Cardiac Troponin I Predicts Elevated B-type Natriuretic Peptide in Patients Treated with Anthracycline-Containing Chemotherapy.

BACKGROUND: Anthracycline is used to treat various types of cancer; however, cardiotoxicity negatively affects patient prognosis. OBJECTIVES: The aim of the present study was to investigate serial changes in levels of cardiac troponin I (TnI) and B-type natriuretic peptide (BNP) in patients treated with anthracycline-containing therapy. METHODS: 91 consecutive cancer patients planned for anthracycline treatment were enrolled and followed up for 12 months. All patients underwent echocardiography and blood sampling at baseline, 3, 6, and 12 months. RESULTS: The patients were divided into two groups based on their TnI level during the follow-up period: the elevated TnI group (TnI ≥0.03 ng/mL; n = 37) and the normal TnI group (n = 54). In the elevated TnI group, the TnI levels increased at 3 and 6 months, but they returned to within normal range at 12 months after anthracycline administration. Unlike TnI, the BNP levels began to increase after 6 months, and remained increased at 12 months. The occurrence of cancer therapeutics-related cardiac dysfunction was higher in the elevated TnI group than in the normal TnI group. When we set the cut-off value of TnI at 0.029 ng/mL, sensitivity and specificity to predict an elevated BNP level of more than 100 pg/mL were 90 and 63%, respectively. Multivariate logistic regression analysis revealed that elevated TnI was an independent predictor of elevated BNP levels. CONCLUSION: Elevated TnI was an independent predictor for the development of BNP increase. The different characteristics of TnI and BNP should be considered when managing patients treated with anthracycline-containing therapy.

Modification of the Dialysate Port of Plasma Separators for Safe Blood Purification in Japan.

A fatal mix-up of a hemofilter with a plasma separator occurred in 2011. The close resemblance between the two blood purification columns commonly used in Japan posed a fundamental risk for such mix-ups. Both the in-hospital case investigation committee and the relevant academic societies have independently proposed the modifications of the dialysate port (D port) of the plasma separator to avoid this type of misuse. To make these devices foolproof, medical professionals, including physicians and clinical engineers, and members of the Medical Technology Association of Japan discussed measures to prevent this type of recurrence. Since new standards were soon to be issued by the International Organization for Standardization (ISO), the modifications were temporarily postponed. In September 2016, the ISO released new standards for small-bore connectors. The shape changes of the D port from the current slip-in type (ISO8637) to the Luer lock type (ISO80369-7) had been already approved by the Ministry of Health, Labor and Welfare of Japan by the end of November 2018, including a temporal use of a converter to connect the current type of D port to the new type of blood circuit. We must address the next issue that the new standard and the older standard coexist in the clinical setting, which may create a new risk.

Early aggressive intervention for infantile atopic dermatitis to prevent development of food allergy: a multicenter, investigator-blinded, randomized, parallel group controlled trial (PACI Study)-protocol for a randomized controlled trial.

BACKGROUND: Atopic dermatitis is the first clinical manifestation of the atopic march, with the highest incidence in the first year of life. Those affected often go on to develop other allergic diseases including food allergy, asthma, and allergic rhinitis. Recent evidence suggests that sensitization to foods may occur through a defective skin barrier which is common in atopic dermatitis in early life. We hypothesize that therapeutic aggressive intervention to treat new onset atopic dermatitis may prevent the development of later allergen sensitization, and associated food allergy, asthma, and allergic rhinitis. METHODS: This study is a multi-center, pragmatic, two-parallel group, assessor-blind, superiority, individually randomized controlled trial. Atopic dermatitis infants (N = 650) 7-13 weeks old who develop an itchy rash within the previous 28 days are randomly assigned to the aggressive treatment or the conventional treatment in a 1:1 ratio. The primary outcome is oral food challenge-proven IgE-mediated hen's egg allergy at the age of 28 weeks. DISCUSSION: This is a novel pragmatic RCT study to examine the efficacy of early aggressive treatment for atopic dermatitis to prevent later food allergy. If our hypothesis is correct, we hope that such a strategy might impact on disease prevention in countries where food allergy is common, and that our results might reduce the frequency and associated costs of all food allergies as well as hens egg food allergy. Long-term follow and other similar studies will help to determine whether such a strategy will reduce the burden of other allergic diseases such as asthma and allergic rhinitis.Trial registration UMIN-CTR: UMIN000028043.

Usefulness of Urinary N-Terminal Fragment of Titin to Predict Mortality in Dilated Cardiomyopathy.

Titin is associated with myocardial stiffness and hypertrophy, and mutations in its gene have been identified in cardiac myopathies such as dilated cardiomyopathy (DC). It has recently been reported that in damaged muscle, the N-terminal fragment of titin (Titin-N) is cleaved by calpain-3, and urinary Titin-N (U-TN) could be a marker of sarcomere damage. We aimed to investigate the impact of U-TN on prognosis of DC. We measured urinary levels of Titin-N/creatinine ratio (U-TN/Cr; pmol/mg/dl) in 102 patients with DC, and followed up all the patients (mean 1,167 days). The patients were divided into 3 groups based on the U-TN/Cr: first (U-TN/Cr <3.35, n = 34), second (3.35 ≤ U-TN/Cr <7.26, n = 34), and third (7.26 ≤ U-TN/Cr, n = 34) tertiles. In the Kaplan-Meier analysis, cardiac and all-cause mortality progressively increased from the first to the second and third groups (p <0.05, respectively). In the Cox proportional hazard analyses, U-TN/Cr was a predictor of cardiac and all-cause mortality in patients with DC (p <0.05, respectively). U-TN, a possible marker of sarcomere damage, can identify high-risk patients with DC.

Relation of Testosterone Levels to Mortality in Men With Heart Failure.

We aimed to investigate the impact of testosterone on the prognosis of heart failure (HF), as well as the underlying cardiac function, cardiac damage, and exercise capacity. We analyzed consecutive 618 men with HF (age 65.9 years). These patients were divided into quartiles based on their serum levels of total testosterone (TT): first (TT > 631 ng/dl, n = 154), second (462 < TT ≤ 631 ng/dl, n = 155), third (300 < TT ≤ 462 ng/dl, n = 156), and fourth (TT ≤ 300 ng/dl, n = 153) quartiles. In the Kaplan-Meier analysis (mean 1,281 days), all-cause mortality progressively increased throughout from the first to the fourth groups. In the multivariable Cox proportional hazard analysis, TT was found to be an independent predictor of all-cause mortality (hazard ratio 0.929, p = 0.042). In addition, we compared the parameters of echocardiography and cardiopulmonary exercise testing, as well as levels of B-type natriuretic peptide and cardiac troponin I, among the 4 groups. Left ventricular ejection fraction and B-type natriuretic peptide did not differ among the groups. In contrast, the fourth quartile, compared with the first, second, and third groups, had higher levels of troponin I and lower peak VO2 (p <0.05, respectively). Decreased serum testosterone is associated with myocardial damage, lower exercise capacity, and higher mortality in men with HF.

Impact of nutritional indices on mortality in patients with heart failure.

Background: Malnutrition is a common condition that is associated with adverse prognosis in patients with heart failure (HF). The Prognostic Nutritional Index (PNI), Geriatric Nutritional Risk Index (GNRI) and controlling nutritional status (CONUT) have all been used as objective indices for evaluating nutritional status. We aimed to clarify the relationship between these nutritional indices and the parameters of inflammatory markers, cardiac function and exercise capacity, as well as to compare the ability of these indexes for predicting mortality. Methods: We evaluated PNI, GNRI and CONUT in consecutive 1307 patients with HF. Results: First, there were significant correlations between nutritional indices and the following: C reactive protein; tumour necrosis factor-α; adiponectin; B-type natriuretic peptide; troponin I; inferior vena cava diameter and peak VO2 (P<0.05, respectively). Second, in the Kaplan-Meier analysis (follow-up 1146 days), all-cause mortality progressively increased from normal to mild, moderate and severe disturbance groups in the indices (log-rank, P<0.01, respectively). In the Cox proportional hazard analysis, each index was an independent predictor of all-cause mortality in patients with HF (P<0.001, respectively). Third, receiver operating curve demonstrated that the areas under the curve of PNI and GNRI were larger than that of CONUT score (P<0.05, respectively). Conclusion: Patients with HF being malnourished had higher mortality accompanied by higher levels of C reactive protein, tumour necrosis factor-α, adiponectin, B-type natriuretic peptide, troponin I, right-sided volume overload and impaired exercise capacity, rather than left ventricular systolic function. Additionally, PNI and GNRI were superior to CONUT score in predicting mortality in patients with HF.

Subclinical Hypothyroidism Is Associated With Adverse Prognosis in Heart Failure Patients.

BACKGROUND: It is widely recognized that overt hyper- as well as hypothyroidism are potential causes of heart failure (HF). Additionally it has been recently reported that subclinical hypothyroidism (sub-hypo) is associated with atherosclerosis, development of HF, and cardiovascular death. We aimed to clarify the effect of sub-hypo on prognosis of HF, and underlying hemodynamics and exercise capacity. METHODS: We measured the serum levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4) in 1100 consecutive HF patients. We divided these patients into 5 groups on the basis of plasma levels of TSH and FT4, and focused on euthyroidism (0.4 ≤ TSH ≤ 4 µIU/mL and 0.7 ≤ FT4 ≤ 1.9 ng/dL; n = 911; 82.8%) and sub-hypo groups (TSH > 4 µIU/mL and 0.7 ≤ FT4 ≤ 1.9 ng/dL; n = 132; 12.0%). We compared parameters of echocardiography, cardiopulmonary exercise testing, and cardiac catheterization, and followed up for cardiac event rate and all-cause mortality between the 2 groups. RESULTS: Although left ventricular ejection fraction did not differ between the 2 groups, the sub-hypo group had lower peak breath-by-breath oxygen consumption and higher mean pulmonary arterial pressure than the euthyroidism group (peak breath-by-breath oxygen consumption, 14.0 vs 15.9 mL/min/kg; P = 0.012; mean pulmonary arterial pressure, 26.8 vs 23.5 mm Hg, P = 0.020). In Kaplan-Meier analysis (mean 1098 days), the cardiac event rate and all-cause mortality were significantly higher in the sub-hypo group than those in the euthyroidism group (log rank, P < 0.01, respectively). In Cox proportional hazard analysis, sub-hypo was a predictor of cardiac event rate and all-cause mortality in HF patients (P < 0.05, respectively). CONCLUSIONS: Sub-hypo might be associated with adverse prognosis, accompanied by impaired exercise capacity and higher pulmonary arterial pressure, in HF patients.

Association of Hypocalcemia With Mortality in Hospitalized Patients With Heart Failure and Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease--mineral and bone disorders (CKD-MBD) are associated with vascular calcification and abnormal electrolytes that lead to cardiovascular disease and mortality. CKD-MBD is identified by imbalances in serum calcium (Ca), phosphate, and parathyroid hormone (PTH). Although the relation of phosphate and PTH with the prognosis of HF patients has been reported, the association of Ca with prognosis in patients with heart failure (HF) and CKD remains unclear. METHODS AND RESULTS: We examined 191 patients admitted for HF and CKD (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)), and they were divided into 2 groups based on levels of corrected Ca: low Ca (Ca <8.4 mg/dL; n = 32) and normal-high Ca (8.4 ≤Ca; n = 159). We compared laboratory and echocardiographic findings, as well as followed cardiac and all-cause mortality. The low-Ca group had 1) higher levels of alkaline phosphatase (308.9 vs. 261.0 U/L; P = .026), 2) lower levels of 1,25-dihydroxy vitamin D (26.1 vs. 45.0 pg/mL; P = .011) and hydrogen carbonate (22.4 vs. 24.5 mmol/L; P = .031), and 3) a tendency to have a higher PTH level (87.5 vs. 58.6 pg/mL; P = .084). In contrast, left and right ventricular systolic function, estimated glomerular filtration rate, urine protein, phosphate, sodium, potassium, magnesium, and zinc did not differ between the 2 groups. In the Kaplan-Meier analysis, cardiac and all-cause mortality were significantly higher in the low-Ca group than in the normal-high-Ca group (P < .05). In the multivariable Cox proportional hazard analyses, hypocalcemia was an independent predictor of all-cause mortality in HF and CKD patients (P < .05). CONCLUSIONS: Hypocalcemia was an independent predictor of all-cause mortality in HF and CKD patients.

High Mobility Group Box 1 Promotes Angiogenesis from Bone Marrow-derived Endothelial Progenitor Cells after Myocardial Infarction.

AIMS: High mobility group box 1 (HMGB1) is a DNA-binding protein secreted into the extracellular space from necrotic cells that acts as a cytokine. We examined the role of HMGB1 in angiogenesis from bone marrow-derived cells in the heart using transgenic mice exhibiting the cardiac-specific overexpression of HMGB1 (HMGB1-TG). METHODS: HMGB1-TG mice and wild-type littermate (WT) mice were lethally irradiated and injected with bone marrow cells from green fluorescent protein mice through the tail vein. After bone marrow transplantation, the left anterior descending artery was ligated to induce myocardial infarction (MI). RESULTS: Flow cytometry revealed that the levels of circulating endothelial progenitor cells (EPCs) mobilized from the bone marrow increased after MI in the HMGB-TG mice versus the WT mice. In addition, the size of MI was smaller in the HMGB1-TG mice than in the WT mice, and immunofluorescence staining demonstrated that the number of engrafted vascular endothelial cells derived from bone marrow in the border zones of the MI areas was increased in the HMGB1-TG mice compared to that observed in the WT mice. Moreover, the levels of cardiac vascular endothelial growth factor after MI were higher in the HMGB1-TG mice than in the WT mice. CONCLUSIONS: The present study demonstrated that HMGB1 promotes angiogenesis and reduces the MI size by enhancing the mobilization and differentiation of bone marrow cells to EPCs as well as their migration to the border zones of the MI areas and engraftment as vascular endothelial cells in new capillaries or arterioles in the infarcted heart.

Impact of sleep-disordered breathing on myocardial damage and metabolism in patients with chronic heart failure.

Sleep-disordered breathing (SDB) has a critical association with mortality and morbidity of patients with chronic heart failure (CHF). Troponin T is a marker of ongoing myocardial damage and predicts adverse clinical outcomes in patients with CHF. Carnitine plays an important role in the utilization of fatty acids in the myocardium. It has been reported that myocardial carnitine levels decrease in the failing heart. We hypothesized that plasma troponin T and carnitine are increased due to the leakage from damaged cardiomyocytes or the alteration of myocardial metabolism in CHF patients with SDB. We examined the relation of plasma troponin T and carnitine levels with severity of SDB in CHF. We used portable sleep monitor and measured the apnea-hypopnea index (AHI), plasma levels of high-sensitive troponin T and carnitine in 131 CHF patients. These patients were divided into three groups based on AHI: group A (None-mild SDB AHI < 15/h, n = 45), group B (Moderate SDB 15 ≤ AHI < 30/h, n = 32) and group C (Severe SDB AHI ≥ 30/h, n = 54). Levels of high-sensitive troponin T and plasm total carnitine were significantly higher in group C than in groups A and B [high-sensitive troponin T; group A 0.009 (0.005-0.016), group B 0.012 (0.006-0.021), group C 0.021 (0.011-0.039) ng/ml, total carnitine; group A 61.0 ± 15.1, group B 65.0 ± 13.5, group C 73.3 ± 17.5 µmol/l, P < 0.01 vs. group A and P < 0.05 vs. group B, respectively]. Furthermore, in the multiple regression analysis, the independent factors to determine plasma levels of log (high-sensitive troponin T) were high-sensitive C-reactive protein and AHI, and the independent factors to determine plasma levels of carnitine were glomerular filtration rate and AHI. The present study suggests that SDB is associated with latent myocardial damage and alteration of myocardial carnitine metabolism in patients with CHF, presented by higher circulating troponin T and carnitine levels.

Impact of body mass index on mortality in heart failure patients.

BACKGROUND: Higher body mass index (BMI) is associated with incident heart failure (HF), but paradoxically associated with better prognosis, recognized as the obesity paradox in HF. However, the impact of BMI on detailed prognosis on HF and the mechanism of obesity paradox remain still unclear. MATERIALS AND METHODS: We researched consecutive 648 patients admitted for HF as follows: underweight (BMI < 18·5 kg/m(2) , n = 86), normal (18·5 ≤ BMI < 25, n = 380), overweight (25 ≤ BMI < 30, n = 147) and obese (30 ≤ BMI, n = 35) and compared the results from their laboratory tests and echocardiography. We also followed cardiac and all-cause mortality. RESULTS: Obese group had a higher prevalence of obesity-related comorbidity (hypertension, diabetes, dyslipidemia); however, tumour necrosis factor-α, adiponectin, troponin T and systolic pulmonary arterial pressure were higher in the underweight group than in the other groups (P < 0·05, respectively). Left and right ventricular systolic function did not differ among the groups. In the Kaplan-Meier analysis, cardiac and all-cause mortality progressively increased from obese to overweight, normal and underweight group. Importantly, in the Cox proportional hazard analyses after adjusting for known risk factors, BMI was an independent predictor of cardiac and all-cause mortality (P < 0·01, respectively) in HF patients. CONCLUSIONS: Body mass index was an independent predictor of cardiac death and all-cause mortality in HF patients. Furthermore, lower BMI was associated with higher circulating levels of tumour necrosis factor-α, adiponectin and troponin T and higher systolic pulmonary arterial pressure.

Liver dysfunction assessed by model for end-stage liver disease excluding INR (MELD-XI) scoring system predicts adverse prognosis in heart failure.

AIMS: Liver dysfunction due to heart failure (HF) is often referred to as cardiac or congestive hepatopathy. The composite Model for End-Stage Liver Disease excluding INR (MELD-XI) is a robust scoring system of liver function, and a high score is associated with poor prognosis in advanced HF patients with a heart transplantation and/or ventricular assist device. However, the impact of MELD-XI on the prognosis of HF patients in general remains unclear. METHODS AND RESULTS: We retrospectively analyzed 562 patients who were admitted to our hospital for the treatment of decompensated HF. A MELD-XI score was graded, and patients were divided into two groups based on the median value of MELD-XI score: Group L (MELD-XI <10, n = 289) and Group H (MELD-XI ≥10, n = 273). We compared all-cause mortality and echocardiographic findings between the two groups. In the follow-up period (mean 471 days), 104 deaths (62 cardiac deaths and 42 non-cardiac deaths) were observed. The event (cardiac death, non-cardiac death, all-cause death)-free rate was significantly higher in group L than in group H (logrank P<0.05, respectively). In the Cox proportional hazard analysis, a high MELD-XI score was found to be an independent predictor of cardiac deaths and all-cause mortality in HF patients. Regarding echocardiographic parameters, right atrial and ventricular areas, inferior vena cava diameter, and systolic pulmonary artery pressure were higher in group H than in group L (P<0.05, respectively). CONCLUSIONS: The MELD-XI scoring system, a marker of liver function, can identify high-risk patients with right heart volume overload, higher pulmonary arterial pressure and multiple organ failure associated with HF.

Adaptive servo-ventilation therapy improves long-term prognosis in heart failure patients with anemia and sleep-disordered breathing.

Sleep disordered breathing (SDB) and anemia influences the progression of chronic heart failure (CHF). Adaptive servo-ventilation (ASV) is an effective therapeutic device for treatment of CHF, however, the impacts of ASV on CHF patients with or without anemia remain unclear.A total of 139 patients with CHF and SDB were divided into two groups: those treated with ASV (n = 53) and without ASV (n = 86). All patients were prospectively followed after discharge with the endpoints of cardiac death or progressive heart failure requiring rehospitalization. There were 65 patients (47%) with anemia among all subjects. The apnea hypopnea index was improved, and plasma BNP and high sensitive C-reactive protein levels were decreased in both groups with and without anemia by ASV therapy. The Kaplan-Meier survival curve demonstrated that the cardiac event-free rate in patients with ASV was significantly higher than in those without ASV in the anemia group (P = 0.008). However, in the non-anemia group, the cardiac event-free rate was similarly high in patients both with and without ASV (P = 0.664). Multivariate Cox proportional hazard analysis demonstrated that ASV use was an independent predictor of cardiac events in the anemia group (P = 0.0308), but not in the non-anemia group.ASV treatment for CHF and SDB has more favorable impacts in patients with anemia than in those without anemia.

Cardiovascular function and prognosis of patients with heart failure coexistent with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) often coexists with heart failure (HF), and is considered to be associated with adverse outcomes in HF patients. However, the features of cardiovascular function and the detailed all-cause mortality of HF with COPD remain unclear. METHODS AND RESULTS: Consecutive 378 patients admitted for HF who underwent spirometry were divided into three groups: HF without COPD (non-COPD group, n=272), HF with mild COPD (GOLD I group, n=82), and HF with moderate COPD (GOLD II group, n=24). The GOLD II group, as compared to non-COPD group, had (1) higher troponin T (p=0.009); (2) greater cardio-ankle vascular index (p=0.032); and (3) similar cardiac systolic and diastolic function of the right and left ventricle. In addition, rates of cardiac (p=0.049), non-cardiac (p=0.001), and all-cause mortality (p=0.002) were higher in GOLD II group than in non-COPD and GOLD I groups. Importantly, in the Cox proportional hazard analyses, the GOLD stage II was an independent predictor of cardiac (p=0.038), non-cardiac (p=0.036), and all-cause mortality (p=0.015) in HF patients. CONCLUSIONS: HF patients with coexistent moderate COPD (GOLD stage II) have greater myocardial damage, greater arterial stiffness, and higher cardiac and non-cardiac mortality.

High-sensitivity cardiac troponin T predicts non-cardiac mortality in heart failure.

BACKGROUND: Cardiac troponins are independent predictors of cardiac mortality in patients with heart failure (HF). Recently, elevation of troponins was described in non-cardiac diseases such as stroke and infection, among others, but it remains unclear whether high-sensitivity troponin T (hs-TnT) predicts non-cardiac mortality in HF patients. METHODS AND RESULTS: Four-hundred and forty-four consecutive HF patients admitted to hospital for the treatment of decompensated HF were divided into 2 groups based on median hs-TnT: group L (<0.028ng/ml, n=220) and group H (≥0.028ng/ml, n=224). We compared all-cause mortality and echocardiographic findings between the 2 groups. In the follow-up period (mean 472 days), 77 deaths (49 cardiac deaths and 28 non-cardiac deaths) were observed. The event-free rate was significantly lower in group H than in group L for non-cardiac death (P=0.025), cardiac death (P<0.001), and all-cause mortality (P<0.001). On multivariate Cox proportional hazard analysis, high hs-TnT was found to be an independent predictor of non-cardiac death (P=0.042), cardiac death (P<0.001) and all-cause mortality (P<0.001) in HF patients after adjusting for risk factors. Regarding echocardiographic parameters, left ventricular wall thickness was higher (P<0.001), and ejection fraction was lower (P=0.011) in group H than in group L. CONCLUSIONS: Hs-TnT is an independent predictor not only of cardiac mortality, but also of non-cardiac mortality in HF patients.

Senescence marker protein 30 inhibits angiotensin II-induced cardiac hypertrophy and diastolic dysfunction.

BACKGROUND AND OBJECTIVE: Senescence marker protein 30 (SMP30) is assumed to behave as an anti-aging factor. Recently, we have demonstrated that deficiency of SMP30 exacerbates angiotensin II-induced cardiac hypertrophy, dysfunction and remodeling, suggesting that SMP30 may have a protective role in the heart. Thus, this study aimed to test the hypothesis that up-regulation of SMP30 inhibits cardiac adverse remodeling in response to angiotensin II. METHODS: We generated transgenic mice with cardiac-specific overexpression of SMP30 gene using α-myosin heavy chain promoter. Transgenic mice and wild-type littermate mice were subjected to continuous angiotensin II infusion (800 ng/kg/min). RESULTS: After 14 days, heart weight and left ventricular weight were lower in transgenic mice than in wild-type mice, although blood pressure was similarly elevated during angiotensin II infusion. Cardiac hypertrophy and diastolic dysfunction in response to angiotensin II were prevented in transgenic mice compared with wild-type mice. The degree of cardiac fibrosis by angiotensin II was lower in transgenic mice than in wild-type mice. Angiotensin II-induced generation of superoxide and subsequent cellular senescence were attenuated in transgenic mouse hearts compared with wild-type mice. CONCLUSIONS: Cardiac-specific overexpression of SMP30 inhibited angiotensin II-induced cardiac adverse remodeling. SMP30 has a cardio-protective role with anti-oxidative and anti-aging effects and could be a novel therapeutic target to prevent cardiac hypertrophy and remodeling due to hypertension.

Deficiency of senescence marker protein 30 exacerbates angiotensin II-induced cardiac remodelling.

AIMS: Ageing is an important risk factor of cardiovascular diseases including heart failure. Senescence marker protein 30 (SMP30), which was originally identified as an important ageing marker protein, is assumed to act as a novel anti-ageing factor in various organs. However, the role of SMP30 in the heart has not been previously explored. In this study, our aim was to elucidate the functional role of SMP30 on cardiac remodelling. METHODS AND RESULTS: SMP30 knockout (KO) mice and wild-type (WT) mice were subjected to continuous angiotensin II (Ang II) infusion. After 14 days, the extent of cardiac hypertrophy and myocardial fibrosis was significantly higher in SMP30-KO mice than in WT mice. Echocardiography revealed that SMP30-KO mice had more severely depressed systolic and diastolic function with left ventricular dilatation compared with WT mice. Generation of reactive oxygen species related with activation of nicotinamide adenine dinucleotide phosphate-oxidase was greater in SMP30-KO mice than in WT mice. The number of deoxynucleotidyl transferase-mediated dUTP nick end-labelling positive nuclei was markedly increased in SMP30-KO mice with activation of caspase-3, increases in the Bax to Bcl-2 ratio and phosphorylation of c-Jun N-terminal kinase compared with WT mice. Furthermore, the number of senescence-associated ß-galactosidase-positive cells was significantly increased via up-regulation of p21 gene expression in SMP30-KO mice compared with WT mice. CONCLUSION: This study demonstrated the first evidence that deficiency of SMP30 exacerbates Ang II-induced cardiac hypertrophy, dysfunction, and remodelling, suggesting that SMP30 has a cardio-protective role in cardiac remodelling with anti-oxidative and anti-apoptotic effects in response to Ang II.

Age-related oxidant stress with senescence marker protein-30 deficiency plays a pivotal role in coronary artery spasm.

OBJECTIVES: We examined the mechanism of coronary artery spasm related to oxidant stress with aging in senescence marker protein-30 (SMP30)-deficient mice because SMP30 decreases with aging and SMP30 knockout (KO) mice show a short life with increased oxidant stress. METHODS: To examine the effect of SMP30 on coronary artery vasomotor tone, we measured the endothelium-dependent [5-hydroxytryptamine (5-HT)] response of isolated, pressurized coronary arteries from SMP30 KO and wild-type (WT) mice (n=10 each). RESULTS: In SMP30 KO mice, 5-HT-induced vasoconstriction occurred, which altered vasodilation with dithiothreitol, a thiol-reducing agent. In WT mice, 5-HT-induced vasodilation occurred. Administration of 5-HT from the aortic sinus induced a coronary artery spasm in SMP30 KO mice, which was prevented by the intravenous administration of Y-27632, rho-kinase inhibitor. The fluorescence level of monochlorobimane in coronary arteries, which covalently labels the reduced total thiols, decreased in SMP30 KO mice, but reverted to a level comparable with that of WT mice on treatment with Y-27632. From these results, SMP30 provides protection against coronary artery spasm. CONCLUSION: Chronic oxidant stress associated with aging plays an important role in coronary artery spasm related to thiol oxidation and rho-kinase signaling.

Short-term use of adaptive servo ventilation improves renal function in heart failure patients with sleep-disordered breathing.

Sleep-disordered breathing (SDB) deteriorates the prognosis of patients with chronic heart failure (CHF). Adaptive servo ventilation (ASV) is a new therapeutic modality to treat SDB including Cheyne-Stokes respiration associated with central sleep apnea. Renal function plays critical roles in the progression of CHF and is a strong predictor of clinical outcomes. Cystatin C is a marker of renal function, and more sensitive than serum creatinine. The purpose of the present study was to examine whether ASV is effective for cardiac overload and renal dysfunction in CHF patients with SDB. Fifty patients with CHF and SDB (mean left ventricular ejection fraction 34.0 %, estimated glomerular filtration rate (eGFR) 62.8 ml/min/1.73 cm(2)) were examined. We performed polysomnography for two consecutive days (baseline and on ASV), and measured levels of serum N terminal-pro B-type natriuretic peptide (NT-pro BNP), cystatin C, and estimated glomerular filtration rate based on cystatin C (eGFR Cyst C). ASV significantly improved the apnea hypopnea index, central apnea index, obstructive apnea index, arousal index, mean SPO2, and lowest SPO2 compared to baseline. ASV decreased NT-pro BNP (1,109.0 (2,173.2) to 912.8 (1,576.7) pg/ml, p < 0.05), cystatin C (1.391 ± 0.550-1.348 ± 0.489 mg/l, p < 0.05), and increased eGFR Cyst C (61.9 ± 30.8-65.7 ± 33.8 ml/min/1.73 cm(2), p < 0.01). ASV improved SDB, reduced cardiac overload, and ameliorated renal function in CHF patients with SDB. ASV has short-term beneficial effects on not only SDB but also cardio-renal function. ASV might be a promising useful tool for CHF as an important non-pharmacotherapy with cardio-renal protection.

Left ventricular plasty improved cardiac function in a case of takotsubo cardiomyopathy with persistent aneurysm.

A 72-year-old woman was admitted to a local hospital due to repeated chest pain in December 2011. On admission, blood tests showed elevation of cardiac enzyme and B-type natriuretic peptide levels. Electrocardiography showed ST-segment elevation in almost all leads. Echocardiography showed akinesis in left ventricular (LV) apex, and hyperkinesis in basal LV. Urgent cardiac catheterization was performed. Coronary angiography showed no significant organic stenosis and the acetylcholine provocation test did not evoke coronary spasm. The left ventriculography revealed marked akinesis of the apical ballooning with hyperkinesis of the basal LV segments, suggesting takotsubo cardiomyopathy. Following the diagnosis, she started treatment for LV dysfunction with standard pharmacotherapy including beta blocker, aldosterone receptor blocker, and angiotensin-converting enzyme inhibitor. Even after 3 months, echocardiography demonstrated that LV wall motion was not recovered, and her symptoms of heart failure were not improved. Based on these findings, we considered that surgical LV plasty was necessary for the treatment of cardiac dysfunction in this patient. She underwent surgical operation (aneurysma resection and LV volume reduction) in April 2011. Pathological examination of the excised myocardial tissue from the aneurysm revealed damaged cardiomyocytes replaced with interstitial fibrosis and adipose tissue. After surgery, her LV systolic function and clinical symptoms dramatically improved. .