.

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.

Increase in oxidized low-density lipoprotein level according to hyperglycemia in patients with cardiovascular disease: A study by structure equation modeling.

AIMS: Malondialdehyde-modified low-density lipoprotein (MDA-LDL) level has been reported to be strongly associated with the pathogenesis of cardiovascular diseases. We focused on diabetic status and investigated its possible contribution to MDA-LDL level. METHODS: The study sample consisted of 2705 patients who were admitted to our hospital and underwent cardiac catheterization. Blood samples were obtained to measure the levels of fasting blood sugar (FBS), hemoglobin A1c (HbA1c), insulin, LDL, MDA-LDL and others. Body mass index (BMI) was also used in constructing structural equation modeling and Bayesian estimation. RESULTS: To explore the factors theoretically associated with MDA-LDL level, we performed structural equation modeling. We generated a path model that revealed that BMI, LDL level and FBS were significantly associated with MDA-LDL level (P < 0.001 for each factor), whereas insulin level and HbA1c level were not significantly associated (P = NS for both factors). Noted above was clearly demonstrated on the image of 2-D contour line by Bayesian structure equation modeling. CONCLUSIONS: This study clearly showed that hyperglycemia affects MDA-LDL level. An interaction between diabetes and dyslipidemia was shown in terms of activation of lipid oxidation.