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Background: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. Methods: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. Results: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m 2 and 63.8±14.0 g/m 2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was –0.30 g/m 2 (–2.1 to 1.5 g/m 2 ; P =0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20–105 pg/mL) and 55 pg/mL (21–132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were –1.3 mm Hg (–5.2 to 2.6 mm Hg; P =0.52), 0.69 mm Hg (–1.9 to 3.3 mm Hg; P =0.60), and –6.1 pg/mL (–37.0 to 24.8 pg/mL; P =0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. Conclusions: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04461041.

Few studies have demonstrated an association of sarcopenia-associated body measurements with chronic diseases through a comprehensive methodology. This study aims to examine the relationship between sarcopenia-associated body measurements and chronic diseases. This is a cohort study. We recruited 316 community dwellers, including 76 patients with sarcopenia and 240 controls, and obtained their body measurements associated with sarcopenia. We collected three-dimensional anthropometric body-surface measurements from 11,158 participants during 2000–2008 and followed up this cohort for 15 years to examine the association of these measurements with the risk of chronic diseases such as hypertension, type 2 diabetes mellitus (T2DM), heart disease, and nephrotic syndrome. Univariate analysis, canonical correlation, and Cox regression analysis were performed to explore the associations. Decreased waist width, upper left arm circumference, and left thigh circumference were significantly associated with sarcopenia. The adverse body measure score (ABMS) was derived by combining significant measurements, namely left upper arm circumference, waist width, and left thigh circumference, and used to predict the risk of hypertension, T2DM, heart diseases, and nephrotic syndrome. A positive association was observed between the ABMS and chronic diseases. Considering the first quartile of the ABMS as a reference, we determined hazard ratios of 2.259, 2.495, 1.332, and 1.595 for hypertension, T2DM, heart disease, and nephrotic syndrome, respectively, in the fourth quartile. Chronic diseases were more strongly associated with the ABMS than with sarcopenia-related body measurements alone. A high ABMS, which includes higher upper arm circumference, higher waist width, and lower thigh circumference, can significantly predict chronic diseases.

Heart failure (HF) is a major global healthcare problem with an estimated prevalence of approximately 26 million. In Asia-Pacific regions, HF is associated with a significant socioeconomic burden and high rates of hospital admission. Epidemiological data that could help to improve management approaches to address this burden in Asia-Pacific regions are limited, but suggest patients with HF in the Asia-Pacific are younger and have more severe signs and symptoms of HF than those of Western countries. However, local guidelines are based largely on the European Society of Cardiology and American College of Cardiology Foundation/American Heart Association guidelines, which draw their evidence from studies where Western patients form the major demographic and patients from the Asia-Pacific region are underrepresented. Furthermore, regional differences in treatment practices likely affect patient outcomes. In the following review, we examine epidemiological data from existing regional registries, which indicate that these patients represent a distinct subpopulation of patients with HF. In addition, we highlight that patients with HF are under-treated in the region despite the existence of local guidelines. Finally, we provide suggestions on how data can be enriched throughout the region, which may positively affect local guidelines and improve management practices.

Additional file 2. Table S2. Individual drug for study co-medication.

This investigation explored how aerobic interval training influences central or peripheral hemodynamic response(s) to exercise in patients with heart failure (HF) with preserved ejection fraction (HFpEF) or those with HF with reduced ejection fraction (HFrEF).One hundred twenty HF patients were divided into four groups: HFpEF and HFrEF with aerobic interval training (3-min intervals at 40% and 80% VO2peak for 30 mins/day, 3 days/wk for 12 wks) and general health care groups. Exercise hemodynamics in the heart, frontal cerebral lobe, and vastus lateralis muscle, and oxygenation in the frontal cerebral lobe and vastus lateralis muscle were measured before and after the intervention.Aerobic interval training significantly (1) improved pumping function with enhanced peak cardiac power index in the HFrEF group and improved diastolic function with reduction of the E/E' ratio in the HFpEF group, (2) increased blood distribution to the frontal cerebral lobe/vastus lateralis muscle and O2 extraction by vastus lateralis muscle during exercise in the HFpEF group compared with the HFrEF group, (3) heightened VO2peak in both HFpEF and HFrEF groups and lowered the VE/VCO2 slope in the HFpEF group, and (4) increased the Short Form-36 physical/mental component scores and decreased the Minnesota Living with Heart Failure questionnaire score in both HFpEF and HFrEF groups.Aerobic interval training effectively enhances cardiac hemodynamic response to exercise in HFrEF patients while increasing the delivery/use of O2 to exercising skeletal muscles and frontal cerebral lobe tissues in HFpEF patients, thereby improving global/disease-specific quality-of-life measures in these HF patients.

Background Identification of novel biomarkers is needed to improve the diagnosis and prognosis of heart failure (HF). Metabolic disturbance is remarkable in patients with HF. Objectives This study sought to assess the diagnostic and prognostic values of metabolomics in HF. Methods Mass spectrometry–based profiling of plasma metabolites was performed in 515 participants; the discovery phase study enrolled 51 normal control subjects and 183 HF patients, and the validation study enrolled 63 control subjects and 218 patients with stage C HF. Another independent group of 32 patients with stage C HF who recovered to New York Heart Association functional class I at 6 and 12 months was profiled as the “recovery” group. Results A panel of metabolites, including histidine, phenylalanine, spermidine, and phosphatidylcholine C34:4, has a diagnostic value similar to B-type natriuretic peptide (BNP). In the recovery group, the values of this panel significantly improved at 6 and 12 months. To evaluate the prognostic values, events were defined as the combined endpoints of death or HF-related re-hospitalization. A metabolite panel, which consisted of the asymmetric methylarginine/arginine ratio, butyrylcarnitine, spermidine, and the total amount of essential amino acids, provided significant prognostic values (p Conclusions Metabolomics demonstrate powerful diagnostic value in estimating HF-related metabolic disturbance. The profile of metabolites provides better prognostic value versus conventional biomarkers.

Background and aims Type 2 diabetes is a global health problem that is associated with a wide variety of vascular complications and associated morbidity and mortality. Klotho is an enzyme and transmembrane protein, and increasing evidence suggests that Klotho may contribute to reduced oxidative stress, improved endothelial function, and vasoprotection. To date, the physiological role of Klotho in vascular complications associated with diabetes is unclear. Methods We prospectively recruited 252 patients with type 2 diabetes, who visited an outpatient clinic at our hospital between 2009 and 2011. Patients in the top and bottom tertiles of circulating Klotho levels were enrolled for analysis. Results Of the 168 patients enrolled, 45.8% were male, the mean age was 57.2 years, and the average duration of diabetes was 7.58 years. In multiple regression analysis, a high Klotho level was associated with a reduced risk of developing coronary artery disease and cerebrovascular accidents. Klotho level was also an independent predictor for the development of macroangiopathies within the 7-year study period. Conclusions Our results suggest that circulating Klotho level is a predictor of long-term macrovascular outcomes in patients with type 2 diabetes.

Supplemental Digital Content is available in the text, The CHADS2, CHA2DS2-VASc, and R2CHADS2 scores are well-known predictors of stroke caused by atrial fibrillation (AF), but no studies have evaluated their use for stratifying all-cause mortality risk in patients discharged for systolic heart failure (SHF) with or without AF. This study analyzed data in the Taiwan Society of Cardiology—heart failure with reduced ejection fraction (TSOC-HFrEF) registry. These data were obtained by a prospective, multicenter, observational survey of patients treated at 21 medical centers in Taiwan after hospitalization for acute, pre-existing or new onset SHF from May, 2013 to October, 2014. During 1 year follow-up, 198 patients were lost follow-up, and final 1311 (86.8%) patients were included for further analysis. During the follow-up period, 250 (19%) patients died. Multivariate analysis revealed that body mass index, thyroid disorder, valvular surgery history, chronic kidney disease (CKD), and scores for CHADS2, CHA2DS2-VASc, and R2CHADS2 were significant independent predictors of mortality in the overall population of SHF patients (all P

Heart failure (HF) is a global health problem. The Taiwan Society of Cardiology-Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry was a multicenter, observational survey of patients admitted with HFrEF in Taiwan. The aim of this study was to report the one-year outcome in this large-cohort of hospitalized patients presenting with acute decompensated HFrEF.Patients hospitalized for acute HFrEF were recruited in 21 hospitals in Taiwan. A total of 1509 patients were enrolled into the registry by the end of October 2014. Clinical status, readmission rates and dispensed medications were collected and analyzed 1 year after patient index hospitalization.Our study indicated that re-hospitalization rates after HFrEF were 31.9% and 38.5% at 6 and 12 months after index hospitalization, respectively. Of these patients, 9.7% of them were readmitted more than once. At 6 and 12 months after hospital discharge, all-cause mortality rates were 9.5% and 15.9%, respectively, and cardiovascular mortality rates were 6.8% and 10.5%, respectively. Twenty-three patients (1.5%) underwent heart transplantation. During a follow-up period of 1 year, 46.4% of patients were free from mortality, HF re-hospitalization, left ventricular assist device use and heart transplantation. At the conclusion of follow-up, 57.5% of patients were prescribed either with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers; also, 66.3% were prescribed with beta-blockers and 40.8% were prescribed with mineralocorticoid receptor antagonists.The TSOC-HFrEF registry showed evidence of suboptimal practice of guideline-directed medical therapy and high HF re-hospitalization rate in Taiwan. The one-year mortality rate of the TSOC-HFrEF registry remained high. Ultimately, our data indicated a need for further improvement in HF care.

Background: Aging-associated functional impairment of endothelial progenitor cells (EPCs) contributes to delayed re-endothelialization after vascular injury and exaggerated intimal hyperplasia (IH). This study tested if bone marrow (BM) rejuvenation accelerates post-injury re-endothelialization in aging mice. Methods and Results: Using BM transplantation (BMTGfp→Wild), youngGfp to youngWild (YTY), oldGfp to oldWild (OTO), youngGfp to oldWild (YTO), and oldGfp to youngWild (OTY) groups were created. After vascular injury, IH was significantly greater in the old group than the young group (P

Objective:This study investigated whether multidisciplinary disease management programs (MDPs) exert the same effects in heart failure (HF) patients across risk levels stratified by galectin-3 (Gal-3) level and what factors are associated with inadequate effectiveness of MDP.Methods:We used a longitudinal follow-up design based on a previous randomized trial. A total of 355 stabilized hospitalized HF patients were enrolled. The effects of MDP on death and HF-related rehospitalization were analyzed according to Gal-3 levels.Results:During the 4-year follow-up, Gal-3 levels predicted mortality and composite events ( p < .001). Multivariable analysis demonstrated the event-lowering effect of MDP (hazard ratio [HR] = 0.49, p = .001 for death and HR = 0.50, p < .001 for composite events). However, the effect of MDP was inadequate for those with high Gal-3 levels (≥17.9 ng/ml), whose 4-year composite event rate was 43% in the MDP arm. Further analysis showed that, in patients with Gal-3 ≥ 17.9 ng/ml, the independent factors associated with a high composite event rate were no MDP, older age, worse New York Heart Association functional class, no angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use, higher predischarge natriuretic peptide levels, and wider QRS complexes.Conclusions:The effectiveness of MDP for HF patients at high risk was inadequate. Our findings identified the characteristics of these MDP nonresponders. Better integration of advanced care plans based on strategies guided by Gal-3 level is needed to improve care quality.

The discovery of circulating endothelial progenitor cells (EPCs) opened up a new era of EPC-based therapies for cardiovascular diseases. While researchers are enthusiastic about applying EPCs to clinical therapy, progress has been substantially limited due to the lack of a thorough characterization and understanding of early and late outgrowth EPCs (also called endothelial colony-forming cell, ECFCs) biology. As a means of facilitating the understanding of how late EPCs can most effectively be applied to clinical therapeutics, this article reviews the recent progress covering 5 important issues: (1) The best passages of ex vivo-cultivated EPCs for cell therapy; (2) inflammatory activation of late EPCs: a real world consideration; (3) late EPC is not an endothelial cell: an issue of cell contamination; (4) ways to improve EPC function and differentiation; and (5) how to separate and delete smooth muscle progenitor cells (SPCs).Cardiovascular disease; Cell therapy; Endothelial progenitor cell; Smooth muscle progenitor cell.

A segmental multifrequency bioelectrical impedance analysis (SMBIA) is a noninvasive and reproducible modality for estimating the fluid state. The aim of this study was to test whether the SMBIA-derived edema index provides prognostic value in patients hospitalized due to acute heart failure (AHF).To estimate the 6-month prognostic value of the predischarge edema index in patients hospitalized due to AHF, 112 patients were consecutively enrolled. Both predischarge edema index and B-type natriuretic peptide (BNP) were measured. Outcome follow-up focused on heart failure-related and all-cause re-hospitalizations and all events.On the basis of a cutoff value of edema index of 0.390, patients were separated into two groups: edema index more than 0.390 (n = 44) and edema index of 0.390 or less (n = 68). Compared with patients with edema index 0.390 or less, those with edema index of more than 0.390 were older, had lower blood albumin and hemoglobin levels, and had higher predischarge BNP levels, functional class, incidence of diabetes mellitus, valvular cause, and diuretic use. Although edema indexes were correlated with BNP levels (r = 0.47, P 0.0001), a mismatch was noted in 33 (29%) patients. Univariate and multivariate analysis showed that an edema index of more than 0.390 predicted a higher incidence of heart failure-related re-hospitalization [odds ratio (OR) = 4.14, confidence interval (CI) = 1.05-15.28, P = 0.04] and all events (OR = 3.97, CI = 1.4-11.25, P = 0.01). The edema index provided a prognostic value superior to that of BNP. Reducing the edema index in high-risk patients resulted in fewer heart failure-related re-hospitalizations (OR = 0.81, CI = 0.77-0.84, P 0.001) and all events (OR = 0.8, CI = 0.76-0.85, P 0.001).Edema index provides 6-month prognostic values in patients hospitalized due to AHF. Reducing the edema index in high-risk patients results in better outcomes.

Although inhibition of Rho-associated coiled-coil containing protein kinase (ROCK) has been shown to prevent coronary vasospastic angina (CVA), direct evidence linking ROCK activity and CVA is lacking. Accordingly, we investigated whether ROCK activity is an independent marker for CVA and is altered after treatment with antispastic medications.We prospectively studied 31 Taiwanese patients who were diagnosed with CVA and 33 control subjects. Subject demographics were recorded, and blood samples were obtained at baseline in all participants and in CVA patients after 3 months of antispastic treatment. Compared with control subjects, leukocyte ROCK activity was greater in CVA patients (136% versus 91%, P0.001). A cutoff value for leukocyte ROCK activity of 104% predicted the presence of CVA with specificity and sensitivity rates of 88% and 84%, respectively. ROCK activity increased with the severity of CVA (P for trend0.001). Following 3-month treatment of antispastic agents, leukocyte ROCK activity, high-sensitivity C-reactive protein, and interleukin-6 levels were reduced by 43%, 42% and 27%, respectively (P0.05 for all).Increased levels of leukocyte ROCK activity independently predicted the presence of CVA and correlated with CVA severity. Treatment with antispastic agents substantially reduced the level of leukocyte ROCK activity.

Thyroid dysfunction has an important role in renal insufficiency. The aim of the study was to correlate the change of renal function with other clinical factors after thyroxine therapy in hypothyroid patients. A prospective study was designed and 30 hypothyroid patients were included. All study subjects received 0.15–0.2 mg/day thyroxine for 12 weeks. Diastolic blood pressure and serum levels of creatine phosphokinase (CPK) and myoglobulin decreased significantly after thyroxine therapy. Serum creatinine decreased (0.87 ± 0.22 vs. 0.70 ± 0.17 mg/dl, p < 0.001) and estimated glomerular filtration rate (eGFR) increased significantly (82.06 ± 31.08 vs. 100.31 ± 31.79 ml/min/1.73 m2; p < 0.001) after thyroxine replacement. Left ventricular ejection fraction (LVEF) was significantly increased after thyroxine replacement (64.47 ± 11.94 vs. 72.40 ± 13.89%, p = 0.026). No significant vascular functional changes of peripheral (pulse wave velocity) and renal interlobar arteries (pulsatility index and resistance index) were noted. The change of eGFR significantly correlated with the changes of serum-free T4 (fT4), CPK, myoglobulin and LVEF. The correlation between the change of eGFR and thyroid-stimulating hormone (TSH) level was not significant. In conclusion, the GFR of hypothyroid patients increased significantly after thyroxine replacement. The change of GFR was significantly correlated with the changes of fT4, CPK, myoglobulin and LVEF, but not with TSH.

Background: Cardiac remodeling has been demonstrated in patients on hemodialysis and in predialysis patients with chronic kidney disease (CKD). Using functional echocardiographic parameters to study the association of hemodynamic status and predialysis CKD has not yet been established. Methods: From November 2007 to September 2008, ninety-six patients (50 men and 46 women) with different stages of CKD were enrolled consecutively to undergo echocardiography. Group 1 consisted of 27 patients with mild CKD (CKD stages 1 and 2) and group 2 consisted of 69 patients with moderate/severe CKD (CKD stages 3–5). Results: Higher values were observed for the products of serum calcium and phosphorus, serum phosphorus, and intact parathyroid hormone; lower values were observed for hematocrit and serum albumin in group 2 patients. Higher mitral E and A velocities, longer isovolumic relaxation time, more prevalence of moderate-to-severe left ventricular (LV) diastolic dysfunction and higher mitral E/Em value were noted in group 2 patients. Eccentric left ventricular hypertrophy (LVH) had effects on systolic contraction disturbance in group 2 patients. CKD severity without LVH had effects on LV filling pressure elevation and relaxation impairment. Among biochemical and echocardiographic parameters, mitral E/Em was most independently associated with a diagnosis of moderate/severe CKD (odds ratio = 1.29, P = 0.023) and it was the most predictive variable with sensitivity and specificity values for a cutoff value of ≥13 of 64% and 74%, respectively. Conclusions: CKD severity without LVH increased LV filling pressure and impaired LV relaxation. Mitral E/Em was significantly associated with moderate/severe CKD. (Echocardiography 2010;27:621-629)

BACKGROUND Real-time three-dimensional echocardiography (RT3DE) has emerged as a more accurate and effective tool for assessing left ventricular (LV) function, compared to traditional two-dimensional (2D) methods. In this study, we used this new tool to revise the controversial relationship between LV function and intra-dialytic hypotension. METHODS This study enrolled 29 intra-dialytic hypotensive patients (the IDH group) and 34 controls (the CON group) on regular maintenance haemodialysis. The RT3DE- and 2D-derived ejection fraction (EF), stroke volume index (SVI) and ratio of early transmitral inflow velocity to diastolic early tissue velocity were assessed at pre-dialysis and mid-dialysis. The intravascular volume was assessed by the inferior vena cava collapsibility index. RESULTS Pre-dialysis evaluation showed no difference in RT3DE- and 2D-derived parameters between the two groups. At mid-dialysis, the IDH group had a lower 2D EF (54 +/- 9.1 versus 62 +/- 6.8% in the CON group, P < 0.001), RT3DE EF (53 +/- 6 versus 60 +/- 7% in the CON group, P < 0.001) and SVI (24.3 +/- 8 versus 30.6 +/- 12.2 mL in the CON group, P = 0.02). From pre-dialysis to mid-dialysis, the IDH group had greater decrease in the change in 2D EF (-4.8% +/- 12.6% versus 5% +/- 13.7% in the CON group, P = 0.004), RT3DE EF (-11.8 +/- 10.3 versus -3.4 +/- 11.5% in the CON group, P = 0.003) and SVI (-17.3 +/- 18.5 versus -9.2 +/- 19.8% in the CON group, P = 0.004). The calculated cardiac index change also showed a greater decrease in the IDH group (-17.8 +/- 20.2 versus -5.7 +/- 18.5% in the CON group, P = 0.02). No significant difference in the ratio of early transmitral inflow velocity to diastolic early tissue velocity, heart rate, systemic vascular resistance index or inferior vena cava collapsibility index was found between the two groups at the baseline or mid-dialysis. A lack of an increase in heart rate and the systemic vascular resistance index in the IDH group during the hypotensive episodes implies that these patients have autonomic dysfunction. Multivariate analysis showed that the RT3DE EF change of < -9.5% (odds ratio = 6, P = 0.003) and the presence of diabetes (odds ratio = 4.4, P = 0.013) had significant and independent associations with intra-dialytic hypotension. CONCLUSIONS By adopting RT3DE to assess LV performance, our data demonstrated that an inadequate compensation in the LV systolic function is the main mechanism mediating the occurrence of intra-dialytic hypotension in patients with autonomic dysfunction.

Background A positive noninvasive stress test result is often considered as a false-positive indicator of coronary artery disease (CAD) when coronary angiography reveals no hemodynamically significant CAD. Methods From January 2001 through December 2004, 5474 patients scheduled to undergo exercise electrocardiogram (ECG) [exercise ECG without imaging or exercise ECG with thallium-201 (201Tl) single photon emission tomography (SPECT)] or dipyridamole 201Tl tomography at our outpatient clinic because of chest oppressive sensation were included in this prospective study. Coronary angiography was performed when a noninvasive test result was positive for ischemia or when ischemic chest pain was suspected. Intracoronary methylergonovine testing was performed when spastic angina was suspected and coronary angiography showed no hemodynamically significant CAD. Results Noninvasive stress testing was positive in 113 (67%) patients with coronary spasm. Of the 53 patients who had positive exercise ECG (exercise ECG with or without imaging), ST depression was found in 50 patients and ST elevationin in 3 patients. Multivessel spasm was found in 6 (15%), 6 (15%), and 7 (21%) of the patients with a positive result on exercise ECG without imaging, exercise ECG with 201Tl SPECT, and dipyridamole 201Tl SPECT, respectively. There was no significant difference in the results of noninvasive stress testing and the number of vessels with coronary spasm (1-vessel spasm versus multivessel spasm) among these 3 noninvasive stress testing groups. Conclusion Intracoronary ergonovine testing induced coronary spasm in over 50% of patients who had suspected ischemic chest pain, a positive noninvasive stress test, and no hemodynamically significant CAD.

Background Limited information is available comparing the clinical characteristics and prognosis for patients with coronary vasospastic angina in the absence of hemodynamically significant coronary artery disease (CAD) (defined as >50% stenosis) versus patients with significant fixed CAD presenting with either stable angina pectoris (SAP) or acute coronary syndromes (ACS). Methods Patients who underwent cardiac catheterization for suspected ischemic heart disease between August 1999 and February 2003 were followed clinically. For patients without hemodynamically significant CAD, a provocation test for coronary vasospasm was undertaken using a step-wise dose of intracoronary ergonovine administration. Results A total of 1134 patients were enrolled in the final analysis and stratified into 4 diagnostically distinct groups: control group (n = 239; mild CAD without coronary vasospasm); vasospasm group (n = 284; coronary vasospastic angina pectoris without hemodynamically significant CAD); SAP group (n = 110; hemodynamically significant CAD with SAP); ACS group (n = 501; hemodynamically significant CAD with ACS). Comparison of these 4 groups revealed that the ACS patients were more likely to be male, current smokers, and have hypercholesterolemia. In addition, this group had a significantly higher incidence of typical angina pectoris, 3-vessel CAD, and lower left ventricular ejection fraction. Between-group comparison revealed that vasospasm patients had a significantly higher incidence of early morning angina pectoris. Multivariate analysis showed that current smoking was the most independent risk factor associated with the diagnosis of coronary vasospastic angina pectoris in patients without hemodynamically significant CAD. During a median follow-up period of 49 months, recurrent angina pectoris was noted in patients from the control (n = 6; 3%), SAP (n = 9; 8%), vasospasm (n = 30, 11%), and ACS groups (n = 92; 18%); with nonfatal myocardial infarction identified during follow-up in the SAP (n = 5; 5%), vasospasm (n = 3; 1%), and ACS groups (n = 37; 7%). In addition, 29 and 3 cardiac deaths occurred in the ACS and SAP groups, respectively, whereas there were no such mortalities in the control and vasospasm groups. Conclusions Early morning angina pectoris and cigarette smoking were the most common clinical characteristics in patients with coronary vasospasm. These patients had an excellent prognosis despite the possibility of recurrences of vasospastic angina pectoris.

Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, reduces cardiovascular events in patients with acute myocardial infarction. However, whether the beneficial effect of enalapril is mediated in part through endothelial progenitor cells (EPCs) has yet to be elucidated. This study investigated the role of the CD26/dipeptidylpeptidase IV (DPP IV) system in enalapril-modulated EPC mobilization. C57 BL/6 mice were divided into control and enalapril-treated groups. Peripheral EPCs were enumerated before and after ischemic stress. CD26/DPP IV activity and stroma-derived factor-1alpha (SDF-1alpha) levels were measured in the blood and the bone marrow. In response to ischemic stress, the enalapril group displayed a significant increase in circulating EPCs (with a 3.6-fold increase of sca-1+KDR+ cells and a 2.2-fold increase of c-kit+CD31+ cells versus controls at 12 h). Enalapril also caused a sixfold increase in the contribution of bone marrow-derived EPCs to the ischemia-induced neovascularization. In the bone marrow, enalapril did not alter CD26+ cell numbers; however, it did amplify DPP IV activity. In the blood, through the anti-inflammatory effect, enalapril significantly decreased CD26+ cell numbers, leading to a decrease in total DPP IV activity. These phenomena were associated with a lower SDF-1alpha concentration in the bone marrow but higher in the blood in the enalapril group, compared to the controls. All these findings were not demonstrated without ischemic stress. The effect of enalapril on EPC mobilization could be substantially blocked by Diprotin-A, a DDP IV antagonist. This study demonstrates that one of the pleiotropic effects of enalapril on the cardiovascular system involves the modulation of circulating EPC numbers via the CD26/DPP IV system, which may serve as a potential target for mobilizing EPCs for therapeutic purposes.

Background Exercise-induced ST-segment elevation is a relatively uncommon problem and occurs more frequently in patients who have had a myocardial infarction. Data is limited on the characteristics of Taiwanese patients without prior myocardial infarction who develop exercise-induced ST-segment elevation. Methods and Results Exercise-induced ST-segment elevation developed in 9 of 6,147 consecutive patients without myocardial infarction who underwent treadmill exercise testing at out institution over a 4-year period. The clinical and angiographic characteristics of these patients were studied. Angiographically normal coronary arteries with coronary vasospasm were found in 5 patients, hemodynamically significant coronary stenosis was found in 3 patients, and coexisting spasm in angiographically normal coronary arteries combined with hemodynamically significant coronary stenosis in the different vessel was found in 1 patient. During a median follow-up of 71 months, 2 patients with coronary vasospasm developed recurrent angina after self-discontinuation of calcium antagonists and 2 patients (1 with coronary vasospasm and 1 with hemodynamically significant coronary stenosis) died of cardiac causes before arrival at the emergency department. Conclusion Coronary vasospasm was a more common underlying pathology of exercise-induced ST-segment elevation in this Taiwanese cohort. Coronary angiography ± intracoronary ergonovine provocation testing is necessary in these patients to identify the underlying pathology and appropriate treatment. (Circ J 2006; 70: 254 - 261)

We prospectively investigated the relation of high-sensitivity C-reactive protein (hs-CRP) to coronary vasospasm and no hemodynamically significant coronary artery disease (CAD) in a sample of 428 patients who underwent coronary angiography. These patients were assigned to 1 of 3 groups. The control group consisted of 66 patients who had no coronary vasospasm and no hemodynamically significant CAD. The vasospasm group consisted of 116 patients who had coronary vasospasm and no hemodynamically significant CAD. The acute coronary syndrome (ACS) group consisted of 246 patients who had ACS and hemodynamically significant CAD. Serum hs-CRP was measured immediately before coronary angiography. Patients were followed for subsequent cardiac events and mortality. Median hs-CRP levels in the control, vasospasm, and ACS groups were 1.0, 5.5, and 8.2 mg/L, respectively. The proportion of hs-CRP increased from the lowest to the highest tertile in the control, vasospasm, and ACS groups, respectively. In the control and vasospasm groups, multivariate analysis showed that hs-CRP was independently associated with a diagnosis of coronary vasospastic angina pectoris (odds ratio 68.74, 95% confidence interval 8.03 to 588.71, p0.001). During a median follow-up period of 26 months (range 0.4 to 48), 27 cardiac deaths occurred in the ACS group, whereas no cardiac death occurred in the control and vasospasm groups. In conclusion, serum hs-CRP level measured immediately before coronary angiography was an independent marker of coronary vasospasm in patients who had no hemodynamically significant CAD.

Rationale: Metastatic cardiac tumor (MCT) is rare in clinical practice. MCT presenting initially as atrial fibrillation (AF) is even rarer. Patient concerns: We report a 47-year-old woman with no previous medical history presented with intermittent palpitation for 3 days. Diagnoses: The electrocardiography showed AF with rapid ventricular rate. The transthoracic echocardiography showed a 4 × 4 cm mass occupying the left atrium (LA). The contrast enhanced computed tomography (CT) showed a left lower lung mass with invasion to the LA and left upper pulmonary vein (PV). The chest CT guided biopsy revealed poorly differentiated squamous cell carcinoma. Further workup including bone scan showed no significant findings. The diagnosis of lung squamous cell carcinoma with cardiac invasion was made. Interventions: She went on to received palliative chemotherapy. Outcomes: She is being followed up regularly at the outpatient department. Lessons: Tumor invasion of the LA and PV was thought to be the cause of the AF. This condition is rare, but clinically important. Physicians should be alert that MCT could be an important differential diagnosis in patients presenting with unexplained AF.

Brain natriuretic peptide (BNP) has an established role in diagnosing heart failure (HF) and has shown to provide independent prognostic information. However, its prognostic value has limitations, leading to the development of other prognostic biomarkers such as ST2 and galectin-3 (1,2). With recent advances, we have gained more understanding into the bioactivity and metabolism of BNP. In different individuals, there are actually many BNP fragments in the circulation as a response to the degradation process.

Identification of novel biomarkers is needed to improve the diagnosis and prognosis of heart failure (HF). Metabolic disturbance is remarkable in patients with HF.This study sought to assess the diagnostic and prognostic values of metabolomics in HF.Mass spectrometry-based profiling of plasma metabolites was performed in 515 participants; the discovery phase study enrolled 51 normal control subjects and 183 HF patients, and the validation study enrolled 63 control subjects and 218 patients with stage C HF. Another independent group of 32 patients with stage C HF who recovered to New York Heart Association functional class I at 6 and 12 months was profiled as the "recovery" group.A panel of metabolites, including histidine, phenylalanine, spermidine, and phosphatidylcholine C34:4, has a diagnostic value similar to B-type natriuretic peptide (BNP). In the recovery group, the values of this panel significantly improved at 6 and 12 months. To evaluate the prognostic values, events were defined as the combined endpoints of death or HF-related re-hospitalization. A metabolite panel, which consisted of the asymmetric methylarginine/arginine ratio, butyrylcarnitine, spermidine, and the total amount of essential amino acids, provided significant prognostic values (p0.0001) independent of BNP and traditional risk factors. The prognostic value of the metabolite panel was better than that of BNP (area under the curve of 0.85 vs. 0.74 for BNP) and Kaplan-Meier curves (log rank: 17.5 vs. 9.95). These findings were corroborated in the validation study.Metabolomics demonstrate powerful diagnostic value in estimating HF-related metabolic disturbance. The profile of metabolites provides better prognostic value versus conventional biomarkers.

Multidisciplinary disease management programmes (MDPs) for heart failure have been shown to be effective in Western countries. However, it is not known whether they improve outcomes in a high population density country with a national health insurance programme.In total, 349 patients hospitalized because of heart failure were randomized into control and MDP groups. All-cause death and re-hospitalization related to heart failure were analyzed. The median follow-up period was approximately 2 years.Mean patient age was 60 years; 31% were women; and 50% of patients had coronary artery disease. MDP was associated with fewer all-cause deaths [hazard ratio (HR) = 0.49, 95% confidence interval (CI) = 0.27-0.91, P = 0.02] and heart failure-related re-hospitalizations (HR = 0.44, 95% CI = 0.25-0.77, P = 0.004). MDP was still associated with better outcomes for all-cause death (HR = 0.53, 95% CI = 0.29-0.98, P = 0.04) and heart failure-related re-hospitalization (HR = 0.46, 95% CI = 0.26-0.81, P = 0.007), after adjusting for age, diuretics, diabetes mellitus, chronic kidney disease, hypertension, sodium, and albumin. However, MDPs' effect on all-cause mortality and heart failure-related re-hospitalization was significantly attenuated after adjusting for angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers or β-blockers. A stratified analysis showed that MDP combined with guideline-based medication had synergistic effects.MDP is effective in lowering all-cause mortality and re-hospitalization rates related to heart failure under a national health insurance programme. MDP synergistically improves the effectiveness of guidelines-based medications for heart failure.

Background: Two fibrosis biomarkers, galectin-3 (Gal-3) and suppression of tumorigenicity 2 (ST2), provide prognostic value additive to natriuretic peptides and traditional risk factors in patients with heart failure (HF). However, it is to be investigated whether their combined measurement before discharge provides incremental risk stratification for patients after acute HF. Methods: A total of 344 patients with acute HF were analyzed with Gal-3, and ST2 measured. Patients were prospectively followed for 3.7 ± 1.3 years for deaths, and composite events (death/HF-related re-hospitalizations). Results: The levels of Gal-3 and ST2 were only slightly related (r = 0.20, p < 0.001). The medians of Gal-3 and ST2 were 18 ng/mL and 32.4 ng/mL, respectively. These biomarkers compensated each other and characterized patients with different risk factors. According to the cutoff at median values, patients were separated into four subgroups based on high and low Gal-3 (HG and LG, respectively) and ST2 levels (HS and LS, respectively). Kaplan-Meier survival curves showed that HGHS powerfully identified patients at risk of mortality (Log rank = 21.27, p < 0.001). In multivariable analysis, combined log(Gal-3) and log(ST2) was an in­dependent predictor. For composite events, Kaplan-Meier survival curves showed a lower event- -free survival rate in the HGHS subgroup compared to others (Log rank = 34.62, p < 0.001; HGHS vs. HGLS, Log rank = 4.00, p = 0.045). In multivariable analysis, combined log(Gal-3) and log(ST2) was also an independent predictor. Conclusions: Combination of biomarkers involving heterogeneous fibrosis pathways may identify patients with high systemic fibrosis, providing powerful risk stratification value.

Introduction: Little is known about the time-course changes in left ventricular myocardial deformation in patients with Takotsubo cardiomyopathy (TC) using layer-specific quantification of myocardial deformation assessed by 2-dimensional speckle tracking echocardiography (2DSTE). Case summary: In this retrospective 2DSTE follow-up study of 3 female patients with sepsis-induced TC, we examined changes in strain among the 3 myocardial layers, and examined the changes in left ventricular diastolic function and right ventricular systolic function. In all 3 patients, there was improvement of at least 15% in left ventricular ejection fractions, and improvement in left ventricular longitudinal and circumferential strains. The absolute differences in left ventricular global strains between the endocardium and epicardium, and between the first and the third 2DSTE studies reflect the following: a decrease in all 3 myocardial layers in patients with acute TC; and a slower improvement in mid-myocardial and epicardial function during recovery of TC. In addition, the right ventricular free wall strains were also impaired in the acute stage of TC with gradual improvement during recovery. Conclusions: Left ventricular strains did not fully recover even 1 month after acute TC. In addition, right ventricular free wall strains were also impaired in all 3 patients initially. In this case series, we found that layer-specific 2DSTE is a more sensitive method for myocardial function assessment than standard echocardiography.

The efficacy of heart failure (HF) management programs is compromised by the challenge of early identification of patients at imminent risk. Segmental multifrequency bioelectrical impedance analysis can generate an "edema index" (EI) as a surrogate for the body fluid status. In this study, we tested whether integration of EI-guided management improved the 6-month outcomes of HF patients under multidisciplinary care. In total, 159 patients with acute HF were randomized into control, case management (CM), and EI-guided CM (EI) groups (n = 53 in each group). In the EI group, a management algorithm was designed based on the measured EI. The analyzed endpoints included HF-related and all cause-related events during the 6-month follow-up period. In the 6 months, there were 11 (6.9%) deaths, 19 (11.9%) HF-related rehospitalizations, and 45 (28.3%) all-cause-related rehospitalizations. Compared to the control (26.4%) and CM groups (15.1%), the EI group had a lower rate of HF-related death and rehospitalization (3.8%, P = 0.004). Multivariate analysis revealed that EI-guided management was an independent predictor of a lower HF-related event rate (hazard ratio = 0.15, 95%CI = 0.03~0.66, P = 0.012). Patients with a higher pre-discharge EI were older, had lower blood albumin and hemoglobin levels, and had a higher functional class and incidences of diabetes mellitus and chronic kidney disease. An increase in the pre-discharge EI by 0.001 increased the HF-related event rate by 6% (P = 0.002). Use of EI-guided management lowered this risk (P = 0.03). In conclusion, an EI-based HF management program demonstrated an event-lowering effect superior to traditional nurse-led multidisciplinary care in 6 months after an acute HF episode.

Computed tomographic coronary angiography (CTA) is a non-invasive alternative to conventional coronary angiography (CCA) in detecting chronic coronary artery disease (CAD). However, the value of CTA in estimating acute myocardial infarction (AMI) has not been evaluated.CTA and CCA were performed on 10 patients with non-ST-elevated AMI and 17 patients with stable angina pectoris. The plaque components and stenosis severity were assessed by both modalities to clarify the diagnostic values of CTA in AMI and stable angina pectoris.A high total coronary artery calcium (CAC) score was significantly correlated with the presence of CAD and the target lesion CAC score (p0.01). The AMI group tended to have a lower target CAC score (p = 0.10) and target plaque burden (p = 0.27), compared to the stable angina pectoris group. To estimate the coronary artery stenotic severity, CTA and CCA had concordant correlations in all segments, except in the proximal left anterior descending (LAD) artery. The calcium score and calcification fraction percentage in the proximal LAD artery were significantly higher than those of other segments (p0.01). Compared to CCA, CTA overestimated the severity of stenosis in the proximal LAD arterial segment in the stable angina pectoris group (p = 0.028), but not in the AMI group.CTA has diagnostic values similar to those of CCA in detecting coronary lesions in patients with AMI or stable angina pectoris. However, a high level of plaque CAC in the stable angina pectoris group may lead to an overestimation of the severity of coronary stenosis, especially in the proximal LAD arterial segment. Although less remarkable, the impact of CAC on the diagnostic value of CTA was still substantial in patients with AMI.

Background The aim of this study was to investigate the relations of left ventricular (LV) mass and geometry to LV function in patients with predialysis chronic kidney disease (CKD), by real-time 3-dimensional echocardiography (RT3-DE). Methods Echocardiography was performed on 76 consecutively enrolled patients (51 men) with different stages of CKD, including 26 patients with mild CKD (CKD stages 1-2) and 50 patients with moderate-to-severe CKD (CKD stages 3-5). LV mass and LV end-diastolic volume were measured by RT3-DE. Results Greater prevalence of LV diastolic dysfunction and higher mitral E/myocardial velocities in early diastole (Em) values were noted in patients with moderate-to-severe CKD. In the moderate-to-severe CKD group, patients with increased LV mass had lower myocardial velocities in peak systole (Sm) and longer isovolumic relaxation time (IVRT). In the mild CKD group, patients with increased LV mass to volume ratios had lower Em. Moderate-to-severe CKD was associated with lower Sm and Em and higher mitral rapid filling to Em (E/Em) ratios by LV mass quartile stratification. Using LV mass/volume quartile stratification, moderate-to-severe CKD was associated with longer IVRT, lower Sm and higher mitral E/Em. Multivariable logistic regression analysis showed that CKD severity was the most independent predictor of elevated LV filling pressure (odds ratio = 2.96, p=0.019). Conclusions Increased LV mass impaired LV contraction and relaxation in patients with moderate-to-severe CKD. Concentric remodeling impaired LV diastolic function in patients with mild CKD. CKD severity was positively associated with elevated LV filling pressure.

An increased serum interleukin-6 (IL-6) level is associated with an increased risk of cardiovascular events in healthy subjects. However, it is unknown whether the level of serum IL-6 or genetic IL-6 polymorphism is correlated with the complexity of coronary plaque in patients with stable coronary artery disease (CAD). Patients with stable CAD (n = 135) were divided into 3 groups: insignificant coronary plaque (n = 77), simple coronary plaque (n = 15), and complex coronary plaque (n = 43). IL-6-174GC polymorphism and serum levels of IL-6 and C-reactive protein (CRP) were investigated. No significant difference in the distribution of IL-6 genotypes was found among the groups. The presence of complex coronary plaque was associated with higher serum concentrations of IL-6 (P = 0.026) and CRP (P0.0001). To predict the presence of complex lesions, IL-65.8 ng/L and CRP2.6 mg/L had sensitivities of 86% and 74%, and specificities of 61% and 62%, respectively. By multivariate analysis, IL-65.8 ng/L and CRP2.6 mg/L were independently related to the presence of complex coronary plaque (P = 0.0002 and 0.004, respectively). IL-65.8 ng/L and CRP2.6 mg/L were associated with a 4.5-fold increase in the odds of having complex coronary plaque (P0.005). A simple measurement of the serum IL-6 level in patients with CAD can potentially identify subjects with complex coronary lesions and provide the option of aggressive medical strategies in a clinical setting.

Background Little information is available regarding the relationship between three-dimensional (3-D) echocardiographic parameters in acute stage of acute myocardial infarction (AMI) and subsequent left ventricular (LV) remodeling after AMI. Methods Consecutive patients with AMI were analyzed for echocardiographic predictors of subsequent LV remodeling after AMI using two-dimensional (2-D) echocardiography and real-time 3-D echocardiography at baseline and month 3 of follow-up. LV adverse and favorable remodeling were defined as a >10% and ≤10% increase in 3-D derived LV end diastolic volume index (LVEDVI) at 3 months' follow-up compared with baseline, respectively. Results 19 AMI patients underwent real-time 3-D echocardiography at baseline and at 3 months after AMI. In patients with favorable remodeling (n = 12), baseline, LVEDVI, LV end-systolic volume index (LVESVI) and LV stroke volume index (LVSVI) were significantly increased compared with patients with adverse remodeling. At 3 months of follow-up, patients with favorable remodeling had significant 3-D LVEDVI, LVESVI, and systolic sphericity index reductions compared to patients with adverse remodeling in which these variables were increased. Baseline clinical and echocardiographic variables were analyzed for the identification of favorable LV remodeling. Of these, LVESVI was the most predictive variable with sensitivity, specificity, and positive and negative predictive values for a cutoff value of >42 mL/m2 of 75%, 71%, 75%, and 71%, respectively. Conclusions LVESVI assessed by 3-D echocardiography was the most predictive parameter indicating favorable LV remodeling after AMI. LV shape on contraction changed from elliptical shape to more globular in the adverse remodeling process after AMI.

Cyclosporin A (CsA) improves the success rate of transplantation. The CD26/dipeptidylpeptidase IV (DPP IV) system plays a critical role in mobilizing endothelial progenitor cells (EPCs) from bone marrow. This study investigated whether CsA manipulates CD26/DPP IV activity and increases EPC mobilization. C57BL/6 mice were divided into control and CsA-treated groups. Before and after hindlimb ischemia was induced, circulating EPC number and serum levels of different cytokines were measured. Compared with the controls, CsA treatment significantly increased the blood levels of stroma-derived factor-1α and stem cell factor after ischemic stress ( P < 0.001). The CsA group displayed a significant increase in the number of circulating EPCs (sca-1+KDR+ and c-kit+CD31+ EPCs, both P < 0.05). In vivo, CsA caused a significant increase in the numbers of EPCs incorporated into the Matrigel and ischemic limbs ( P < 0.05). In the peripheral blood, CsA significantly decreased CD26+ cell numbers and attenuated the plasma CD26/DPP IV activity ( P < 0.001). Furthermore, short-term CsA treatment significantly improved the perfusion of ischemic limbs and decreased the spontaneous digital amputation rate. In summary, CsA manipulates the mobilization of EPCs into the circulation via the CD26/DPP IV system. Short-term CsA treatment has beneficial effects on angiogenesis of ischemic tissues.

Objectives— Mesenchymal stem cells (MSCs) are one of a number of cell types undergoing extensive investigation for cardiac regeneration therapy. It has not yet been determined whether this cell therapy also substantially contributes to vascular remodeling of diseased vessels. Methods and Results— Human MSCs and a variety of progenitor and vascular cells were used for in vitro and in vivo experiments. Wire-induced vascular injury mobilized MSCs into the circulation. Compared with human aortic smooth muscle cells, MSCs exhibited a 2.8-fold increase in the adhesion capacity in vitro ( P P P Conclusions— Tissue regeneration therapy with MSCs or cell populations containing MSCs requires a strategy to attenuate the high potential of MSCs to develop intimal hyperplasia on diseased vessels.

Cyclosporine A (CsA), an immunosuppressant, has remarkably improved the short-term success rate of transplantation. The CD26/dipeptidylpeptidase IV (DPP IV) system plays a critical role in mobilizing endothelial progenitor cells (EPCs) from bone marrow. This study investigated whether CsA manipulates CD26/DPP IV activity and increases EPC mobilization. C57 BL/6 mice were divided into control and CsA-treated groups. Circulating EPCs were enumerated before and after hindlimb ischemia was induced. Levels of stroma-derived factor-1α (SDF-1α), stem cell factor (SCF), vascular endothelial grow factor (VEGF), and granulocyte-colony stimulating factor (G-CSF) were measured in the blood. Compared to the controls, CsA treatment significantly increased the serum levels of SDF-1α and SCF (p < 0.001), but not of VEGF or G-CSF after ischemic stress. The CsA group displayed a significant increase in the number of circulating EPCs (with a 7-fold increase in sca-1 + KDR + cells and a 1.5-fold increase in c-kit + CD31 + cells versus the controls at 18 h after ischemia was induced, both p < 0.05). In vivo , CsA also caused 2- and 5-fold increases in the numbers of bone marrow-derived EPCs incorporated into the Matrigel and ischemic limbs, respectively (p < 0.05). In the peripheral blood, CsA significantly decreased CD26 + cell numbers (p < 0.001) and attenuated the plasma CD26/DPP IV activity (p < 0.001). CsA did not alter the acitivty of MMP-2 or MMP-9 in vitro or in vivo . Compared to the controls, short-term CsA treatment significantly improved the perfusion of ischemic limbs and decreased the spontaneous digital amputation rate. In conclusions, this study demonstrated that CsA manipulates the mobilization of bone marrow-derived EPCs into the circulation via the CD26/DPP IV system. Short-term CsA treatment has beneficial effects on angiogensis of ischemic tissues.