Clinical usefulness of phase angle as an indicator of muscle wasting and malnutrition in inpatients with cardiovascular diseases.

Background and Objectives: Extracellular water is increased in patients with edema, such as those with chronic heart failure, and it is difficult to assess skeletal muscle mass with the skeletal muscle mass index when extracellular water is high. We investigated the relationship between phase angle and physical function, nutritional indices, and sarcopenia in patients with cardiovascular diseases, including chronic heart failure. Methods and Study Design: In 590 patients with cardiovascular diseases (372 men), handgrip strength, gait speed, and anterior mid-thigh muscle thickness by ultrasound were measured, and the skeletal muscle mass index, phase angle, and the extracellular water: total body water ratio were measured with a bioelectrical impedance analyzer, and presence of sarcopenia was evaluated. Results: Phase angle, but not the skeletal muscle mass index, was correlated with serum albumin (r = 0.377, p < 0.001) and hemoglobin values in women. Multivariate regression analysis showed that at the extracellular water: total body water ratio below 0.4, both phase angle and skeletal muscle mass index were independent determinants of handgrip strength and log mid-thigh muscle thickness in men, after adjustment for age and presence of chronic heart failure. In contrast, for the ratio of 0.4 or greater, after adjustment for age and presence of chronic heart failure, phase angle was a stronger independent determinant of handgrip strength and log mid-thigh muscle thickness than the skeletal muscle mass index in men. Conclusions: Phase angle is a good marker of muscle wasting and malnutrition in patients with cardiovascular disease, including chronic heart failure.

Effect of Novel Stratified Lipid Risk by "LDL-Window" and Flow-Mediated Dilation on the Prognosis of Coronary Artery Disease Using the FMD-J Study A Data.

BACKGROUND: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. CONCLUSIONS: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

Effects of switching from clopidogrel to prasugrel at the chronic phase after coronary stenting on antiplatelet action and vascular endothelial function: Switch-Pras study.

Compared to clopidogrel, prasugrel has a lower incidence of ischemic events following percutaneous coronary intervention (PCI) because of an early reduction during the acute phase in P2Y12 reaction units (PRU). The objective of this study was to compare the antiplatelet effect and vascular endothelial function of both drugs during the chronic phase after PCI. Patients who had undergone PCI and were confirmed to have no restenosis by follow-up coronary angiography under dual anti-platelet therapy with clopidogrel (75 mg/day) and aspirin (100 mg/day) were randomized to either continue clopidogrel or switch to prasugrel (3.75 mg/day). At baseline, prior to randomization we determined the CYP2C19 genotype. At the baseline and 24 weeks after randomization, the P2Y12 reactivity unit (PRU) was measured using the VerifyNow™ P2Y12 assay. Endothelial function was evaluated by flow-mediated vasodilation (FMD) and reactive hyperemia peripheral arterial tonometry (RH-PAT), while and circulating CD34+/CD133+/CD45low progenitor cells were measured by flow cytometric analysis. Serum high-sensitivity C-reactive protein (hsCRP) level was also measured. The PRU was reduced significantly in the prasugrel group (P = 0.0008), especially in patients who were intermediate or poor metabolizers based on the CYP2C19 genotype (P < 0.0001). This reduction was not observed in the clopidogrel group. The number of CD34+/CD133+/CD45low cells increased in the clopidogrel group (P = 0.008), but not in the prasugrel group. The hsCRP, FMD and reactive hyperemia index measured by RH-PAT did not change in either group. Prasugrel is potentially better than clopidogrel for preventing thrombotic events, although clopidogrel may have an advantage over prasugrel in terms of preventing atherosclerotic events. Proper use of thienopyridine drugs based on the CYP2C19 genotype has promising clinical potential.

Repeated In-Stent Restenosis Despite Aggressive Lipid Loweringby PCSK-9 Inhibitor Treatment: A Case Report.

A 76-year-old woman with unstable angina underwent coronary stent implantation. At the same time, rosuvastatin therapy was started. However, she experienced repeated in-stent restenosis (ISR). Treatment with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor along with rosuvastatin (5 mg/day) reduced plasma low-density lipoprotein cholesterol to 10 mg/dL, but failed to prevent further ISR. Eventually, an increase in the rosuvastatin dose to the permitted maximum of 20 mg/day succeeded in preventing further in-stent restenosis. Rather than using PCSK9 inhibitors, intensive statin treatment, using the maximum dose of statins, should be prioritized for the secondary prevention of coronary artery disease.

Vascular Endothelial Dysfunction and Autonomic Nervous Hyperactivity among Premenopausal Women with Cold-Sensitivity Constitution (Hiesho).

The cold-sensitivity constitution (CSC), termed "Hiesho" in Japanese, is a woman-specific cold sense of peripheral sites. The etiology of and criteria for CSC are not yet well established. We defined CSC as temperature gradient > 6˚C between body surface and core, and investigated the autonomic nervous activity by measuring heart rate variability and the vascular endothelial function by determining reactive hyperemia index (RHI) in 43 healthy premenopausal women, aged 18-47 years. Twenty five women had CSC during both the follicular and luteal phases of their menstrual cycles (sustained-CSC group), 8 women did not show CSC during both phases (non-CSC group), and the remaining 10 women showed CSC in either menstrual phase (occasional CSC). To identify the pathophysiological bases of CSC, we compared the sympathetic nervous activity and vascular endothelial function between sustained-CSC and non-CSC. We thus found that sympathetic nervous activity was higher among the sustained-CSC group (p = 0.042) during the follicular phase, compared with the non-CSC group, while the RHI was similar in both groups. Furthermore, the sympathetic nervous activity was similar between the sustained-CSC women aged ≥ 40 years (n = 10) and those aged < 40 years (n = 15) during either menstrual phase, whereas the RHI of the women aged < 40 years was lower during the follicular phase (p = 0.045), compared with the women aged ≥ 40 years. In conclusion, CSC is associated with sympathetic nervous hyperactivity in premenopausal women, and vascular endothelial dysfunction is also involved in CSC among younger women.

Flow-Mediated Vasodilation and Reactive Hyperemia Index in Heart Failure with Reduced or Preserved Ejection Fraction.

Vascular endothelial dysfunction is part of the underlying pathophysiology of heart failure. However, there are no reports in which vascular endothelial function of both conduit arteries and microvasculature was assessed in patients with heart failure. This study was aimed to assess vascular endothelial function separately in heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF). We performed simultaneous measurement of both flow-mediated vasodilation for endothelial function of conduit arteries and reactive hyperemia-peripheral arterial tonometry for that of microvasculature in 88 consecutive patients with chronic heart failure. In 55 patients with ischemic heart disease as an underlying cause of heart failure, flow-mediated vasodilation value was comparable between the two groups of HFrEF (left ventricular ejection fraction < 50%, n = 31) and HFpEF (left ventricular ejection fraction ≥ 50%, n = 24). Reactive hyperemia index measured by reactive hyperemia peripheral arterial tonometry, however, was lower in HFrEF patients compared to HFpEF patients (P = 0.014). In contrast, among 33 patients with non-ischemic heart disease, the degree of flow-mediated vasodilation was lower in HFpEF patients (n = 18) compared with HFrEF patients (n = 15) (P = 0.009), while reactive hyperemia index was comparable between the two groups. The clinical and pathophysiological significance of endothelial function in heart failure differs between conduit artery and microvasculature, and these differences may contribute to the underlying pathophysiology of HFpEF and HFrEF, as well as in ischemic heart disease and non-ischemic heart disease.

Patients With CONgestive Heart Failure Benefit From Long-Term Treatment Effects With Novel Treatment Using Azosemide Compared With Furosemide Derived From Existing Retrospective Study Data: CONTENTED.

A long-acting loop diuretic, azosemide, has been shown to improve long-term prognosis in patients with heart failure compared with a short-acting loop diuretic, furosemide. However, the therapeutic advantages of azosemide over furosemide have not been clearly established. In this study, we retrospectively analyzed clinical outcomes and laboratory data in patients with congestive heart failure treated with furosemide or azosemide, and the efficacy of these agents was compared. First, we screened 1900 patients and selected 124 (furosemide group: n = 40; azosemide group: n = 84) as the total study population. From these patients, we next selected 72 patients for the propensity score-matched analysis (furosemide group: n = 36; azosemide group: n = 36). The incidence of all-cause death and rehospitalization due to worsening heart failure during 24 months of follow-up was similar between the furosemide and azosemide groups in both the total study population and the propensity score-matched population. However, in the propensity score-matched analysis, the estimated glomerular filtration rate time-dependently decreased during 36 months of follow-up in the furosemide group (56.5 ± 19.5-43.2 ± 16.3 mL/min/1.73 m), whereas it did not change in the azosemide group (58.6 ± 22.0-50.3 ± 17.8 mL/min/1.73 m) (P = 0.032). Azosemide might have some potential advantage for renal protection over furosemide in patients with congestive heart failure.

Echocardiographic surrogates of right atrial pressure in pulmonary hypertension.

Right atrial pressure (RAP), a representative parameter of right heart failure, is very important for prognostic evaluation and risk assessment in pulmonary hypertension. However, its measurement requires invasive cardiac catheterization. In this study, we determined the most accurate echocardiographic surrogate of catheterization-based RAP. In 23 patients with pulmonary hypertension, a total of 66 cardiac catheterization procedures were performed along with 2-dimensional echocardiography. We evaluated tricuspid E/A, E', A' and E/E', and estimated RAP by the respirophasic variation of the inferior vena cava diameter (eRAP-IVCd) as possible surrogates of catheterization-based RAP. In simple linear regression analysis, E/A (R = 0.452, P = 0.0001) and eRAP-IVCd (R = 0.505, P < 0.0001) were positively correlated with catheterization-based RAP, whereas A' (R = - 0.512, P < 0.0001) was negatively correlated with RAP. In multiple regression analysis, A' was the most significant independent predictor of catheterization-based RAP (R = - 0.375, P = 0.0007). In 16 patients who had multiple measurements, there were a total of 43 measurements before and after medication changes. The absolute change in catheterization-based RAP was negatively correlated with the percent change in A'. Receiver operating characteristic curve analysis indicated that the optimal cut-off value of A' to predict a catheterization-based RAP > 10 mmHg was 11.3 cm/s (area under the curve = 0.782, sensitivity = 0.70, specificity = 0.78). In 20 measurements of 20 patients with left heart failure, catheterization-based RAP was not correlated with any of 5 echocardiographic parameters. However, it was closely correlated with catheterization-based pulmonary capillary wedge pressure. The echocardiographic parameter, A', was the best surrogate of catheterization-based RAP in patients with pulmonary hypertension.

Theophylline-Induced Left Ventricular Relaxation Disturbance in Magnesium-Deficient Rats: Improvement by K201, a Novel 1,4-Benzothiazepine Derivative.

BACKGROUND: Although magnesium deficiency induces left ventricular dysfunction, it is not known whether both systolic and diastolic functions are altered to the same extent. In this study, we investigated the effects of theophylline on left ventricular function in rats fed a normal diet or a magnesium-deficient diet for 1 month, and determined whether K201, a multi-channel blocker, modulated the effects of theophylline. METHODS: Theophylline was infused at 5 mg/kg/min for 15 min in 6 control rats and 6 magnesium-deficient rats, and hemodynamic measurements were performed. In another 6 magnesium-deficient rats, K201 was infused at 0.1 mg/kg/min for 15 min simultaneously with theophylline. RESULTS: Theophylline induced persistent increases in heart rate, peak positive first derivative of left ventricular pressure (+dP/dt), and a transient increase in left ventricular end-diastolic pressure (LVEDP), but did not affect left ventricular systolic pressure (LVSP) and peak negative first derivative of left ventricular pressure (-dP/dt) in the control rats. In contrast, in the magnesium-deficient rats, there was a persistent decrease in LVSP and a persistent increase in -dP/dt after theophylline infusion, although increases in heart rate, +dP/dt and LVEDP were similar to those in the control rats. When K201 was infused along with theophylline in the magnesium-deficient rats, both the decrease in LVSP and increase in -dP/dt were suppressed. CONCLUSIONS: Theophylline impaired left ventricular function in the magnesium-deficient rats, and this was improved by K201. K201 may provide new insights regarding future strategies for heart failure treatment.

Comparison of echocardiographic parameters to assess right ventricular function in pulmonary hypertension.

Although measurement of right ventricular ejection fraction (RVEF) may be relevant for evaluation of therapeutic efficacy and/or prognosis in patients with pulmonary hypertension, RVEF obtained by echocardiography has limited accuracy. In contrast, radionuclide and/or magnetic resonance imaging can measure RVEF more reliably. In this study, we investigated the relationship between RVEF measured by radionuclide angiography and the echocardiographic parameters that are recommended by the American Society of Echocardiography as representative of right heart function. There were 23 study participants with pulmonary hypertension who underwent radionuclide angiography and 2-dimensional and Doppler echocardiography (n = 30 measurements). RVEF measured by radionuclide angiography correlated with right ventricular Tei index (RV Tei index) measured by Doppler echocardiography (r = -0.601, P < 0.0005). Receiver operating characteristic curve analysis showed that an RV Tei index cut-off value of 0.371 was the best of predictor of RVEF ≤35% (area under the curve = 0.768, sensitivity = 0.857, selectivity = 0.667). Multiple regression analysis showed that RVEF was correlated with the RV Tei index, and this association was independent of other echocardiographic right ventricular function parameters (r = -0.644, P < 0.005). The RV Tei index measured by Doppler echocardiography may be an acceptable surrogate marker of RVEF in patients with pulmonary hypertension.

Radiation-Induced Coronary Artery Disease Manifested at Very Late Phase.

We report the case of a 51-year-old female, in whom coronary artery disease such as occlusion of septal perforators was manifested, on the occasion of hospitalization with congestive heart failure. The patient had a history of radiation therapy for a mediastinal tumor 19 years previously. As she had no conventional coronary risk factors, the cause of the coronary artery disease is thought to have been related to the radiation therapy. As survival rates of cancer patients improve as a consequence of therapeutic advances, we should be aware of the possibility of coronary artery disease as a very late complication of radiation therapy, even in patients who have no coronary risk factors.

The wound healing response after implantation of a drug-eluting stent is impaired persistently in the long term.

A 70-year-old man underwent stent implantation for right coronary artery (RCA) lesions with a bare metal stent (BMS) and two sirolimus-eluting stents (SES). However, as both the BMS and SES stented sites developed restenosis after 13 months, he underwent target lesion revascularization using directional coronary atherectomy (DCA). On histopathology, the restenosis lesion at the SES-deployed site showed greater inflammation and less re-endothelialization than that at the BMS-deployed site. Three months later, the SES-deployed site developed a second restenosis, in which paclitaxel-eluting stents (PES) were implanted (PES-in-SES), while the BMS-deployed site was restenosis free. Five years later, restenosis was absent in these RCA lesions. However, by optical coherence tomography and/or coronary angioscopy, the PES-in-SES site in the RCA showed poor neointimal coverage over the stent struts and yellowish neointima, suggesting lipid-rich neoatheroma formation, whereas at the BMS site appropriate white neointima formation was observed. Drug-eluting stents still have problems of persistent inflammation, inappropriate neointima formation, and neoatherosclerosis. Although we are now in the era of second generation DESs in which better stent performance would be promising, we should remember that we are obliged to continue to follow-up all patients in whom first generation DESs such as SES or PES have been placed.

Comparison of the performance of zotarolimus- and everolimus-eluting stents by optical coherence tomography and coronary angioscopy.

Overall stent performance should be characterized by geometric luminal gain acquisition, neointimal coverage of the stent struts, and stabilization of the underlying inflammatory neoatheroma. The aim of this study was to compare the performance of zotarolimus-eluting stent (ZES), everolimus-eluting stent (EES) and bare metal stent (BMS) using optical coherence tomography (OCT) and coronary angioscopy. For 36 stented coronary lesions (BMS, 12 lesions; ZES, 11 lesions; EES, 13 lesions) in 27 patients, we calculated neointimal area and uncovered stent strut rate based on OCT findings at 10 months after stent placement. The grades of neointimal coverage and yellow color, both of which were classified from 0 to 3, were also assessed by coronary angioscopy. The plaque area of the ZES lesions was larger than that of the EES lesions (P < 0.05) but smaller than that of the BMS lesions (P < 0.05). The OCT-based uncovered rate of the ZES lesions was less than that of the EES lesions (P < 0.01), but similar to that of the BMS lesions. The stent coverage grade by angioscopy was higher in the ZES lesions than in the EES lesions (P < 0.05), but similar to the BMS lesions. The yellow grade was less in the ZES lesions than in the EES lesions (P < 0.01), but similar to the BMS lesions. ZES might be better than BMS in terms of neointimal thickening, and better than EES in terms of neointimal coverage as well as prevention of neoatheroma formation. ZES may have superior performance compared with EES.

Impact of Obstructive Sleep Apnoea on Heart Failure with Preserved Ejection Fraction.

BACKGROUND: The impact of obstructive sleep apnoea on heart failure with preserved ejection fraction is unknown. METHODS: Fifty-eight patients who had heart failure with a left ventricular ejection fraction; ≥50% underwent a sleep study. Brain natriuretic peptide (BNP) levels were determined at enrolment and at one, six, 12 and 36 months after enrolment. RESULTS: Obstructive sleep apnoea was found in 39 patients (67%), and they were all subsequently treated with continuous positive airway pressure. Echocardiography at admission showed that E/E' tended to be higher in the 39 patients with, than in the 19 patients without, obstructive sleep apnoea (15.0±3.6 vs 12.1±1.9, respectively, P=0.05). The median BNP levels at enrolment were similar in patients with and without obstructive sleep apnoea [median (interquartile range): 444 (233-752) vs 316 (218-703) pg/ml]. Although BNP levels decreased over time in both groups, the reduction was less pronounced in patients with obstructive sleep apnoea (P<0.05). Consequently, BNP levels were higher in patients with sleep apnoea at six months, [221 (137-324) vs 76 (38-96) pg/ml, P<0.05], 12 months [123 (98-197) vs 52 (38-76) pg/ml, P<0.05] and 36 months [115 (64-174) vs 56 (25-74) pg/ml, P<0.05]. CONCLUSION: Obstructive sleep apnoea, even when treated appropriately, may worsen long-term cardiac function and outcomes in patients who have heart failure with preserved ejection fraction.

The late-phase inflammatory response after drug-eluting stent implantation.

Recent advances in drug-eluting stent (DES) technology have succeeded in preventing restenosis. In addition to inhibiting smooth muscle cell proliferation, DES greatly inhibits the local inflammatory response in the acute phase after implantation, leading to prevention of restenosis. However, a unique issue in DES implantation is an impairment of reendothelialization, which may result in abnormal wound healing. Consequently, a late-phase inflammatory relapse could appear in the long term after DES implantation. In this study, we measured serum levels of inflammatory markers, including interleukin (IL)-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metalloproteinase-9, and myeloperoxidase, as well as high-sensitivity C-reactive protein at follow-up coronary angiography (mean 9 months) in 54 patients who received DES stenting who did not experience restenosis, and compared them with 51 patients receiving bare-metal stents (BMS) without restenosis. The level of IL-6 was over the measurement threshold (≥2.22 pg/ml) in 12 patients (21 %) in the DES group, but in only 2 patients (4 %) in the BMS group (P = 0.003). IL-8 was significantly higher in the DES group than in the BMS group (4.51 ± 2.40 vs 3.84 ± 1.34 pg/ml, P = 0.015). The levels of other biomarkers were similar between the two groups. DES showed an increase in inflammatory cytokines in the late phase after implantation in comparison with patients who received BMS, suggesting late-stage inflammation. Therefore, the wound-healing response after DES implantation might be different from that after BMS.

Pathophysiological roles of the serum acylcarnitine level and acylcarnitine/free carnitine ratio in patients with cardiovascular diseases.

Introduction: L-carnitine exerts protective effects, such as maintaining mitochondrial functions and decreasing reactive oxygen species, while acylcarnitine (AC) is linked to the development of heart failure and atherosclerosis. Hypothesis: Serum carnitines play important pathophysiological roles in cardiovascular diseases. Methods: Pre-operative biochemical data were obtained from 117 patients (71 men, average age 69.9 years) who underwent surgery for cardiovascular diseases. Measurements included pre-operative biochemical data including estimated glomerular filtration rate (eGFR), physical functions, skeletal muscle mass index (SMI) measured by bioelectrical impedance analysis, anterior thigh muscle thickness (MTh) measured by ultrasound, and routine echocardiography. Carnitine components were measured with the enzyme cycling method. Muscle wasting was diagnosed based on the Asian Working Group for Sarcopenia criteria. Results: Plasma brain natriuretic peptide (BNP) level was correlated with serum free carnitine (FC) and AC level, and the acylcarnitine/free carnitine ratio (AC/FC). AC/FC was elevated with stage of chronic kidney disease. In multivariate analysis, log (eGFR) and log (BNP) were extracted as independent factors to define log (serum AC) (eGFR: ß = 0.258, p = 0.008; BNP: ß = 0.273, p = 0.011), even if corrected for age, sex and body mass index. AC/FC was negatively correlated with hand-grip strength (r = -0.387, p = 0.006), SMI (r = -0.314, p = 0.012), and anterior thigh MTh (r = -0.340, p = 0.014) in men. Conclusions: A significant association between serum AC level and AC/FC, and chronic kidney disease and heart failure exists in patients with cardiovascular diseases who have undergone cardiovascular surgery. Skeletal muscle loss and muscle wasting are also linked to the elevation of serum AC level and AC/FC.

Physiological Role of Serum Growth Differentiation Factor-15 (GDF-15) Level and Iron Metabolism in Community-Dwelling Older Adults.

Background Anemia is common in older adults and, together with heart failure and chronic kidney disease, forms a vicious cycle, whereas diseases such as chronic inflammation and cancer are associated with the anemia of chronic disease (ACD). Researchers have linked growth differentiation factor-15 (GDF-15) to a variety of conditions such as cardiovascular disease, inflammation, cancer, and kidney disease, and have reported hepcidin as a biomarker for iron regulation in ACD. Therefore, anemia, GDF-15, and hepcidin have significance in aging physiology. Hypothesis GDF-15 and hepcidin play important physiological roles in community-dwelling older adults. This study sought to explore the relationship between these biomarkers and anemia, inflammation, or other health outcomes. Methods This was a prospective study of 73 community-dwelling older adults (six men and 67 women, mean age of 76.3 years). Their serum iron level, percentage transferrin saturation (TSAT), high-sensitivity C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) were measured. Enzyme-linked immunosorbent assays were used to assess their serum GDF-15, ferritin, and hepcidin levels. The participants' grip strength and walking speed were measured. The skeletal muscle mass index (SMI) of each participant was determined by bioelectrical impedance analysis. Results The GDF-15 level was significantly inversely correlated with serum iron, ferritin, and hepcidin levels; percentage TSAT; the eGFR; and gait speed. Serum hepcidin was positively correlated with levels of ferritin, albumin, and hemoglobin. Handgrip strength, SMI, and hs-CRP were not correlated with either GDF-15 or hepcidin levels. After adjusting for age, sex, and body mass index (BMI), multivariate analysis identified the log GDF-15 and serum iron level (log GDF-15: ß=-0.248, iron: ß=0.296) as significant factors determining hemoglobin levels, whose findings have significance due to novel results. Multivariate analysis identified eGFR and levels of hemoglobin and hepcidin as significant factors associated with log GDF-15 (eGFR: ß=-0.406, hemoglobin: ß=-0.269, hepcidin: ß=-0.235). Similarly, ferritin and albumin levels were identified as significant factors associated with hepcidin levels (ferritin: ß=0.590, Alb: ß=0.277). Conclusions Anemia in community-dwelling older adults was determined not only by increasing serum iron levels but also by decreasing GDF-15 levels. Also, the increasing GDF-15 level was determined by a decreasing hepcidin level as well as the presence of anemia and renal dysfunction, and the decreasing hepcidin level was determined by decreasing stored iron and decreasing albumin levels. Serum GDF-15 and hepcidin could potentially inform diagnostic or treatment strategies for anemia or age-related health conditions.

Left atrial reservoir strain is a marker of atrial fibrotic remodeling in patients undergoing cardiovascular surgery: Analysis of gene expression.

Left atrial strain (LAS) measured by two-dimensional speckle tracking echocardiography (2DSTE) is considered to be a marker of LA structural remodeling, but it remains unsettled. We investigated the potential usefulness and clinical relevance of LAS to detect atrial remodeling including fibrosis by analyzing gene expression in cardiovascular surgery patients. Preoperative 2DSTE was performed in 131 patients (92 patients with sinus rhythm [SR] patients including paroxysmal AF [PAF], 39 atrial fibrillation [AF]) undergoing cardiovascular surgery. Atrial samples were obtained from the left atrial appendages, and mRNA expression level was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR) in 59 cases (24 PAF, 35 AF). Mean value of left atrial reservoir strain (mLASr) correlated with left atrial volume index (LAVI), and left atrial conduit strain (mLAScd). mLASr also correlated with left atrial contractile strain (mLASct) in SR patients including PAF. mLASr was significantly lower, and LAVI was higher, in the AF group, compared with SR patients including PAF. The expression of COL1A1 mRNA encoding collagen type I α1 significantly increased in AF patients (p = 0.031). mLASr negatively correlated with COL1A1 expression level, and multivariate regression analysis showed that mLASr was an independent predictor of atrial COL1A1 expression level, even after adjusting for age, sex, and BMI. But, neither mLAScd / mLASct nor LAVI (bp) correlated with COL1A1 gene expression. The expression level of COL1A1 mRNA strongly correlated with ECM-related genes (COL3A1, FN1). It also correlated ECM degradation-related genes (MMP2, TIMP1, and TIMP2), pro-fibrogenic cytokines (TGFB1 encoding TGFß1, END1, PDGFD, CTGF), oxidant stress-related genes (NOX2, NOX4), ACE, inflammation-related genes (NLRP, IL1B, MCP-1), and apoptosis (BAX). Among the fibrosis-related genes examined, univariable regression analysis showed that log (COL1A1) was associated with log (TGFB1) (adjusted R2 = 0.685, p<0.001), log (NOX4) (adjusted R2 = 0.622, p<0.001), log (NOX2) (adjusted R2 = 0.611, p<0.001), suggesting that TGFB1 and NOX4 was the potent independent determinants of COL1A1 expression level. mLASr negatively correlated with the ECM-related genes, and fibrosis-related gene expression level including TGFB1, NOX2, and NLRP3 in PAF patients. PAF patients with low mLASr had higher expression of the fibrosis-related gene expression, compared with those with high mLASr. These results suggest that LASr correlates with atrial COL1A1 gene expression associated with fibrosis-related gene expression. Patients with low LASr exhibit increased atrial fibrosis-related gene expression, even those with PAF, highlighting the utility of LAS as a marker for LA fibrosis in cardiovascular surgery patients.