Jen-Kuang Lee

Plasma levels of tumor necrosis factor-α and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase.

Objective:The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-&agr; and interleukin-6), diastolic heart failure, and the possible molecular mechanism. Design:Prospective case-controlled cohort and molecular studies. Setting:University hospital and research laboratory. Subjects:Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure. Interventions:Soluble plasma levels of tumor necrosis factor-&agr; and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-&agr; and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated. Measurements and Main Results:Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-&agr; and interleukin-6 than the control subjects. Significant correlations (p < .01 for each) were found for tumor necrosis factor-&agr; and E/Em (r = .87) and E/A (r = −0.69), and for interleukin-6 and E/Em (r = .80) and E/A (r = −0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-&agr;, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-&agr; and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes. Conclusions:Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions.

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.

Association of low glomerular filtration rate and albuminuria with peripheral arterial disease: The National Health and Nutrition Examination Survey, 1999–2004

Microalbuminuria may be an early sign of intra-renal vascular dysfunction and a marker of vascular risk in the general population as well as in high-risk individuals. However, the association between albuminuria and PAD has been demonstrated only in few small studies. The aim of current study is to evaluate the relative impact of albuminuria and glomerular filtration rate on the risk of peripheral artery disease (PAD) in a nationally representative sample population. Data (ankle brachial index [ABI], urine albumin, fasting glucose, and glomerular filtration rate [GFR] estimated using the Modification of Diet in Renal Disease [MDRD] Study equation) were collected on 7068 adults from the National Health and Nutrition Examination Survey (NHANES 1999-2004). PAD was defined as ABI <0.9 or >1.4. There was a trend towards an association between the presence of abnormal renal function (GFR<60mL/min/1.73m(2)) and PAD in the non-diabetic patients (OR of 1.43, 95% CI: 0.98-2.09; P=0.07) where as the presence of abnormal renal function was strongly associated PAD in the diabetic patients (OR of 2.3, 95% CI: 1.34-3.95; P=0.046). On the contrary, albuminuria was independently associated with PAD in the non-diabetic (OR, 1.87; 95% CI, 1.38-2.52; P=0.0003) but not in the diabetic patients (OR: 1.08, 95% CI: 0.68-1.73, P=0.7411). We concluded that albuminuria, independent of renal function, is strongly associated with PAD in non-diabetic subjects. As diabetes develops and HbA1c level increases, the predictive value of albuminuria gradually diminishes after adjustment for renal function.

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.

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.

Demonstrating the pharmacogenetic effects of angiotensin-converting enzyme inhibitors on long-term prognosis of diastolic heart failure

The objective of this study was to evaluate the effects of angiotensin-converting enzyme (ACE) inhibitors and pharmacogenetic interaction on the survival of the patients with diastolic heart failure (DHF). A total of 285 subjects with DHF confirmed by echocardiography were recruited in the period between 1995 and 2003. Baseline characteristics (age, sex, prior history, medication, and echocardiographic findings) and genetic polymorphisms (ACE gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphisms of the angiotensin II type I receptor (AT1R)) were collected and matched (by propensity score) in those who received and those who did not receive ACE inhibitors. The patients were followed up to 10 years. Kaplan–Meier curves and Cox regression models were used to demonstrate the survival trend. The 85 patients who received ACE inhibitors and the other 85 patients who did not were found to have comparable baseline characteristics and polymorphism distribution. Prescription of ACE inhibitors was associated with a significant decrease in overall mortality (hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.24–0.83; P=0.01), and a lower rate of cardiovascular events at 4000 days (HR, 0.53; 95% CI, 0.32–0.90; P=0.02). In addition, ACE I/D gene D allele was associated with higher overall mortality as compared with the I allele (HR, 2.04; P=0.003). This effect was diminished in those who received ACE inhibitors. The use of ACE inhibitor was associated with a significant decrease in long-term mortality and cardiovascular events in the patients with DHF. Genetic variants in the renin-angiotensin system genes were also associated, but their effects could be modified by the use of ACE inhibitors.

In-vitro recording of adult zebrafish heart electrocardiogram — A platform for pharmacological testing

BACKGROUND Recently zebrafish has become a powerful vertebrate model system for cardiac arrhythmia and another advantage is that the heart could be rapidly excised for in-vitro electrophysiological recording. METHODS We made direct in-vitro recordings of adult zebrafish heart ECG using the microelectrode and tested the effects of various drugs on zebrafish heart ECG. RESULTS The QT interval change in the ECG was verified by optically mapped action potential duration (APD). The mean in-vitro heart rate (HR) of the adult zebrafish was 118 ± 22 beats/min. The mean QT interval was 312 ± 36 ms and mean HR corrected QT interval (QTc) 439 ± 39 ms. The mean optically mapped APD was 308 ± 30 ms, which was close to the QT interval in ECG (p=0.815). We found that sympathomimetic drug isoproterenol increased HR, whereas L-type calcium channel blocker verapamil decreased HR. Sodium channel blocker quinidine and L-type calcium channel activator BayK8644 prolonged QTc interval in a dose-dependent manner (515 ± 24 ms and 519 ± 27 ms, respectively, both p<0.01). The APD was also prolonged accordingly. Both rapidly and slowly activating delayed rectifier potassium channel (IKr and IKs) blockers E4031 and chromanol 293B, respectively, also prolonged QTc interval in a dose-dependent manner (523 ± 25 ms and 529 ± 27 ms, respectively, both p<0.01). Quinidine, E4031 and chromanol 293B also decreased HR. CONCLUSIONS Direct in-vitro recording of adult zebrafish heart is an efficient platform for test of drugs which exert electrophysiological effects on cardiomyocytes, and perturbation of ionic channels that are responsible for human long QT syndrome also modulates QT interval in adult zebrafish heart.

Carotid stenting improves cognitive function in asymptomatic cerebral ischemia

OBJECTIVES Asymptomatic critical internal carotid artery (ICA) stenosis may lead to cognitive impairment. Carotid stenting (CS) may improve cerebral perfusion, but its impact on neuro-cognitive function has been controversial. METHODS We prospectively enrolled 34 asymptomatic patients with unilateral ICA stenosis or occlusion, in whom CS was attempted. Computed tomography cerebral perfusion (CTP), and functional assessments including National Institutes of Health Stoke Scale (NIHSS), Bathel Index (BI), and a battery of neuropsychological tests including Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive Subtest (ADAS-Cog), verbal fluency, and Color Trail Making A and B, were done prior to and 3 months after the procedure. RESULTS Successful CS was achieved in 28 of 34 patients (82%). Based on the baseline CTP finding and intervention result, patients were divided into three groups: group I (n=6) as ipsilateral cerebral ischemia with failed CS procedure, group II (n=17) as ipsilateral cerebral ischemia with successful CS procedure, and group III (n=11) as normal baseline CTP with successful CS procedure. The demographics and baseline cognitive performances were similar among the three groups. In group II, there were significant improvement in Alzheimer Disease Assessment Scale (pre 6.8 ± 4.3 vs post 4.9 ± 2.8, p=0.033), Mini-Mental State Examination Score (pre 25.8 ± 3.8 vs post 27.4 ± 3.5, p=0.007), and Color Trail test A (pre 120.4 ± 73.9s vs post 95.8 ± 57.6s, p=0.004) after CS. In groups I and III, however, no significant difference was observed in any of the cognitive tests. CONCLUSIONS Successful CS improves neurocognitive function in asymptomatic ICA stenosis or occlusion with objective ipsilateral ischemia.

The Relationship Among Central Obesity, Systemic Inflammation, and Left Ventricular Diastolic Dysfunction as Determined by Structural Equation Modeling

The purpose of this study was to investigate the associations among central obesity, inflammation, and left ventricular (LV) diastolic dysfunction by structural equation modeling. Echocardiographic parameters were assessed in 102 otherwise‐healthy adults over age 30. The participants were classified as having LV diastolic dysfunction by echocardiographic findings including mitral inflow E/A ratio <1, deceleration time >220 cm/s, or decreased peak annular early diastolic velocity in tissue Doppler imaging or otherwise the control group. Serum C‐reactive protein (CRP) and lipid profile were also measured. The homeostasis model of insulin resistance (HOMA) was calculated. Central obesity was assessed by computerized tomography (CT) at the L4 level. In a multivariate regression analysis, the relationship between visceral adipose tissue (VAT) and LV diastolic dysfunction became insignificant when CRP was introduced into the model, although CRP itself was significantly associated with LV diastolic dysfunction (odds ratio (OR): 1.32, 95% confidence interval (CI): 1.01–1.72, P = 0.04). A significant correlation was also found between VAT and CRP (r = 0.70; P < 0.001). We then performed path analysis as illustrated by the structural equation model. This proved our hypotheses that VAT might affect LV diastolic dysfunction through the effect of CRP (total fat load with inflammation (B = 1.133, P < 0.001) and that inflammation might affect LV diastolic dysfunction (B = 0.373. P < 0.001)). Using structural equation modeling, we concluded that higher amounts of VAT were associated with low‐grade inflammation and this may lead to subclinical LV diastolic dysfunction in otherwise‐healthy subjects.

The association of serum potassium level with left ventricular mass in patients with primary aldosteronism

Eur J Clin Invest 2011; 41 (7): 743–750