Ning-I Yang

Late-Outgrowth Endothelial Cells Attenuate Intimal Hyperplasia Contributed by Mesenchymal Stem Cells After Vascular Injury

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<0.001) and a 6.3-fold increase in vivo (P<0.001). In all animal models, a significant amount of MSCs contributed to intimal hyperplasia after vascular injury. MSCs were able to differentiate into cells of endothelial or smooth muscle lineage. Coculture experiments demonstrated that late-outgrowth endothelial cells (OECs) guided MSCs to differentiate toward an endothelial lineage through a paracrine effects. In vivo, cell therapy with OECs significantly attenuated the thickness of the neointima contributed by MSCs (intima/media ratio, from 3.2±0.4 to 0.4±0.1, P<0.001). 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.

Aerobic Interval Training Elicits Different Hemodynamic Adaptations Between Heart Failure Patients with Preserved and Reduced Ejection Fraction.

ObjectiveThis 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). DesignOne 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. ResultsAerobic 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. ConclusionsAerobic 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.

Edema index established by a segmental multifrequency bioelectrical impedance analysis provides prognostic value in acute heart failure.

Objectives 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). Methods 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. Results 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). Conclusion 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.

Echocardiographic Assessment of Structural and Functional Cardiac Remodeling in Patients with Predialysis Chronic Kidney Disease

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)

TSOC-HFrEF Registry: A Registry of Hospitalized Patients with Decompensated Systolic Heart Failure: Description of Population and Management

INTRODUCTION Heart failure (HF) is a medical condition with a rapidly increasing incidence both in Taiwan and worldwide. The objective of the TSOC-HFrEF registry was to assess epidemiology, etiology, clinical management, and outcomes in a large sample of hospitalized patients presenting with acute decompensated systolic HF. METHODS The TSOC-HFrEF registry was a prospective, multicenter, observational survey of patients presenting to 21 medical centers or teaching hospitals in Taiwan. Hospitalized patients with either acute new-onset HF or acute decompensation of chronic HFrEF were enrolled. Data including demographic characteristics, medical history, primary etiology of HF, precipitating factors for HF hospitalization, presenting symptoms and signs, diagnostic and treatment procedures, in-hospital mortality, length of stay, and discharge medications, were collected and analyzed. RESULTS A total of 1509 patients were enrolled into the registry by the end of October 2014, with a mean age of 64 years (72% were male). Ischemic cardiomyopathy and dilated cardiomyopathy were diagnosed in 44% and 33% of patients, respectively. Coronary artery disease, hypertension, diabetes, and chronic renal insufficiency were the common comorbid conditions. Acute coronary syndrome, non-compliant to treatment, and concurrent infection were the major precipitating factors for acute decompensation. The median length of hospital stay was 8 days, and the in-hospital mortality rate was 2.4%. At discharge, 62% of patients were prescribed either angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers, 60% were prescribed beta-blockers, and 49% were prescribed mineralocorticoid receptor antagonists. CONCLUSIONS The TSOC-HFrEF registry provided important insights into the current clinical characteristics and management of hospitalized decompensated systolic HF patients in Taiwan. One important observation was that adherence to guideline-directed medical therapy was suboptimal.

Effect of multidisciplinary disease management for hospitalized heart failure under a national health insurance programme.

Aim 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. Methods 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. Results 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 &bgr;-blockers. A stratified analysis showed that MDP combined with guideline-based medication had synergistic effects. Conclusions 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.

Role of Coronary Spasm for a Positive Noninvasive Stress Test Result in Angina Pectoris Patients Without Hemodynamically Significant Coronary Artery Disease

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.

Comparison of Clinical Characteristics and Prognosis in Taiwanese Patients With Coronary Vasospastic Angina Pectoris Without Significant Fixed Coronary Artery Disease Versus Patients With Significant Fixed Coronary Artery Disease and Either Stable Angina Pectoris or Acute Coronary Syndromes

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.

Real-time three-dimensional echocardiography provides advanced haemodynamic information associated with intra-dialytic hypotension in patients with autonomic dysfunction

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.

Three-dimensional echocardiographic assessment of left ventricular remodeling in predialysis chronic kidney disease patients

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.