Wen-Jin Cherng

Short- and long-term results of catheter balloon percutaneous transvenous mitral commissurotomy

Percutaneous transvenous mitral commissurotomy (PTMC) was performed in 219 patients with symptomatic, severe rheumatic mitral stenosis. There were 59 men and 160 women, aged 19 to 76 years (mean 43). Pliable, noncalcified valves were present in 139 (group 1), and calcified valves or severe mitral subvalvular lesions, or both, in 80 patients (group 2). Atrial fibrillation was present in 133 patients (61%) and 1+ or 2+ mitral regurgitation in 59 (27%). Technical failure occurred with 3 patients in our early experience. There was no cardiac tamponade or emergency surgery. The only in-hospital death occurred 3 days after the procedure in a group 2 premoribund patient in whom last-resort PTMC created 3+ mitral regurgitation. Mitral regurgitation appeared or increased in 72 patients (33%); 3+ mitral regurgitation resulted in 12 patients (6%). There were 3 systemic embolisms. Atrial left-to-right shunts measured by oximetry developed in 33 patients (15%). Immediately after PTMC, there were significantly reduced (p = 0.0001) left atrial pressure (24.2 +/- 5.6 to 15.1 +/- 5.1 mm Hg), mean pulmonary artery pressure (39.7 +/- 13.0 to 30.6 +/- 10.9 mm Hg) and mitral valve gradient (13.0 +/- 5.1 to 5.7 +/- 2.6 mm Hg). Mitral valve area increased from 1.0 +/- 0.3 to 2.0 +/- 0.7 cm2 (p = 0.0001) and cardiac output from 4.4 +/- 1.4 to 4.7 +/- 1.2 liters/min (p less than 0.01). The results mirrored clinical improvements in 209 patients (97%). Multivariate analysis showed an echo score greater than 8, and valvular calcification and severe subvalvular lesions as independent predictors for suboptimal hemodynamic results.(ABSTRACT TRUNCATED AT 250 WORDS)

Rosiglitazone Facilitates Angiogenic Progenitor Cell Differentiation Toward Endothelial Lineage A New Paradigm in Glitazone Pleiotropy

Background—Peroxisome proliferator–activated receptor-&ggr; (PPAR-&ggr;) agonists inhibit vascular smooth muscle proliferation and migration and improve endothelial function. It is unknown whether PPAR-&ggr; agonists favorably modulate bone marrow (BM)–derived angiogenic progenitor cells (APCs) to promote endothelial lineage differentiation and early reendothelialization after vascular intervention. Methods and Results—C57/BL6 mice, treated with or without rosiglitazone (8 mg/kg per day), a PPAR-&ggr; agonist, underwent femoral angioplasty. Rosiglitazone treatment attenuated neointimal formation (intima/media ratio: 0.98±0.12 [rosiglitazone] versus 3.1±0.5 [control]; P <0.001; n=10 per group). Using a BM transplantation model, we identified that 58±12% of the cells within the neointima at 4 weeks were derived from the BM. Pure endothelial marker–positive, pure &agr;-smooth muscle actin (&agr;SMA)–positive, or double-positive APCs could be found both in mouse BM and in human peripheral blood after culture in conditional medium enriched with vascular endothelial growth factor. Rosiglitazone caused a 6-fold (P <0.001) increase in colony formation by human endothelial progenitor cells, promoted the differentiation of APCs toward the endothelial lineage in mouse BM in vivo (0.66±0.06% [control] to 0.95±0.08% [rosiglitazone]; P <0.05) and in human peripheral blood in vitro (13.2±1.5% [control] to 28.4±3.3% [rosiglitazone]; P <0.05), and inhibited the differentiation toward the smooth muscle cell lineage. Within the neointima, rosiglitazone also stimulated APCs to differentiate into mature endothelial cells and caused earlier reendothelialization compared with controls (31±5 versus 8±2 CD31-positive cells per millimeter of neointimal surface on day 14; P <0.01). Conclusions—Similar to embryonic stem cell–derived progenitors, the adult BM and peripheral blood harbor APCs that are at least bipotential and able to differentiate into endothelial and smooth muscle lineages. The PPAR-&ggr; agonist rosiglitazone promotes the differentiation of these APCs toward the endothelial lineage and attenuates restenosis after angioplasty.

Aerobic interval training improves oxygen uptake efficiency by enhancing cerebral and muscular hemodynamics in patients with heart failure

BACKGROUND Abnormal ventilatory/hemodynamic responses to exercise contribute to functional impairment in patients with heart failure (HF). This study investigates how interval and continuous exercise regimens influence functional capacity by modulating ventilatory efficiency and hemodynamic function in HF patients. METHODS Forty-five HF patients were randomized to perform either aerobic interval training (AIT; 3-minute intervals at 40% and 80% VO(2peak)) or moderate continuous training (MCT; sustained 60% VO()for 30 min/day, 3 days/week for 12 weeks, or to a control group that received general healthcare (GHC). A noninvasive bio-reactance device was adopted to measure cardiac hemodynamics, whereas a near-infrared spectroscopy was employed to assess perfusion/O2 extraction in frontal cerebral lobe (∆[THb]FC/∆[HHb]FC) and vastus lateralis (∆[THb]VL/∆[HHb]VL), respectively. RESULTS Following the 12-week intervention, the AIT group exhibited higher oxygen uptake efficiency slope (OUES) and lower VE-VCO2 slope than the MCT and GHC groups. Furthermore, AIT, but not MCT, boosted cardiac output (CO) and increased ∆[THb]FC, ∆[THb]VL, and ∆[HHb]VL during exercise. In multivariate analyses, CO was the dominant predictor of VO(2peak). ∆[THb]FC and ∆[THb]VL, which modulated the correlation between CO and OUES, were significantly correlated with OUES. Simultaneously, ∆[THb]VL was the only factor significantly associated with VE-VCO2 slope. Additionally, AIT reduced plasma brain natriuretic peptide, myeloperoxidase, and interleukin-6 levels and increased the Short Form-36 physical/mental component scores and decreased the Minnesota Living with Heart Failure questionnaire score. CONCLUSIONS AIT effectively improves oxygen uptake efficiency by enhancing cerebral/muscular hemodynamics and suppresses oxidative stress/inflammation associated with cardiac dysfunction, and also promotes generic/disease-specific qualities of life in patients with HF.

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.

Effects of hormone replacement therapy on cardiovascular risk factors in postmenopausal women.

OBJECTIVE To investigate changes in plasma lipoprotein profile, hemostatic factors, platelet aggregation, endothelin-1, and cardiac function during postmenopausal sequential 6-month hormone replacement therapy (HRT). DESIGN Open longitudinal prospective study. SETTING Gynecologic department of a medical center. PATIENT(S) Twenty-one healthy hysterectomized postmenopausal women. INTERVENTION(S) Oral E2 valerate (2 mg/d) combined with medroxyprogesterone acetate (MPA) (10 mg/d) during the last 10 days of each 21-day cycle. The treatment period was 6 months. MAIN OUTCOME MEASURE(S) Plasma lipoprotein profile, hemostatic parameters, platelet aggregation, endothelin-1, and left ventricular function. RESULT(S) After 6 months of treatment, total cholesterol, triglyceride, and low density lipoprotein (LDL) cholesterol were significantly progressively reduced. Atherogenic indices of total cholesterol-to-high-density lipoprotein (HDL) cholesterol and LDL-to-HDL cholesterols also showed a significant progressive decline. The concentrations of antithrombin III were significantly increased. The maximum aggregation and slope of platelet aggregation were significantly reduced, but all parameters were more pronounced at 1 month of HRT than at 3 or 6 months. The concentrations of endothelin-1 were significantly reduced (by 16.1%). In the evaluation of left ventricular function, only peak atrial diastolic velocity was significantly reduced. CONCLUSION(S) Combined HRT had favorable effects on lipids and lipoproteins, hemostatic factors, platelet aggregation, endothelin-1, and left ventricular function. However, further study is needed to evaluate the long-term effects of combined HRT, especially on platelet aggregation and cardiac function.

Stem Cell Factor Attenuates Vascular Smooth Muscle Apoptosis and Increases Intimal Hyperplasia After Vascular Injury

Objective—Stem cell factor (SCF) through its cognate receptor, the tyrosine kinase c-kit, promotes survival and biological functions of hematopoietic stem cells and progenitors. However, whether SCF/c-kit interactions exacerbate intimal hyperplasia through attenuating VSMC apoptosis induced by vascular injury has not been thoroughly investigated. Methods and Results—VSMCs were stimulated with serum deprivation and H2O2 to induce apoptosis. The transcription of c-kit mRNA and the expression of the c-kit protein by VSMCs were estimated by Q-polymerase chain reaction and Western blotting, respectively. The interactions of SCF and c-kit were investigated by in vitro and in vivo experiments. In vitro, H2O2 stimulation significantly induced apoptosis of VSMCs as evidenced by the 3- and 3.2-fold increases of cleaved caspase-3 compared with those in the control group by Western blot and flow cytometric analyses, respectively (P<0.01). Stimulation of apoptosis also caused 3.5- and 9-fold increases in c-kit mRNA transcription and protein expression, respectively, by VSMCs compared with those in the control group. Administration of SCF (10 to 1000 ng/mL) significantly lowered the amount of cleaved caspase-3 in H2O2-treated VSMCs (P<0.01). Specifically, SCF exerted this effect through activating Akt, followed by increasing Bcl-2 and then inhibiting the release of cytochrome-c from the mitochondria to the cytosol. In vivo, the mouse femoral artery was injured with a wire in SCF mutant (Sl/Sld), c-kit mutant (W/Wv), and colony control mice. In colony control mice, confocal microscopy demonstrated that the wire-injury generated a remarkable activation of caspase-3 on medial VSMCs, coinciding with upregulation of c-kit expression. The wire-injury also caused an increase in the expression of SCF on surviving medial VSMCs and cells in the adventitia. The upregulated c-kit expression in the vessel wall also facilitated homing by circulating SCF+ cells. Compared with colony control mice, vascular injury in SCF mutant and c-kit mutant mice caused a higher number of apoptotic VSMCs on day 14 and a lower number of proliferating cells, and resulted in significantly less neointimal formation (P<0.01) on day 28. Conclusions—The interactions between SCF and the c-kit receptor play an important role in protecting VSMCs against apoptosis and in maintaining intimal hyperplasia after vascular injury.

Suppression of cerebral hemodynamics is associated with reduced functional capacity in patients with heart failure

This investigation elucidated the underlying mechanisms of functional impairments in patients with heart failure (HF) by simultaneously comparing cardiac-cerebral-muscle hemodynamic and ventilatory responses to exercise among HF patients with various functional capacities. One hundred one patients with HF [New York Heart Association HF functional class II (HF-II, n = 53) and functional class III (HF-III, n = 48) patients] and 71 normal subjects [older control (O-C, n = 39) and younger control (Y-C, n = 32) adults] performed an incremental exercise test using a bicycle ergometer. A recently developed noninvasive bioreactance device was adopted to measure cardiac hemodynamics, and near-infrared spectroscopy was employed to assess perfusions in the frontal cerebral lobe (Δ[THb](FC)) and vastus lateralis muscle (Δ[THb](VL)). The results demonstrated that the Y-C group had higher levels of cardiac output, Δ[THb](FC), and Δ[THb](VL) during exercise than the O-C group. Moreover, these cardiac/peripheral hemodynamic responses to exercise in HF-III group were smaller than those in both HF-II and O-C groups. Although the change of cardiac output caused by exercise was normalized, the amounts of blood distributed to frontal cerebral lobe and vastus lateralis muscle in the HF-III group significantly declined during exercise. The HF-III patients had lower oxygen-uptake efficiency slopes (OUES) and greater Ve-Vo(2) slopes than the HF-II patients and age-matched controls. However, neither hemodynamic nor ventilatory response to exercise differed significantly between the HF-II and O-C groups. Cardiac output, Δ[THb](FC), and Δ[THb](VL) during exercise were directly related to the OUES and Vo(2peak) and inversely related to the Ve-Vco(2) slope. Moreover, cardiac output or Δ[THb](FC) was an effect modifier, which modulated the correlation status between Δ[THb](VL) and Ve-Vco(2) slope. We concluded that the suppression of cerebral/muscle hemodynamics during exercise is associated with ventilatory abnormality, which reduces functional capacity in patients with HF.

Diagnosis of coronary artery dissection following blunt chest trauma by transesophageal echocardiography.

How to differentiate relevant from trivial cardiac injury in blunt chest trauma has been an ongoing debate. In a 32-year-old victim of a motorcycle crash, the electrocardiographic pattern of an acute anterior wall myocardial infarction was identified as being due to a dissection, after an intimal flap in the proximal left anterior descending artery was noted on transesophageal echocardiography.

c-Src-dependent MAPKs/AP-1 activation is involved in TNF-α-induced matrix metalloproteinase-9 expression in rat heart-derived H9c2 cells

TNF-α plays a critical mediator in the pathogenesis of chronic heart failure contributing to cardiac remodeling and peripheral vascular disturbances. The implication of TNF-α in inflammatory responses has been shown to be mediated through up-regulation of inflammatory genes, including matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of TNF-α-induced MMP-9 expression are largely unclear in the heart cells. Here, we demonstrated that in rat embryonic-heart derived H9c2 cells, TNF-α could induce MMP-9 mRNA expression associated with an increase in the secretion of MMP-9, determined by real-time PCR, zymography, and promoter activity assays. TNF-α-mediated responses were attenuated by pretreatment with the inhibitor of c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), PI3K (LY294002), Akt (SH-5), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of c-Src, EGFR, PDGFR, p110, Akt, or c-Jun. TNF-α stimulated c-Src, PDGFR, and EGFR phosphorylation, which were reduced by PP1. In addition, TNF-α-stimulated Akt phosphorylation was inhibited by PP1, AG1478, AG1296, or LY294002. We further demonstrated that TNF-α markedly stimulated p38 MAPK, p42/p44 MAPK, and JNK1/2 phosphorylation via a c-Src/EGFR, PDGFR/PI3K/Akt pathway. Finally, we showed that, in H9c2 cells, TNF-α-stimulated AP-1 promoter activity, c-Jun mRNA expression, and c-Jun phosphorylation were attenuated by PP1, AG1478, AG1296, LY294002, SB202190, SP600125, or U0126. These results suggested that TNF-α-induced MMP-9 expression is mediated through a c-Src/EGFR, PDGFR/PI3K/Akt/MAPKs/AP-1 cascade in H9c2 cells. Consequently, MMP-9 induction may contribute to cell migration and cardiovascular inflammation.

Coronary Vasospasm Induced During Isoproterenol Head-Up Tilt Test

C spasm has been reported to be related to syncope and sudden death.1 The head-up tilt test is known as a useful method in the evaluation of syncope of unknown origin.2 No report has shown that the tilt test can provoke coronary spasm. We present 3 cases in which coronary spasm was induced during an isoproterenol tilt-table test and discuss the mechanism. • • • CASE 1: A 47-year-old man was admitted for workup of recurrent syncope, which followed chest tightness in the early morning. Physical examination, resting 12lead electrocardiogram, chest xray, echocardiogram, and biochemistry were normal. Exercise stress testing did not provoke an ischemic response and his coronary angiogram showed normal coronary arteries. Then, a tilt test was performed with an isoproterenol infusion at doses of 1, 2, and 3 mg/min at each stage including supine and 70° head-up tilt for 6 minutes. The baseline heart rate was 59 beats/min. After progressively increasing the dose of isoproterenol to 3 mg/min for 6 minutes, his heart rate increased a little to 61 beats/ min with a blood pressure of 96/48 mm Hg. Five minutes after head upright tilting with a 3 mg/min isoproterenol infusion, blood pressure and heart rate increased to 109/54 mm Hg and to 90 beats/min respectively, and meanwhile, a progressive elevation in the ST segment in multiple leads was also noted (Figure 1). The initial ST-segment elevation was found in leads II, III, and aVF, subsequently shifting to leads I, aVL, and precordial leads V1 to V6. Thereafter, chest tightness developed with marked hypotension (blood pressure 58/34 mm Hg). These conditions resolved after lying down and after sublingual nitroglycerin was administered. Electrocardiographic abnormalities returned to normal completely after 24 hours. Holter monitoring documented transient ST-segment elevation with nonsustained ventricular tachycardia at 1:30 A.M. (Figure 2). After treatment with nifedipine and isosorbide nitrate, this patient was free of chest pain and syncope, and no more ST-segment changes were induced by repeat tilt test. CASE 2: A 65-year-old man had 4 episodes of near syncope following typical chest discomfort in the morning. Resting electrocardiogram and coronary angiogram were normal. A tilt test were performed with a blood pressure of 115/85 mm Hg and a heart rate of 78 beats/min at baseline. During From the Cardiology Section, Department of Medicine, Chang Gung Medical College, Chang Gung Memorial Hospital, Keelung, Taiwan. Dr. Cherng’s address is: Chang Gung Memorial Hospital, 222 Mai Chin Road, Keelung, Taiwan. Manuscript received June 12, 1997; revised manuscript received and accepted September 5, 1997. FIGURE 1. Twelve-lead electrocardiogram (Case 1) showing ST-segment elevation in leads II, III, and aVF after a 5-minute head-up tilt with an isoproterenol infusion at a rate of 3 mg/min. ST elevation migrated to leads I, aVL, and V1 to V6 8 minutes later with complete resolution after 24 hours.