Yi-Lwun Ho

The relationship between serum galectin-3 and serum markers of cardiac extracellular matrix turnover in heart failure patients

BACKGROUND A growing body of evidence links macrophage activation and fibrosis to the pathogenesis of heart failure (HF). Galectin-3 is one of the most likely mediators between macrophage activation and myocardial fibrosis. However, the exact relationship is unknown in humans. We assessed the impact of galectin-3 on serum markers of cardiac extracellular matrix (ECM) turnover in HF patients. METHODS Patients with HF manifestations and a left ventricular ejection fraction (LVEF) <or=50% were enrolled in this study. Gender, age, medications, serum biochemical data, and outcomes of heart failure were recorded. Serum galectin-3, extracellular matrix including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2 (MMP-2), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. RESULTS A total of 106 (83 males and 23 females) patients were enrolled. The age was 61+/-16 y and LVEF was 35+/-9%. Their mean NYHA functional class was 2.2. Log galectin-3 was significantly correlated with log PIIINP (p=0.006), log TIMP-1 (p=0.025), log MMP-2 (p=0.016), and NYHA functional class (p=0.034); but not age, sex or LVEF. After adjusting for age, sex, smoking status and LVEF, the relationship between galectin-3 and ECM turnover biomarkers (including PIIINP, TIMP, and MMP-2) remained significant. After adjusting for age, sex, smoking status and NYHA functional class, the relationship between galectin-3 and PIIINP or MMP-2 remained significant. CONCLUSIONS Galectin-3 is significantly correlated with serum markers of cardiac ECM turnover in HF patients. This implies a relationship between macrophage activation and ECM turnover in patients with HF.

Assessment of coronary artery disease in women by dobutamine stress echocardiography: Comparison with stress thallium-201 single-photon emission computed tomography and exercise electrocardiography

BACKGROUND Dobutamine stress echocardiography (DSE) is sensitive and specific in detecting myocardial ischemia of male patients. However, there have been few reports about the use of DSE for the detection of coronary artery disease (CAD) in women. METHODS DSE was evaluated in 51 consecutive women who underwent concomitant quantitative coronary angiography. Forty-four of the 51 patients received stress thallium-201 single-photon emission computed tomography (SPECT), and 30 of the 51 patients had interpretable results (exercise level > or = 85% of age-predicted maximal heart rate) of treadmill exercise. Twenty-nine patients had angiographically documented CAD defined as > or = 50% diameter stenosis. RESULTS The overall sensitivity of DSE and stress 201Tl SPECT in detecting CAD was 93% and 79% (p = nonsignificant), and the specificity was 82% and 75% (p = nonsignificant), respectively. A combination of both tests increased the sensitivity (96%) at the expense of some decrease in specificity (60%). The agreement of DSE and 201Tl SPECT was 68% (30 of 44; kappa statistic = 0.35; p < 0.0001). The overall sensitivity, specificity, and accuracy in detecting CAD by treadmill exercise test and DSE were 71% vs 93% (p = nonsignificant), 44% vs 82% (p = 0.036), and 57% vs 88% (p = 0.003). In patients with abnormal results of treadmill exercise testing, the false-positive rate in detecting CAD was 2 (18%) of 11 in patients with abnormal results of DSE and 7 (88%) of 8 in those with normal results of DSE (p = 0.005). In patients with normal results of treadmill exercise testing, the false-negative rate in detecting CAD was 4 (100%) of 4 in patients with abnormal results of DSE and 0 (0%) of 7 in those with normal results of DSE (p = 0.003). CONCLUSION The diagnostic accuracy of DSE was similar to that of stress 201Tl SPECT in women. DSE was able to stratify female patients with either abnormal or normal results of treadmill exercise testing and to avoid unnecessary cardiac catheterization.

The Prognostic Value of Non-Linear Analysis of Heart Rate Variability in Patients with Congestive Heart Failure—A Pilot Study of Multiscale Entropy

Aims The influences of nonstationarity and nonlinearity on heart rate time series can be mathematically qualified or quantified by multiscale entropy (MSE). The aim of this study is to investigate the prognostic value of parameters derived from MSE in the patients with systolic heart failure. Methods and Results Patients with systolic heart failure were enrolled in this study. One month after clinical condition being stable, 24-hour Holter electrocardiogram was recording. MSE as well as other standard parameters of heart rate variability (HRV) and detrended fluctuation analysis (DFA) were assessed. A total of 40 heart failure patients with a mea age of 56±16 years were enrolled and followed-up for 684±441 days. There were 25 patients receiving β-blockers treatment. During follow-up period, 6 patients died or received urgent heart transplantation. The short-term exponent of DFA and the slope of MSE between scale 1 to 5 were significantly different between patients with or without β-blockers (p = 0.014 and p = 0.028). Only the area under the MSE curve for scale 6 to 20 (Area6–20) showed the strongest predictive power between survival (n = 34) and mortality (n = 6) groups among all the parameters. The value of Area6–20 21.2 served as a significant predictor of mortality or heart transplant (p = 0.0014). Conclusion The area under the MSE curve for scale 6 to 20 is not relevant to β-blockers and could further warrant independent risk stratification for the prognosis of CHF patients.

Conditional expression of a myocardium-specific transgene in zebrafish transgenic lines

To develop the first heart‐specific tetracycline (Tet)‐On system in zebrafish, we constructed plasmids in which the cardiac myosin light chain 2 promoter of zebrafish was used to drive the reverse Tet‐controlled transactivator (rtTA) and the green fluorescent protein (GFP) reporter gene was preceded by an rtTA‐responsive element. In the zebrafish fibroblast cell‐line, rtTA‐M2, one of rtTAs derivatives, demonstrated the highest increase in luciferase activity upon doxycycline (Dox) induction. We then generated two germ lines of transgenic zebrafish: line T03 was derived from microinjection of a plasmid containing rtTA‐M2 and a plasmid containing a responsive reporter gene, whereas line T21 was derived from microinjection of a single dual plasmid. Results showed that line T21 was superior to line T03 in terms of greater GFP intensity after induction and with of minimal leakiness before induction. The photographic images of induced GFP in the heart of F2 larvae showed that the fluorescent level of GFP was dose‐responsive. The level of GFP expressed in the F3 3 days postfertilization larvae that were treated with Dox for 1 hr decreased gradually after the withdrawal of the inducer; and the fluorescent signal disappeared after 5 days. The GFP induction and reduction were also tightly controlled by Dox in the F3 adult fish from line T21. This Tet‐On system developed in zebrafish shows much promise for the study of the gene function in a specific tissue at the later developmental stage. Developmental Dynamics 233:1294–1303, 2005.

Adrenalectomy improves increased carotid intima-media thickness and arterial stiffness in patients with aldosterone producing adenoma.

CONTEXT Primary aldosteronism (PA) is the most frequent cause of secondary hypertension, and is associated with more prominent vascular stiffness and atherosclerosis. However, the effect of adrenalectomy on reversibility of vascular damage is unclear. OBJECTIVE Our objective was to investigate the vascular changes and possibility of reversibility after adrenalectomy in PA patients. METHODS We prospectively analyzed 20 patients with aldosterone producing adenoma (APA) that received adrenalectomy from October 2006 to December 2008 and 21 patients with essential hypertension (EH) were enrolled as the control group. Carotid intima media thickness (CIMT) measurement by B-mode ultrasound of the right common carotid arteries and pulse wave velocity (PWV) measurement including brachial-ankle PWV (baPWV) and heart-ankle PWV (haPWV) were performed in both groups. The follow-up measurements were performed one-year after adrenalectomy in APA group. RESULTS APA patients had significantly higher diastolic blood pressure, plasma aldosterone concentration (PAC) and aldosterone-renin ratio (ARR), but lower serum potassium level and plasma renin activity (PRA) than EH patients. APA patients had significantly higher CIMT (0.64±0.13 vs. 0.53±0.10 mm, p=0.006), higher baPWV (1589±296 vs. 1405±187 cm/s, p=0.024) and haPWV (1095±150 vs. 987±114 cm/s, p=0.013) comparing with EH patients. One-year after adrenalectomy, CIMT reduced significantly from 0.64±0.13 mm to 0.59±0.14 mm (p=0.014), and baPWV and haPWV also showed significant reduction (baPWV, 1589±296 to 1463±188 cm/s, p=0.035; haPWV, 1095±150 to 1017±109 cm/s, p=0.019). CONCLUSION APA patients have higher degree of early atherosclerosis and vascular stiffness. Adrenalectomy not only corrects the high blood pressure and biochemical parameters but also reverse adverse vascular change in APA patients.

Adrenalectomy reverses myocardial fibrosis in patients with primary aldosteronism.

Objective: Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with more prominent left ventricular hypertrophy and increased myocardial fibrosis. However, the reversibility of cardiac fibrosis is still unclear. Our objective was to investigate myocardial fibrosis in primary aldosteronism patients and its change after surgery. Method: We prospectively analyzed 20 patients with aldosterone-producing adenoma (APA) who received adrenalectomy from December 2006 to October 2008 and 20 patients with essential hypertension were enrolled as the control group. Plasma carboxy-terminal propeptide of procollagen type I (PICP) determination and echocardiography including ultrasonic tissue characterization by cyclic variation of integrated backscatter (CVIBS) were performed in both groups and 1 year after operation in the APA group. Results: APA patients had significantly higher SBP and DBP, higher plasma aldosterone concentration (PAC), higher aldosterone–renin ratio (ARR), lower serum potassium levels, and lower plasma renin activity (PRA) than patients with essential hypertension. In echocardiography, APA patients had a higher left ventricular mass index than essential hypertension patients. APA patients had significantly lower CVIBS (6.2 ± 1.5 vs. 8.7 ± 2.0 dB, P < 0.001) and higher plasma PICP levels (107 ± 27 vs. 85 ± 24 &mgr;g/l, P = 0.009) than essential hypertension patients. In the correlation study, CVIBS is correlated with log-transformed PRA and log-transformed ARR and PICP is correlated with log-transformed PRA, log-transformed PAC, and log-transformed ARR. One year after adrenalectomy, CVIBS increased significantly (6.2 ± 1.5 to 7.3 ± 1.7 dB, P = 0.033) and plasma PICP levels decreased (107 ± 27 vs. 84 ± 28 &mgr;g/l, P = 0.026). Conclusion: Increases in collagen content in the myocardium of APA patients may be reversed by adrenalectomy.

Time-dependent benefit of initial thrombosuction on myocardial reperfusion in primary percutaneous coronary intervention

Background:  In ST‐segment elevation acute myocardial infarction (STEMI), dislodgement of thrombus within the culprit artery during primary percutaneous coronary intervention (PCI) may cause distal embolisation and impaired myocardial reperfusion. Clinical results of thromboembolic protection strategies have been controversial. We conducted this study to investigate whether the benefit of thrombus removal is time dependent.

Reversal of myocardial fibrosis in patients with unilateral hyperaldosteronism receiving adrenalectomy

BACKGROUND Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with more prominent left ventricular hypertrophy and increased myocardial fibrosis. Unilateral hyperaldosteronism can be cured by adrenalectomy. However, the reversibility of cardiac fibrosis is still unclear. METHODS We analyzed 11 patients prospectively with unilateral hyperaldosteronism (including 10 aldosterone-producing adenomas and 1 unilateral nodular hyperplasia) who received adrenalectomy from October 2006 to October 2007, and 17 patients with essential hypertension (EH) were enrolled as the control group. Echocardiography included ultrasonic tissue characterization by cyclic variation of integrated backscatter; it was performed in both groups and 1 year after operation in the unilateral hyperaldosteronism group. RESULTS Patients with unilateral hyperaldosteronism had significantly higher diastolic blood pressure, higher plasma aldosterone concentration, lower serum potassium level, and lower plasma renin activity than patients with EH. In echocardiography, patients with unilateral hyperaldosteronism had thicker interventricular septal thickness, left ventricular posterior wall thickness, and higher left ventricular mass index than EH patients. Patients with unilateral hyperaldosteronism had significant lower cyclic variation of integrated backscatter than EH patients (7.1 ± 2.1 vs 8.7 ± 1.5 dB, P = .037). After analyzing the correlation of cyclic variation of integrated backscatter with clinical parameters for all participants, only log-transformed plasma renin activity was correlated significantly with cyclic variation of integrated backscatter. One year after adrenalectomy, interventricular septal thickness, left ventricular posterior wall thickness, and left ventricular mass index decreased significantly. In addition, cyclic variation of integrated backscatter increased significantly after adrenalectomy (7.1 ± 2.1 to 8.5 ± 1.5 dB, P = .02). CONCLUSION Adrenalectomy not only reversed left ventricular geometry but also altered myocardial texture in patients with unilateral hyperaldosteronism. This finding implies that increases in collagen content in the myocardium of patients with unilateral hyperaldosteronism might be reversed by adrenalectomy.

Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms

AbstractMutations in cardiac potassium and sodium channel genes are responsible for several hereditary cardiac arrhythmia syndromes. We established a denaturing high-performance liquid chromatography (DHPLC) protocol for rapid mutation screening of these genes, and reported mutations and variations identified by this method. We included 28 patients with Brugada syndrome, 4 with congenital long QT syndrome (LQTS), 11 with drug-induced LQTS, 4 with idiopathic ventricular fibrillation, and 50 normal volunteers. Polymerase chain reactions were performed to amplify the entire coding region of these genes. DHPLC was used to screen for heteroduplexes then DNA sequencing was performed. With this method, we identified the mutation(s) in all four patients with congenital LQTS (KCNQ1 A341V, KCNH2 N633D, KCNH2 2768Cdel and KCNE1 K70 N Y81C double mutations). We also identified the SCN5A A551T mutation in 1 of the 28 patients with Brugada syndrome. All the above-mentioned mutations were novel except KCNQ1 A341V. No mutations were identified in patients with drug-induced LQTS or idiopathic ventricular fibrillation. In total, 25 single nucleotide polymorphisms were identified, 10 of which were novel. In conclusion, DHPLC is a sensitive and rapid method for detection of cardiac sodium and potassium channel gene mutations.

Complexity of heart rate variability predicts outcome in intensive care unit admitted patients with acute stroke

Background Heart rate variability (HRV) has been proposed as a predictor of acute stroke outcome. This study aimed to evaluate the predictive value of a novel non-linear method for analysis of HRV, multiscale entropy (MSE) and outcome of patients with acute stroke who had been admitted to the intensive care unit (ICU). Methods The MSE of HRV was analysed from 1 h continuous ECG signals in ICU-admitted patients with acute stroke and controls. The complexity index was defined as the area under the MSE curve (scale 1–20). A favourable outcome was defined as modified Rankin scale 0–2 at 3 months after stroke. Results The trends of MSE curves in patients with atrial fibrillation (AF) (n=77) were apparently different from those in patients with non-AF stroke (n=150) and controls (n=60). In addition, the values of complexity index were significantly lower in the patients with non-AF stroke than in the controls (25.8±.3 vs 32.3±4.3, p<0.001). After adjustment for clinical variables, patients without AF who had a favourable outcome were significantly related to higher complexity index values (OR=1.15, 95% CI 1.07 to 1.25, p<0.001). Importantly, the area under the receiver operating characteristic curve for predicting a favourable outcome of patients with non-AF stroke from clinical parameters was 0.858 (95% CI 0.797 to 0.919) and significantly improved to 0.903 (95% CI 0.853 to 0.954) after adding on the parameter of complexity index values (p=0.020). Conclusions In ICU-admitted patients with acute stroke, early assessment of the complexity of HRV by MSE can help in predicting outcomes in patients without AF.