A display of combined left ventricular function and dyssynchrony using Doppler tissue imaging: its application in acute response to cardiac resynchronization therapy.

BACKGROUND: We have recently proposed a novel method for displaying left ventricular (LV) function and mechanical dyssynchrony, which is based on the "vector analysis" using Doppler tissue imaging (DTI). The aim of this study was to examine acute-phase impact of cardiac resynchronization therapy (CRT) on the parameters assessed by this method. METHODS: We studied a total of 25 patients with systolic heart failure, 14 undergoing simultaneous acute pacing-hemodynamic study and DTI; and 11 patients DTI within a few days before and one week after CRT. Parameters derived from the displaying method were followings: (1) percentage area of the hexagon, the area divided by the overall graph area, reflecting global LV systolic function; (2) net-delay magnitude, the length of the composite vector for the six vectors, a dyssynchrony index; and (3) delayed contraction site, graphical position of the composite vector. RESULTS: CRT significantly increased cardiac output (3.1 ± 1.0 to 3.4 ± 0.7 L/min, P = 0.02) and +dp/dt (782 ± 149 to 1,089 ± 270 mm Hg/s, P < 0.01), and decreased mitral regurgitaion jet area (7.9 ± 3.0 to 4.8 ± 2.4 cm(2) , P < 0.01). As with the new method, there were significant decreases in the percentage area of the hexagon (20.7 ± 6.6 to 18.6 ± 6.5%, P < 0.01) and the net-delay magnitude (122 ± 59 to 72 ± 48 ms, P < 0.01). The reduction of net-delay magnitude accompanied alteration of delayed contraction site; 16 patients had the most delayed site between the lateral and inferior segments before CRT, and seven patients after CRT (P = 0.02). CONCLUSIONS: The new method would be a useful tool to assess efficacy of CRT in patients with systolic heart failure.

Enhanced expression of the ubiquitin-proteasome system in the myocardium from patients with dilated cardiomyopathy referred for left ventriculoplasty: an immunohistochemical study with special reference to oxidative stress.

The ubiquitin (Ub)-proteasome system (UPS) is an important proteolytic mechanism for selecting and digesting cytotoxic proteins. The aim of this study is to elucidate expression and in situ localization of the UPS in the myocardium from patients with dilated cardiomyopathy (DCM) with refractory heart failure. The expression profile of the oxidative stress-induced cytotoxic proteins was also examined. Myocardium was obtained from 26 patients with DCM at the left ventriculoplasty. Ten normal autopsied hearts served as controls. Myocardial expressions of Ub and proteasomes were studied immunohistochemically. Oxidative stresses were examined in point of localization of the oxidation-induced modifier molecules (OMM). The relationship between immunohistochemical results and clinical parameters was also evaluated. Both Ub and proteasomes were stained positive in granular structures accumulating between the myofibrils and adjacent to nuclei in cardiomyocytes. The OMMs were also positive in the same Ub-positive granular structures. The area fraction of Ub, proteasomes and OMM was significantly higher in DCM hearts than in normal controls. Significant positive correlation was observed between the area fractions of Ub and plasma levels of brain natriuretic peptide (p = 0.046) in DCM hearts. In conclusion, enhanced expression of the UPS colocalized with OMM in cardiomyocytes may be involved in the pathophysiology of DCM hearts.

Incremental prognostic values of serum tenascin-C levels with blood B-type natriuretic peptide testing at discharge in patients with dilated cardiomyopathy and decompensated heart failure.

BACKGROUND: This study investigates the predictive value of serum tenascin-C (TN-C), which is observed at the active sites of ongoing tissue remodeling, for cardiac events of patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: In this trial, 110 consecutive patients hospitalized with heart failure (HF) resulting from DCM underwent assessments of serum TN-C and plasma brain natriuretic peptide (BNP) levels at discharge and were followed up for 22.4 months. Cardiac function and hemodynamics were assessed invasively in 60 of these patients at discharge. There were 19 cardiac events (14 rehospitalizations, 3 deaths from refractory HF, and 2 sudden deaths) during follow-up. The average levels of TN-C and BNP were 73 +/- 38 ng/mL and 279 +/- 414 pg/mL, respectively. The optimal cutoff value for serum TN-C levels predicted cardiac events were >or=78.4 ng/mL, whereas BNP levels were >or=219 pg/mL. Patients with levels higher than this had significantly higher cardiac events and serum TN-C >or=78.4 ng/mL had an incremental predictive power with BNP for cardiac events. Left ventricular end-diastolic volume was significantly larger, and mean pulmonary arterial pressure was elevated in patients with serum TN-C >or=78.4 ng/mL. CONCLUSIONS: The combined index of serum levels for TN-C and BNP at discharge predicts cardiac events from decompensated HF. Additionally, elevated serum TN-C levels reflect left ventricular and pulmonary vascular remodeling in DCM patients.

Suppression of inflammation in rat autoimmune myocarditis by S100A8/A9 through modulation of the proinflammatory cytokine network.

AIMS: S100A8/A9 is expressed in activated monocytes/macrophages and assumed to be heavily involved in the pathogenesis of acute inflammation. Although several studies have asserted that S100A8/A9 has a proinflammatory function, the exact biological function of S100A8/A9 is yet to be described. We examined the anti-inflammatory effects of S100A8/A9 on experimental autoimmune myocarditis (EAM) in rats. METHODS AND RESULTS: Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. The recombinant (R-) S100A8/A9 was injected intraperitoneally into EAM rats. R-S100A8/A9 attenuated the severity of myocarditis, as evidenced by echocardiographic and histological findings. In addition, we found that not only the mRNA expression of proinflammatory cytokines [interleukin (IL)-1beta, IL-6, and tumour necrosis factor (TNF)-alpha] in the myocardium, but also their serum concentrations were suppressed in EAM rats treated with R-S100A8/A9. Nuclear factor-kappa B expression in inflammatory cells was also suppressed in the treated rats. To elucidate the mechanistic function of S100A8/A9 on proinflammatory cytokines in vivo, we used an ELISA on the supernatant of homogenized heart tissue treated with R-S100A8/A9. The findings revealed high-affinity binding of R-S100A8/A9 with IL-1beta, IL-6, and TNF-alpha in the myocardium, suggesting the trapping of proinflammatory cytokines by R-S100A8/A9. CONCLUSION: S100A8/A9 attenuates EAM through modulation of the proinflammatory cytokine network.

High prevalence of chronic myocarditis in dilated cardiomyopathy referred for left ventriculoplasty: expression of tenascin C as a possible marker for inflammation.

The objectives of this study were to analyze the incidence of chronic myocarditis in dilated cardiomyopathy and to evaluate the diagnostic value of tenascin C for assessing inflammatory activity in the resected myocardium. Dilated cardiomyopathy patients with chronic myocarditis have a poor clinical outcome despite recent advances in medical treatments. Therefore, a precise diagnosis of inflammatory activity is critical to ensuring appropriate therapy. Tenascin C is an extracellular matrix glycoprotein that plays an important role in tissue remodeling in various heart diseases. Myocardial samples obtained during left ventriculoplasty from 64 patients (50 +/- 13 years, 56 men and 8 women) with dilated cardiomyopathy were examined by immunostaining for tenascin C. Histologic diagnosis was based on the Dallas criteria modified by the International Society and Federation of Cardiology task force. Nine cases (14%) had active myocarditis, 21 (33%) had borderline myocarditis, and 34 (53%) had no myocarditis. Intense tenascin C expression was observed at the site of active inflammation, with abundant cell accumulation, and in organized granulation tissue during the resolving phase but not in scar tissue during the healing phase. The ratio of tenascin C-positive area to the whole myocardium in the active and borderline myocarditis groups was significantly greater than that in the noninflammatory group. These findings suggest a high prevalence of chronic myocarditis in dilated cardiomyopathy patients and that tenascin C may prove to be a useful marker for distinguishing inflammatory cardiomyopathy from other types of dilated cardiomyopathy.

Novel method for displaying left ventricular function and dyssynchrony using tissue Doppler imaging: evaluation of its applicability in dilated cardiomyopathy with wide and narrow QRS complexes.

BACKGROUND: The present study was conducted to assess the clinical applicability of a novel method of displaying left ventricular (LV) function and dyssynchrony using Doppler tissue imaging (DTI) in patients with dilated cardiomyopathy with wide or narrow QRS complexes. METHODS: The study included 28 patients with wide QRS complexes, 36 with narrow QRS complexes, and 55 apparently healthy subjects (controls). The time to peak velocities (TPVs) obtained from 6 basal LV segments were assumed to be "vectors" and aligned radially such that each terminal point was directed to the corresponding LV segment. The resulting hexagonal graph covered the following aspects of LV function and dyssynchrony: (1) percentage area of the hexagon, the area divided by the overall graph area, reflecting global LV systolic function; (2) the net-delay magnitude of mechanical contraction, the length of the composite vector for the 6 vectors; and (3) delayed contraction site, the graphical position of the composite vector. RESULTS: The percentage area of the hexagon was correlated with the pre-ejection period (r = 0.80; P < .001) and LV ejection fraction (r = -0.66; P < .001). The net-delay magnitude was longest in patients with wide QRS complexes and shortest in controls (123 +/- 61 vs 36 +/- 27 ms; P < .001). LV mechanical dyssynchrony on the basis of the new method (net-delay magnitude > 90 ms) was detectable in 68% of patients with wide QRS complexes and in 39% of those with narrow QRS complexes. The percentages were similar to those obtained using conventional DTI-derived indexes (the standard deviation and dispersion of TPVs in the 12 myocardial segments). The new method, moreover, revealed that patients with wide QRS complexes had delayed contraction sites located more often between the lateral and inferior wall segments than controls (68% vs 35%; P < .001). CONCLUSIONS: The new displaying method permits at-a-glance recognition of LV function and dyssynchrony. Whether the method can be used to predict resynchronization awaits further study.

Enhanced expression of type 1 helper T-cell cytokines in the myocardium of active cardiac sarcoidosis.

BACKGROUND: Various cytokines are involved in the pathogenesis of sarcoidosis, but their expression in the myocardium has not been documented for cardiac sarcoidosis. METHODS AND RESULTS: Myocardial tissue was obtained from 12 patients with cardiac sarcoidosis at the time of left ventriculoplasty, biopsy or autopsy. mRNA expression of various inflammatory cytokines was analyzed using quantitative real-time polymerase chain reaction, as well as by immunohistochemistry. Ten patients with dilated cardiomyopathy (DCM) served as controls. Enhanced expression of interleukin (IL)-1alpha, IL-2, IL-12 p40 and interferon (IFN)-gamma mRNA was limited to the myocardium of cardiac sarcoidosis patients. Expression of IL-1beta, IL-8, IL-10, IL-15 and TNF-alpha occurred in both cardiac sarcoidosis and DCM patients, but IL-4 and IL-5 were not detected in either disease. Immunohistochemistry of the myocardial tissue of sarcoidosis revealed positive staining for IL-12 and IFN-gamma. IL-12 was localized in multinucleated giant cells and macrophages of the sarcoid granulomas, whereas IFN-gamma was detected in lymphocytes and vascular endothelial cells. CONCLUSIONS: Type 1 helper T-cell cytokines may be involved in the pathogenesis of cardiac sarcoidosis.

Enhanced expression of myeloid-related protein complex (MRP8/14) in macrophages and multinucleated giant cells in granulomas of patients with active cardiac sarcoidosis.

BACKGROUND: The myeloid-related protein complex (MRP8/14) is expressed in activated human macrophages and reported to be involved in the inflammatory process. The expression of MRP8/14 in patients with cardiac sarcoidosis and idiopathic dilated cardiomyopathy (DCM) was investigated. METHODS AND RESULTS: Serum MRP8/14 levels were measured in 35 patients with sarcoidosis and 23 patients with DCM. Sera from 30 normal volunteers served as controls. Additionally, the expression profiles of MRP8/14 in the myocardium from 12 patients with active cardiac sarcoidosis and 10 DCM patients were examined immunohistochemically. Serum MRP8/14 levels were significantly higher in patients with sarcoidosis than in normal controls [515+/-549 (SD) ng/ml vs 230+/-115 ng/ml, p=0.0019]. In the sarcoidosis group, serum MRP8/14 levels in patients with definite cardiac involvement (n=10) were significantly higher than in those without (n=25) (974+/-878 ng/ml vs 332+/-204 ng/ml, p=0.0227) and they were also higher than in DCM patients (vs 252+/-108 ng/ml, p=0.0026). Immunohistochemically, MRP8/14 was specifically positive in the cytoplasm of macrophages and multinucleated giant cells in the myocardial granulomas. CONCLUSIONS: MRP8/14 may be involved in the pathogenesis of sarcoid granulomas. The measurement of serum MRP8/14 levels is useful for the diagnosis of sarcoidosis, and their higher levels suggest the cardiac involvement.

Higher serum tenascin-C levels reflect the severity of heart failure, left ventricular dysfunction and remodeling in patients with dilated cardiomyopathy.

BACKGROUND: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is specifically expressed at high levels during embryonic development, but not in the adult heart. TN-C reappears at sites of inflammatory tissue remodeling or wound healing under various pathologic conditions, such as acute myocardial infarction, acute myocarditis, and some cases of cardiomyopathy. Therefore, the expression of TN-C might be useful for detecting the clinical characteristics of, and ventricular remodeling in, dilated cardiomyopathy (DCM). METHODS AND RESULTS: Circulating serum TN-C levels in 107 patients with DCM were measured using an ELISA kit. Clinical data were also assessed by Pearson's or Spearman's correlation analysis to estimate correlations between variables. Serum TN-C levels in DCM patients were higher than those in normal controls (p<0.001). TNC levels showed a significantly positive correlation with New York Heart Association functional class (p<0.001), B-type natriuretic peptide level (p<0.001), cardiothoracic ratio on chest X-ray (p<0.01), left ventricular end-diastolic diameter (p<0.05) and left ventricular end-systolic diameter (p<0.01), and a significantly negative correlation with left ventricular ejection fraction (p<0.01). CONCLUSIONS: The findings suggest that increased serum TN-C levels indicate the severity of heart failure, left ventricular dysfunction and remodeling in patients with DCM.