Plasma carnitine levels as a marker of impaired left ventricular functions

L-Carnitine plays a role in the utilization of fatty acids and glucose in the myocardium. Previous studies have indicated carnitine deficiency in patients with congestive heart failure. However, the extent of altered carnitine metabolism and left ventricular function is not fully determined. This study is designed to determine if plasma L-carnitine levels can serve as a marker for impaired left ventricular function in patients with congestive heart failure.To test this hypothesis, plasma and urinary levels of L-carnitine were measured in 30 patients with congestive heart failure (CHF) and in 10 control subjects. CHF was due to dilated cardiomyopathy (DCM) and rheumatic heart disease (RHD). Cardiac functions such as percentage of fractional shortening (%FS), ejection fraction (EF), left ventricular mass index (LVMI), were determined by echocardiography. All patients and control subjects had normal renal functions.Plasma carnitine was significantly higher in patients with DCM (37.05 ± 7.62, p < 0.0001) and with RHD (47.2 ± 8.04, p < 0.0001) vs. the control subjects (14.4 ± 5.30 mg/L). Urinary carnitine was significantly higher in DCM (49.13 ± 14.11, p < 0.0001) and in RHD 43.53 ± 15.5, p < 0.0001), than the control (25.1 ± 5.78 mg/L). Plasma carnitine level correlated significantly with impaired left ventricular systolic functions in these patients: %FS < 25% (r = -0.38 and p = 0.038), EF < 0.55 (r = -0.502 and p = 0.005) and LMVI > 124 gm/m² (r = 0.436, and p = 0.016). These data suggest that elevated plasma and urinary carnitine levels in patients with CHF could serve as a marker for myocardial damage and impaired left ventricular functions.     

Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy

The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its beta-adrenergic blocking, antioxidant, and/or alpha-adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin, or placebo pellets for 8 wk and compared with sham-operated rabbits without pacing. We found rapid cardiac pacing produced clinical heart failure, left ventricular dilation, and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine, increase of Bax, decrease of Bcl-2, and increase of apoptotic myocytes as measured by anti-single-stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with changes of left ventricular end-diastolic dimension (r = -0.678, P < 0.0001), fractional shortening (r = 0.706, P < 0.0001), and apoptotic myocytes (r = -0.473, P = 0.0001). Thus our findings suggest antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of beta-receptors in the treatment of CHF.     

Failing atrial myocardium: energetic deficits accompany structural remodeling and electrical instability

The failing ventricular myocardium is characterized by reduction of high-energy phosphates and reduced activity of the phosphotransfer enzymes creatine kinase (CK) and adenylate kinase (AK), which are responsible for transfer of high-energy phosphoryls from sites of production to sites of utilization, thereby compromising excitation-contraction coupling. In humans with chronic atrial fibrillation (AF) unassociated with congestive heart failure (CHF), impairment of atrial myofibrillar energetics linked to oxidative modification of myofibrillar CK has been observed. However, the bioenergetic status of the failing atrial myocardium and its potential contribution to atrial electrical instability in CHF have not been determined. Dogs with (n = 6) and without (n = 6) rapid pacing-induced CHF underwent echocardiography (conscious) and electrophysiological (under anesthesia) studies. CHF dogs had more pronounced mitral regurgitation, higher atrial pressure, larger atrial area, and increased atrial fibrosis. An enhanced propensity to sustain AF was observed in CHF, despite significant increases in atrial effective refractory period and wavelength. Profound deficits in atrial bioenergetics were present with reduced activities of the phosphotransfer enzymes CK and AK, depletion of high-energy phosphates (ATP and creatine phosphate), and reduction of cellular energetic potential (ATP-to-ADP and creatine phosphate-to-Cr ratios). AF duration correlated with left atrial area (r = 0.73, P = 0.01) and inversely with atrial ATP concentration (r = -0.75, P = 0.005), CK activity (r = -0.57, P = 0.054), and AK activity (r = -0.64, P = 0.02). Atrial levels of malondialdehyde, a marker of oxidative stress, were significantly increased in CHF. Myocardial bioenergetic deficits are a conserved feature of dysfunctional atrial and ventricular myocardium in CHF and may constitute a component of the substrate for AF in CHF.     

Ventricular cardiotrophin-1 activation precedes BNP in experimental heart failure

Both cardiotrophin-1 (CT-1) and B-type or brain natriuretic peptide (BNP) are activated by cardiomyocyte stretch, and gene expression of CT-1 and BNP are augmented in the heart in experimental and human congestive heart failure (CHF). The goal of this study was to define cardiac gene expression of CT-1 and BNP by Northern blot analysis in normal (n=5), early left ventricular dysfunction (ELVD, n=5) and overt CHF dogs (n=5), in which ventricular function is progressively decreased. CT-1 mRNA was detected in both atria and ventricles in normal dogs. Ventricular CT-1 mRNA production increased in ELVD, and it further increased in overt CHF. Ventricular BNP mRNA remained below or at the limit of detection in normal and ELVD models, and it markedly increased in overt CHF. This study reports differential regulation of gene expression of CT-1 and BNP in the heart during the progression of CHF, and demonstrates that ventricular CT-1 gene activation precedes ventricular BNP gene activation.     

Skeletal muscle ouabain binding sites are reduced in rats with chronic heart failure.

Intrinsic skeletal muscle abnormalities decrease muscular endurance in chronic heart failure (CHF). In CHF patients, the number of skeletal muscle Na(+)-K(+) pumps that have a high affinity for ouabain (i.e., the concentration of [(3)H]ouabain binding sites) is reduced, and this reduction is correlated with peak oxygen uptake. The present investigation determined whether the concentration of skeletal muscle [(3)H]ouabain binding sites found during CHF is related to 1) severity of the disease state, 2) muscle fiber type composition, and/or 3) endurance capacity. Four muscles were chosen that represented slow-twitch oxidative (SO), fast-twitch oxidative glycolytic (FOG), fast-twitch glycolytic (FG), and mixed fiber types. Measurements were obtained 8-10 wk postsurgery in 23 myocardial infarcted (MI) and 18 sham-operated control (sham) rats. Eighteen rats had moderate left ventricular (LV) dysfunction [LV end-diastolic pressure (LVEDP) < 20 mmHg], and five had severe LV dysfunction (LVEDP > 20 mmHg). Rats with severe LV dysfunction had significant pulmonary congestion and were likely in a chronic state of compensated congestive failure as indicated by an approximately twofold increase in both lung and right ventricle weight. Run time to fatigue and maximal oxygen uptake (VO(2 max)) were significantly reduced ( downward arrow39 and downward arrow28%, respectively) in the rats with severe LV dysfunction and correlated with the magnitude of LV dysfunction as indicated by LVEDP (run time: r = 0.60, n = 21, P < 0.01 and VO(2 max): r = 0.93, n = 13, P < 0.01). In addition, run time to fatigue was significantly correlated with VO(2 max) (r = 0.87, n = 15, P < 0.01). The concentration of [(3)H]ouabain binding sites (B(max)) was significantly reduced (21-28%) in the three muscles comprised primarily of oxidative fibers [soleus: 259 +/- 14 vs. 188 +/- 17; plantaris: 295 +/- 17 vs. 229 +/- 18; red portion of gastrocnemius: 326 +/- 17 vs. 260 +/- 14 pmol/g wet tissue wt]. In addition, B(max) was significantly correlated with VO(2 max) (soleus: r = 0.54, n = 15, P < 0.05; plantaris: r = 0.59, n = 15, P < 0.05; red portion of gastrocnemius: r = 0.65, n = 15, P < 0.01). These results suggest that downregulation of Na(+)-K(+) pumps that possess a high affinity for ouabain in oxidative skeletal muscle may play an important role in the exercise intolerance that attends severe LV dysfunction in CHF.     

Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure

The peptide urotensin-II (U-II) has been described as most potent vasoconstrictor identified so far, but plasma values in humans and its role in cardiovascular pathophysiology are unknown. We investigated circulating urotensin-II and its potential role in human congestive heart failure (CHF). We enrolled control individuals (n=13; cardiac index [CI], 3.5+/-0.1 l/min/m2; pulmonary wedge pressure [PCWP], 10+/-1 mm Hg), patients with moderate (n=10; CI, 2.9+/-0.3 l/min/m2; PCWP, 14+/-2 mm Hg) and severe CHF (n=11; CI, 1.8+/-0.2 l/min/m2; PCWP, 33+/-2 mm Hg). Plasma levels of urotensin-II differed neither between controls, patients with moderate and severe CHF nor between different sites of measurement (pulmonary artery, left ventricle, coronary sinus, antecubital vein) within the single groups. Hemodynamic improvement by vasodilator therapy in severe CHF (CI, +78+/-3%; PCWP, -55+/-3%) did not affect circulating U-II over 24 h. Preprourotensin-II mRNA expression in right atria, left ventricles, mammary arteries and saphenous veins did not differ between controls with normal heart function and patients with end-stage CHF. In conclusion, urotensin-II plasma levels and its myocardial and vascular gene expression are unchanged in human CHF. Circulating urotensin-II does not respond to acute hemodynamic improvement. These findings suggest that urotensin-II does not play a major role in human CHF.     

肾脏去神经化在心力衰竭治疗中的研究进展

生理情况下,心脏和肾脏在血流动力学和神经激素等调节中相互作用,对于循环系统的稳态维持起重要作用。但在充血性心力衰竭的病理情况下,心脏和肾脏之间存在明显的调节紊乱。首先,急性失代偿性心力衰竭的患者住院治疗的研究结果证明其有一定程度的肾脏失调。其次,慢性充血性心力衰竭时肾脏交感神经系统也起到重要作用:肾脏交感纤维活性增强可导致肾素的释放、钠水潴留、肾血流的降低、血管阻力增加、左心室重塑、左心功能失调等。众所周知,肾脏交感神经切除术可以减低血压和改善心脏功能,但是由于有创的手术方式限制了其应用。过去两年间,随着新的导管消融肾脏去神经化技术的日益完善,其有望成为治疗高血压病和心力衰竭的手段。在此,本文综述了心力衰竭时肾脏交感传入神经和传出神经的发病机理,对目前进行的经导管肾脏去神经化治疗慢性心力衰竭的基础及临床试验进行安全性及有效性评价。提示我们经导管肾脏去神经化有望成为心力衰竭治疗的新靶点。     

A relation between myocardial taurine contest and pulmonary wedge pressure in dogs with heart failure

Myocardial taurine levels were correlated with pulmonary wedge pressure (PWP) in dogs with congestive heart failure (CHF). Heart failure was induced by creating an infrarenal aortocaval fistula. PWP ranged from 6.6 to 28 mm Hg, suggesting a wide range in severity of heart failure in those dogs. Compared to taurine levels of normal dogs, levels of the CHF group were significantly elevated in both left and right ventricles. Linear regression analysis of ventricular taurine content yielded a highly significant direct relation to PWP. The results suggest that myocardial taurine content increases as heart failure becomes more severe.     

Increased expression of cardiotrophin-1 during ventricular remodeling in hypertensive rats

Cardiotrophin-1 (CT-1) stimulates longitudinal myocardial cell hypertrophy. We examined the expression of CT-1, leukemia inhibitory factor (LIF), and gp130 by competitive RT-PCR and Western blotting in Dahl salt-sensitive (DS) rats with a high-salt diet, which showed a distinct transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF). The expression levels of CT-1 mRNA and protein were significantly increased at the CHF stage compared with the LVH stage and age-matched Dahl salt-resistant (DR) rats (n = 6 for each group). mRNA expression of LIF was not changed in the left ventricle at any stage by RT-PCR. gp130 mRNA and protein levels of DS rats at 11 and 17 wk were significantly increased compared with age-matched DR rats. The isolated myocyte length of DS rats at 17 wk was the longest among the four groups of rats. The LV end-diastolic dimension (LVDd) of DS rats, determined by echocardiography, was significantly increased at the CHF stage. There was a significant correlation between the CT-1 protein level and LVDd. CT-1 may play a role in ventricular remodeling during transition from LVH to CHF in the rat hypertensive model.     

Head-to-head comparison of BNP and IL-6 as markers of clinical and experimental heart failure: Superiority of BNP

Activation of BNP and IL-6 are hallmarks of left ventricular (LV) dysfunction and congestive heart failure (CHF). To assess the relative activation of BNP and IL-6 in clinical and experimental heart failure, we performed a human study in which plasma N-terminal proBNP (NT-proBNP) and IL-6 were measured in a large group of patients in the chronic phase after myocardial infarction (MI) and an animal study in which LV gene expression of BNP and IL-6 was assessed in rapid ventricular pacing-induced heart failure. In the human study, NT-proBNP and IL-6 were measured by non-extracted, enzyme-linked immunoassay in 845 subjects (n=468 outpatients after MI, MONICA MI register Augsburg; and 377 siblings without MI, control). NT-proBNP (295+/-23pg/mL vs. CTRL 84+/-8, P<0.05) and IL-6 (2.7+/-0.1pg/mL vs. CTRL 2.1+/-0.1, P<0.05) were both elevated in subjects with MI. These increases were particularly pronounced in the presence of concomitant CHF (both P<0.01 vs. CTRL) and LV dysfunction (EF<45%, both P<0.05 vs. CTRL). However, NT-proBNP was significantly correlated with several cardiac structural and functional parameters (EF, LVMI, history of MI, CHF symptoms; all P<0.05) upon regression analysis whereas IL-6 was only correlated with history of MI (P<0.001). Accordingly, MI subjects with symptomatic LV dysfunction were detected by NT-proBNP with a greater sensitivity, specificity, and ROC-area (85%, 88%, and 0.87, respectively) as compared to IL-6 (69%, 53%, and 0.67, respectively). In the animal study, IL-6 and BNP expression were both significantly elevated in CHF (both P<0.05) but with a much greater absolute activation of BNP. In addition, BNP mRNA expression displayed a stronger inverse correlation with LV function (r=-0.74; P<0.001) than IL-6 (r=-0.53; P=0.001) and was a markedly more sensitive and specific molecular marker of LV dysfunction (sensitivity 91%, specificity 100%, ROC-area 0.94) than IL-6 (sensitivity 74%, specificity 83%, ROC-area 0.87). Our animal study provides evidence that IL-6 expression is activated in heart failure but to a significantly lesser degree than that of BNP. Both the stronger expression of BNP and the better correlation with LV function provide the molecular basis for a diagnostic superiority of NT-proBNP in clinical LV dysfunction and heart failure.     

C-type natriuretic peptide and its relation to non-invasive indices of left ventricular function in patients with chronic heart failure

C-type natriuretic peptide (CNP) significantly increases in chronic heart failure (CHF) patients as a function of clinical severity. Aim of this study was to evaluate in CHF patients the relationship between circulating CNP concentrations and echo-Doppler conventional indices of left ventricular (LV) function as well as less load independent parameters as dP/dt. LV ejection fraction (EF), left ventricular end-diastolic dimension (LVEDD) and LV dP/dt were evaluated together with plasma CNP levels in 38 patients with CHF and in 63 controls. CNP levels resulted significantly higher in CHF patients than in controls (7.19+/-0.59 pg/ml vs. 2.52+/-0.12 pg/ml, p<0.0001). A significant correlation between dP/dt and CNP levels (r=-0.61, p<0.0001) was observed. A good correlation with EF (r=-0.55, p<0.001) and a less significant relation with LVEDD (r=0.316, p<0.05) were also reported. When patients were divided according to dP/dt values a very significant difference in CNP levels was observed: Group I (<600, n=25) vs. Group II (>600, n=13): 8.46+/-0.69 and 4.75+/-0.75 pg/ml, respectively, p<0.001. This is the first study that reports a correlation between CNP and dP/dt in CHF patients, thus suggesting a possible role on cardiac contractility.     

基质细胞衍生因子-1 与围生期心肌病患者心力衰竭的相关性研究

目的:探讨基质细胞衍生因子-1与围生期心肌病患者心力衰竭的相关性。方法:采用前瞻性研究纳入59例围生期心肌病并发心力衰竭患者,33例单纯围生期心肌病患者作为对照组。患者均接受体检、实验室检查、心电图、心脏彩超评估。选取基质细胞衍生因子-1(SDF-1)、超敏C反应蛋白(hs-CRP)、氨基末端脑钠肽前体(NT-pro BNP)、血清肌钙蛋白(TNI)及心脏彩超相关参数为评价指标。结果:(l)围生期心肌病患者循环中基质细胞衍生因子-1水平明显高于对照组;(2)循环中基质细胞衍生因子-1与超敏C反应蛋白(CRP)、氨基末端脑钠肽前体(NT-pro BNP)呈正相关,与超声心动图左心室射血分数(LVEF)呈负相关。结论:基质细胞衍生因子-1与围生期心肌病患者心力衰竭具有显著相关性。     

Deficiency of iNOS does not attenuate severe congestive heart failure in mice

Inducible nitric oxide synthase (iNOS) has been implicated in the pathophysiology of congestive heart failure (CHF). Given the extensive evidence supporting this concept, we hypothesized that iNOS deficiency (iNOS(-/-)) would attenuate the severity of CHF in mice. Mice were subjected to permanent occlusion [myocardial infarction (MI)] of the proximal left anterior descending coronary artery to produce CHF. Cardiac function was assessed in vivo using echocardiography and ultraminiature ventricular pressure catheters. Sham wild-type (n = 17), sham iNOS(-/-) (n = 8), MI wild-type (n = 56), and MI iNOS(-/-) (n = 48) mice were subjected to MI (or sham MI) and followed for 1 mo. Deficiency of iNOS did not alter survival during CHF compared with wild type (35% vs. 32%, P = not significant). Furthermore, fractional shortening and cardiac output were not significantly different between wild-type (9.6 +/- 2.0% and 441 +/- 20 microl.min(-1).g(-1)) and iNOS(-/-) (9.8 +/- 1.3% and 471 +/- 26 microl.min(-1).g(-1)) mice. The extent of cardiac hypertrophy and pulmonary edema was also similar between wild-type and iNOS(-/-) mice. None of the indexes demonstrated any significant differences between iNOS(-/-) and wild-type mice subjected to MI. These findings indicate that deficiency of iNOS does not significantly affect severe CHF in mice after MI.     

Echocardiographic detection of congestive heart failure in postinfarction rats

In studies of congestive heart failure (CHF) treatment, it is essential to select animals with a similar degree of cardiac dysfunction. However, this is difficult to establish without hemodynamic evaluation in rat postinfarction-induced CHF. This study aimed to diagnose CHF in long-term follow-up postinfarction rats using only echocardiographic criteria through a J-tree cluster analysis and Fisher's linear discriminant function. Two sets of sham and infarcted rats were studied. The first was used to perform cluster analysis and the second to prospectively validate the results. Six months after inducing myocardial infarction (MI), rats were subjected to transthoracic echocardiography. Infarct size was measured by histological analysis. Six echocardiographic variables were used in the cluster analysis: left ventricular (LV) systolic dimension, LV diastolic dimension-to-body weight ratio, left atrial diameter-to-body weight ratio, LV posterior wall shortening velocity, E wave, and isovolumetric relaxation time. Cluster analysis joined the rats into one sham and two MI groups. One MI cluster had more severe anatomical and echocardiographic changes and was called MI with heart failure (MI/HF+, n = 24, infarct size: 42.7 ± 5.8%). The other had less severe changes and was called MI without heart failure (MI/HF-, n = 11, infarct size: 32.3 ± 9.9%; P < 0.001 vs. MI/HF+). Three rats with small infarct size (21.6 ± 2.2%) presenting mild cardiac alterations were misallocated in the sham group. Fisher's linear discriminant function was built using these groups and used to prospectively classify additional groups of sham-operated (n = 20) and infarcted rats (n = 57) using the same echocardiographic parameters. The discriminant function therefore detected CHF with 100% specificity and 80% sensitivity considering allocation in MI/HF+ and sham group, and 100% specificity and 58.8% sensitivity considering MI/HF+ and MI/HF- groups, taking into account pathological criteria of CHF diagnosis. Echocardiographic analysis can be used to accurately predict congestive heart failure in postinfarction rats.     

Progression of heart failure after myocardial infarction in the rat

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple "switching on" of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.     

Beneficial effect of ACE inhibitor in congestive heart failure

The effects of captopril, an angiotensin-converting enzyme inhibitor, on congestive heart failure (CHF) were investigated in animal and clinical studies. Congestive heart failure was induced in rats by a combination of pressure and volume overload. Cardiac pressure overload was induced by constricting one renal artery (Goldblatt rat) and volume overload was induced by aorto-caval fistula. Captopril (100 mg/kg/day) was then administered for 14 weeks. Isometric contraction was assessed using isolated left ventricular papillary muscles. The maximum developed tension and the maximum rate of increase in tension (dT/dtmax) were decreased in untreated rats with CHF and improved in captopriltreated rats. The left ventricular myosin isoenzyme pattern was shifted towards V3 in untreated rats with CHF, and was shifted back towards V1 in the captopril-treated rats. In the clinical study, captopril (37.5–75 mg/day) was administered to patients with cardiomyopathy for 12 months. There was no effect on left ventricular mass in hypertrophic cardiomyopathy, although systolic anterior motion of the mitral valve disappeared in one patient. In dilated cardiomyopathy, however, left ventricular mass tended to decrease. These results indicate that captopril has a beneficial effect in congestive heart failure.     

Urotensin-II receptor blockade with SB-611812 attenuates cardiac remodeling in experimental ischemic heart disease

It is now well established that urotensin-II (UII) levels are increased in several cardiovascular diseases. We previously demonstrated that UII and the UII receptor (UT) protein levels are significantly increased in the hearts of both humans and rats with congestive heart failure (CHF). We have also recently demonstrated that UII blockade, with a selective UII antagonist, improves heart function in a rat model of ischemic CHF. Here, we evaluated the attenuation of cardiac remodeling associated with UII antagonism in the same rat model of ischemic CHF. Animals were administered a specific UT receptor antagonist, SB-611812 (30 mg/kg/day, gavage), or vehicle 30 min prior to coronary artery ligation followed by daily treatment for 8 weeks. Myocardial interstitial fibrosis was analyzed by Masson's trichrome and picrosirius red staining. RT-PCR analysis was utilized for mRNA expression studies. We used Western blotting to assess levels of collagen types I and III. Mitogenic activity of UII on cultured neonatal cardiac fibroblasts was also evaluated. Following coronary ligation, SB-611812 significantly attenuated both myocardial and endocardial interstitial fibrosis, and reduced collagen type I:III ratio (P<0.01). UII induced proliferation of cardiac fibroblasts and this mitogenic effect was significantly inhibited with 1 microM of SB-611218 (P<0.05). We demonstrate here that selective blockade of UT reduces diastolic dysfunction by decreasing myocardial fibrosis post-coronary ligation in vivo, and inhibits UII-mediated fibroblast proliferation in vitro.     

Antiplatelet therapy mitigates cardiac remodeling and dysfunction in congestive heart failure due to myocardial infarction

Antiplatelet agents such as sarpogrelate (SAR), a 5-hydroxytryptamine antagonist, and cilostazol (CIL), a phosphodiesterase-III inhibitor, are used in the management of peripheral vascular disease. In this study, we tested the hypothesis that both SAR and CIL prevent cardiac remodeling and improve cardiac function in congestive heart failure (CHF) due to myocardial infarction (MI). Post-MI rats (3 weeks after the occlusion of coronary artery) received either vehicle (MI+V, n = 36), SAR (MI+SAR; 5 mg xc kg(-1) x day(-1), n = 35) or CIL (MI+CIL; 5 mg x kg(-1) x day(-1), n = 34) from day 21 to day 56. Sham-operated rats (n = 29) served as controls. Electrocardiographic, echocardiographic, and hemodynamic parameters were measured on day 56. Treatment of infarcted animals with SAR or CIL significantly improved the left ventricular (LV) dimensions, LV fractional shortening, cardiac output, stroke volume, mean arterial pressure, LV diastolic function, and LV systolic pressure, as well as rates of LV pressure development and pressure decay. Although cardiac hypertrophy was reduced, both SAR and CIL had no effect on infarct size or MI-associated QTc prolongation. However, SAR decreased whereas CIL increased the incidence of ventricular arrhythmias and the mean number of episodes in infarcted animals. Mortality during the treatment period was decreased by 17% with SAR and increased by 10% with CIL, but these changes were not significant statistically. The data in this study suggest that both SAR and CIL prevent cardiac remodeling and improve cardiac function in MI-induced CHF; however, CIL unlike SAR increased the incidence of arrhythmias and adversely affected patient mortality.     

Plasma profiles of circulating granulocyte-macrophage colony-stimulating factor and soluble cellular adhesion molecules in acute myocardial infarction. Contribution to post-infarction left ventricular dysfunction

No in vivo data exist about the relationship of circulating granulocyte-macrophage colony stimulating factor (GM-CSF) and soluble adhesion molecules ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) to the severity of acute myocardial infarction (AMI) and the pathophysiological events of post-infarction left ventricular dysfunction. We investigated the kinetics of these inflammatory mediators in the plasma of patients with AMI, and correlated the findings with the clinical severity of the disease during the first week of hospitalization as well as the degree of left ventricular dysfunction one month after the AMI. Plasma levels of inflammatory markers were determined in 41 AMI patients (all received thrombolytic treatment) by ELISA assays, serially during the first week of hospitalization and one month after hospital admission. Patients (n = 20) with uncomplicated AMI (Killip class I) were classified as group A, patients (n = 21) with AMI complicated by heart failure manifestations (Killip classes II and III) were classified as group B, while 20 age- and sex-matched volunteers were used as healthy controls. A sustained increase in GM-CSF, sICAM-1 and sVCAM-1 plasma concentrations was observed only in group B during the first week of the study. Patients from group B exhibited significantly higher levels of GM-CSF (P < 0.01), sICAM-1 (P < 0.05) and sVCAM-1 (P < 0.01) than patients from group A and the healthy controls (P < 0.001). In group B patients, significant correlations were observed between the peak of GM-CSF levels and the peak of serum creatine kinase-MB (r = 0.42; P < 0.05), white blood cell counts (r = 0.67; P < 0.001) and LVEF (r =- 0.51; P < 0.01). At one month follow-up, patients (n = 17) with severe post-infarction left ventricular dysfunction (LVEF 35%). Significant correlations were observed between GM-CSF levels and left ventricular end-diastolic volume index (r = 0.55; P < 0.001) or left ventricular end-systolic volume index (r = 0.49; P = 0.001). We have found a significant elevation of plasma GM-CSF and soluble adhesion molecules during the course of AMI, with the highest values in patients with AMI complicated by heart failure manifestations and severe left ventricular dysfunction. These monocyte-related inflammatory mediators may actively contribute to the pathophysiology of the disease and post-infarction cardiac dysfunction.