Myocardial integrated ultrasonic backscatter in patients with dilated cardiomyopathy: prediction of response to beta-blocker therapy

BACKGROUND: Myocardial integrated backscatter (IB) imaging has been reported to be useful for ultrasonic tissue characterization and delineation of myocardial viability or fibrosis. beta-Blocker therapy has beneficial effects for patients with dilated cardiomyopathy (DCM), but there are no clear findings that indicate which patients with DCM will respond to this therapy. This study was performed to evaluate whether myocardial IB analysis can predict the response to beta-blocker therapy. METHODS AND RESULTS: We prospectively performed echocardiographic examination with IB analysis in 29 patients with DCM (20 men, 9 women) before starting bisoprolol therapy and in 15 normal subjects. Standard echocardiographic examination and IB analysis in the left ventricular wall in the 2-dimensional short-axis view were performed and the magnitude of cyclic variation (CV) of IB and calibrated myocardial IB intensity (subtracted pericardial) were obtained from the interventricular septum and the left ventricular posterior wall. Sixteen patients responded to bisoprolol therapy and 13 did not respond after 12 months of full-dose therapy. Calibrated myocardial IB intensity was lower in responders relative to nonresponders in both the interventricular septum (responders, -20.1 +/- 3.6 dB vs nonresponders, -9.8 +/- 5.1 dB, P <.0001; controls, -20.1 +/- 4.4 dB) and posterior wall (responders, -20.6 +/- 3.6 dB vs nonresponders, -14.6 +/- 4.2 dB, P =.0002; controls, -22.7 +/- 3.3 dB). Also, the lower the myocardial intensity in the interventricular septum or posterior wall, the better left ventricular systolic function improved after beta-blocker therapy. However, CV was lower in both DCM groups than in the controls, and CV in the interventricular septum was lower in nonresponders than in responders (responders, 4.0 +/- 4.1 dB vs nonresponders, -0.8 +/- 6. 1 dB, P <.02; controls, 8.3 +/- 2.4 dB). In addition, CV in the posterior wall showed no difference between the 2 DCM groups (responders, 5.6 +/- 1.3 dB vs nonresponders, 5.1 +/- 3.5 dB, P = not significant; controls, 9.6 +/- 2.5 dB). Also, the percent fibrosis on right ventricular endomyocardial biopsy specimens showed no distinctions between these 2 groups (responders, 25.1% +/- 16.1% vs nonresponders, 24.9% +/- 15.0%, P = not significant). CONCLUSIONS: These findings suggest that left ventricular myocardial IB data, especially IB intensity, provide useful information for predicting the response to beta-blocker therapy in patients with DCM. However, right ventricular endomyocardial biopsy findings do not appear to contribute to discriminating between the 2 groups.     

Prognostic implications derived from ultrasonic tissue characterization with myocardial integrated backscatter in patients with dilated cardiomyopathy

BACKGROUND: Various clinical parameters have been reported to predict survival in patients with dilated cardiomyopathy (DCM). Myocardial ultrasonic integrated backscatter (IB) imaging has a potential to perform in vivo tissue characterization. The present study was performed to examine whether myocardial IB analysis can predict the prognosis of DCM patients. METHODS AND RESULTS: We prospectively carried out echocardiographic examinations with IB analysis in 43 patients with DCM (31 males, 12 females) under the standard treatment. IB analysis was performed in the left ventricular wall and the calibrated (subtracting pericardial data) myocardial IB intensity (IBI) was obtained from the interventricular septum and the left ventricular posterior wall. After the follow-up (8-39 months), 31 followed a good clinical course, but eight had cardiac death, one had partial left ventriculectomy for uncontrolled heart failure and three were hospitalized for worsening heart failure. Beta-blocker responded in 27 (87%) of the 31 with good clinical course, but it did not respond in 11 among the 12 with poor course. In these 12 DCM, left ventricular fractional shortening (LVFS) was lower (good: 18+/-5%, poor: 14+/-4, P<0.03) and calibrated IBI was higher in both the septum (good: -16.4+/-5.6 dB, poor: -11.1+/-4.2 dB, P<0.006) and the posterior wall (good: -19.5+/-3.6 dB, poor: -13.8+/-5.6 dB, P<0.004). On the Cox proportional hazard model analysis, only calibrated IBI in the septum >-17 dB, the cut-off score of calibrated IBI discriminating non-responders to beta-blocker therapy in our previous report, was related to the poor outcome (chi(2)=4.43, P=0.035). The stepwise multivariate analysis revealed that both calibrated IBI in the septum>-17 dB (chi(2)=4.43, P=0.035) and LVFS<15% (chi(2)=3.89, P=0.049) were useful to predict the poor clinical outcome. The event free rate assessed by the Kaplan-Meier method was also significantly reduced in patients with calibrated IBI in the septum >-17 dB (chi(2)=6.594, P=0.01) and calibrated IBI in the posterior wall>-17 dB (chi(2)=4.215, P=0.04). However, LVFS<15% (chi(2)=3.576, not significant) did not contribute to discriminating the event free rate in the clinical course. CONCLUSIONS: The present study demonstrated that myocardial IB intensity was higher in DCM patients who followed a poor clinical course rather than in those with a good outcome. Therefore, it is clarified that myocardial ultrasonic tissue characterization in DCM patients is useful for assessing their clinical outcome after receiving not only the standard treatment but also beta-blocker therapy.     

Myocardial ultrasonic tissue characterization for estimating histological abnormalities in hypertrophic cardiomyopathy: comparison with endomyocardial biopsy findings.

AIMS: In this study, we investigated the clinical usefulness of ultrasonic tissue characterization with integrated backscatter for the evaluation of myocardial histological abnormalities in comparison with endomyocardial biopsy findings in patients with hypertrophic cardiomyopathy. METHODS: Twenty patients with hypertrophic cardiomyopathy and 20 normal subjects were enrolled in this study. We measured two parameters for the ultrasonic tissue characterization with integrated backscatter: the magnitude of the cardiac-cycle-dependent variation in integrated backscatter signals (cdv-IB) and the mean value of integrated backscatter signals calibrated by the pericardium (cal-IB). These parameters were measured at both the interventricular septum and the left ventricular posterior wall. Histological findings of right ventricular endomyocardial biopsy specimens were analyzed by computer image analyzer. RESULTS: cdv-IB was significantly lower and cal-IB significantly higher in both the interventricular septum and the left ventricular posterior wall in patients with hypertrophic cardiomyopathy compared with normal subjects. In patients with hypertrophic cardiomyopathy, the degree of myocardial disarray, interstitial fibrosis, and nonhomogeneity of myocyte size showed positive correlations with cal-IB and negative correlations with cdv-IB. CONCLUSIONS: Ultrasonic tissue characterization with IB enables the noninvasive evaluation of myocardial histological abnormalities in patients with hypertrophic cardiomyopathy.     

Ultrasonic tissue characterization in patients with dilated cardiomyopathy: comparison with findings from right ventricular endomyocardial biopsy

Aim: The clinical usefulness of integrated backscatter (IB) imaging was compared with right ventricular endomyocardial biopsy for assessing myocardial damage in patients with dilated cardiomyopathy (DCM). Methods: We examined 15 patients with DCM and 20 healthy controls. In addition to the conventional M-mode echocardiographic parameters, we determined the cyclic variation in IB values (CV-IB) obtained from parasternal short axis views of the left ventricle just under the transducer for both the interventricular septum (IVS) and the left ventricular posterior wall (PW). The per cent fibrosis area (%) and the transverse diameter of myocytes (m) were measured in right ventricular endomyocardial biopsy specimens by computer image analysis. To analyze the relationship between pathological findings and CV-IB, we divided patients into four subgroups on the basis of the pathological characteristics of endomyocardial biopsy specimens as follows: degeneration dominant group (n=5), fibrosis dominant group (n=5), dilated phase hypertrophic cardiomyopathy (n=2), and mixed type (n=3). Results: CV-IB in the IVS and the PW was lower in patients with DCM (8.8 ± 2.9, 8.3 ± 2.7dB, respectively) than in normal subjects (14.4 ± 2.9, 13.6 ± 2.6dB, respectively). Biopsy findings showed a mean per cent fibrosis area of 24.0 ± 12.3%, and a mean myocyte diameter of 14.3 ± 2.9m in patients with DCM. CV-IB was correlated with both of these findings: per cent fibrosis area (r=–0.56 in IVS, r=–0.56 in PW) and myocyte diameter (r=0.67 in IVS, r=0.71 in PW). CV-IB was decreased in all DCM subgroups compared with normal subjects, but there was no significant difference between subgroups. Conclusions: CV-IB was correlated with both the extent of fibrosis in myocardial tissue and the myocyte diameter. These findings suggest that ultrasonic tissue characterization is a good indicator of the severity of fibrosis and myocyte atrophy in patients with DCM.     

Sensitive detection of myocardial contraction abnormality in chronic hemodialysis patients by ultrasonic tissue characterization with integrated backscatter

Since acoustic properties of the myocardium are sensitive to the myocardial structure and the contractile conditions of myocyte, the authors evaluated cardiac dysfunction based on the integrated ultrasonic backscatter in 18 hemodialysis (HD) patients (duration: 102 +/- 84 months, mean age: 57.6 +/- 9.7 years) and 11 age-matched normals. The cyclic variation of integrated backscatter (CV-IB) at interventricular septum (IVS) and left ventricular posterior wall (PW) was measured and compared with percent fractional shortening (%FS) and percent wall thickening (%Th). The CV-IB of HD patients was smaller than that of control subjects (IVS: 6.2 +/- 1.1 dB vs 8.2 +/- 1.1 dB, p = 0.0003 and PW: 8.4 +/- 2.2 vs 10.3 +/- 1.3, p= 0.025). No significant difference was observed in %FS and %Th between HD patients and control subjects. In HD, the ratio of velocities of early diastolic inflow (E) to late atrial inflow was decreased (0.7 +/- 0.2 vs 1.1 +/- 0.7, p = 0.049) and deceleration time of E was prolonged significantly (200 +/- 28 msec vs 159 +/- 30 msec, p = 0.0082). In the absence of overt cardiac systolic dysfunction, myocardial damage indicated as a decrease in CV-IB and diastolic dysfunction identified on transmitral velocity waveform were detected, which may reflect from the myocardial fibrosis. As a mechanism, pressure overload, hyperparathyroidism, and anemia were neglected, and the other humoral factors may contribute to the myocardial damage in chronic renal failure.     

Changes in cardiac tissue characterization in carriers with gene mutations associated with hypertrophic cardiomyopathy

BACKGROUND: Early detection in patients with hypertrophic cardiomyopathy (HCM) is very important. Integrated backscatter (IB) provides a useful noninvasive measure of the acoustic properties of the myocardium, and may detect early myocardial changes. METHODS: Thirty-four carriers who had gene mutations causing HCM were studied. The patients were divided into three groups as follows: (1) 21 patients with wall hypertrophy (Group A), (2) 7 patients with ECG abnormalities but without wall hypertrophy (Group B), and (3) 6 carriers with neither ECG abnormalities nor wall hypertrophy (Group C). All subjects underwent ECG, conventional echocardiography and acoustic densitometry. In addition, we studied subjects < or =20 years old from Groups B and C (Group B-2 and Group C-2, respectively), and compared them with control subjects with no cardiac disorders who were < or =20 years old. RESULTS: In Group A, cyclic variations of integrated backscatter (CV-IB) in the interventricular septum and left ventricular posterior wall were significantly smaller than in Group C. The amplitude of IB in the interventricular septum and left ventricular posterior wall in Group A was significantly higher than those in Group C. Even in Group B, CV-IB in the interventricular septum was significantly smaller than those in Group C. Among patients < or =20 years old, CV-IB in the interventricular septum was significantly smaller in Group B-2 than in control subjects, while that in Group C-2 did not differ from that in control subjects. CONCLUSIONS: Changes in tissue characterization were found in the hearts of HCM gene carriers even in the absence of wall hypertrophy. These results suggest that tissue changes detectable by the acoustic densitometry methods may occur in the hearts of HCM gene carriers without wall hypertrophy, and that they may be detectable at the time of appearance of ECG abnormalities.     

Correlation between serum levels of interleukin-6 and vascular endothelial growth factor in gastric carcinoma

BACKGROUND AND AIM: Vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) are associated with the disease status of gastric carcinoma. However, their relationship remains unclear. This study aims to determine and correlate serum levels of VEGF and IL-6 in gastric carcinoma. METHODS: A total of 107 patients receiving gastrectomy entered this study. Serum levels of VEGF and IL-6 were measured by using ELISA, and were analyzed by using the Student's t-test to compare means and by Pearson correlation analysis to calculate correlation coefficients with respect to pathological characteristics including depth of tumor invasion, Laurén's classification, tumor location, Borrmann classification, and the status of lymph node metastasis. RESULTS: Serum VEGF levels were significantly higher in patients with mixed type carcinoma (387.5 +/- 176.9 vs 255.3 +/- 154.1 pg/mL, P = 0.047) or lymph node metastasis (339.1 +/- 205.1 vs 223.2 +/- 197.4 pg/mL, P = 0.007). Serum IL-6 levels were significantly higher in patients with Borrmann type IV carcinoma, compared with Borrmann type II and III carcinoma. In general, no correlation was noted between serum VEGF levels and IL-6 levels (r = 0.142, P = 0.145), but significant correlation was found in patients with early gastric carcinoma (r = 0.627, P = 0.004) or mixed type carcinoma (r = 0.804, P = 0.016). CONCLUSIONS: This study supports the correlation between serum VEGF and IL-6 levels in distinct subsets of gastric carcinoma patients, and indicates that IL-6 may play a role for the angiogenesis of gastric carcinoma via modulation of VEGF.     

Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy

OBJECTIVES: This study was designed to evaluate the beneficial effect of beta-blockers on circulating cytokine levels in patients with dilated cardiomyopathy (DCM). BACKGROUND: Elevated circulating levels of inflammatory cytokines have been reported in patients with DCM. However, alterations of the levels of inflammatory and anti-inflammatory cytokines in association with beta-blocker therapy are unknown. METHODS: We studied 32 patients with idiopathic DCM who had been treated with digitalis, diuretics and angiotensin-converting enzyme inhibitors. In addition to this combination therapy, beta-blockers were started in all patients. Serum levels of interleukin (IL)-10, tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNF-R1 and R2) were measured at baseline and 12 weeks after the initiation of beta-blocker therapy. We also measured plasma levels of neurohumoral factors, as well as left ventricular (LV) size and function. Ten age-matched subjects with no cardiac disease served as the control group. RESULTS: Baseline levels of IL-10, TNF-alpha and sTNF-R2 were significantly higher in patients with DCM than in control subjects (p < 0.05). There was a significant positive correlation between IL-10 and TNF-alpha levels (r = 0.545, p = 0.029). The TNF-alpha/IL-10 ratio correlated well with plasma epinephrine levels (r = 0.677, p = 0.025), and the level of sTNF-R2 was closely related to LV size. Serum levels of IL-10, TNF-alpha and sTNF-R2 were significantly decreased during beta-blocker therapy (p < 0.005). CONCLUSIONS: Our findings indicate that beta-blockers have an important immunoregulatory role in modifying the dysregulated cytokine network in DCM. This effect of beta-blockers may be partly responsible for the efficacy of therapeutic drugs for heart failure.     

Vascular endothelial growth factor level as a prognostic determinant of small cell lung cancer in Japanese patients

OBJECTIVE: To clarify the clinical significance of vascular endothelial growth factor (VEGF) in Japanese patients with small cell lung cancer (SCLC). MATERIALS AND METHODS: We measured serum VEGF levels using an enzyme-linked immunosorbent assay in 45 patients with SCLC before treatment and in 38 patients with benign pulmonary disease and in 32 healthy subjects (71 non-malignant subjects). VEGF immunostaining was performed in tissue biopsies obtained from 23 SCLC patients during bronchoscopic examination. RESULTS: Median serum VEGF level was 332 pg/ml in patients with SCLC and 160 pg/ml in non-malignant subjects, respectively. The 95% cut-off level to exclude non-malignant subjects was 500 pg/ml. An elevated VEGF level (>500 pg/ml) was found more frequently in patients with extensive disease of SCLC than in those with the limited disease (p<0.01). A significant positive correlation was found between the serum VEGF level and platelet count in SCLC patients (r=0.389; p=0.0083). Serum VEGF level also correlated with serum lactate dehydrogenase in SCLC patients (r=0.381; p=0.0098). However, it did not correlate with serum neuron-specific enolase and pro-gastrin-releasing peptide level. Patients with the elevated VEGF levels had significantly shorter progression-free time than those with the normal VEGF levels (p<0.05). Patients with the elevated VEGF levels had a significantly shorter overall survival time than those with the normal VEGF levels in univariate survival analysis (p<0.05). Further, the elevated VEGF level remained as a significant determinant of poor survival in multivariate analysis (p<0.01). Serum VEGF level was significantly higher in patients with positive VEGF protein immunoreactivity in tumor tissue in SCLC. CONCLUSION: Elevated serum VEGF levels were associated with poor outcome in SCLC.     

Ultrasonic tissue characterization of human hypertrophied hearts in vivo with cardiac cycle-dependent variation in integrated backscatter

Integrated ultrasonic backscatter (IB) is a noninvasive measure of the acoustic properties of myocardium. Previous experimental studies have indicated that altered acoustic properties of the myocardium are reflected by the magnitude of variation of IB during the cardiac cycle. In our study, cardiac cycle-dependent variation of IB was noninvasively measured using a quantitative IB imaging system in 12 patients with uncomplicated pressure-overload hypertrophy and 13 patients with hypertrophic cardiomyopathy. Sixteen normal subjects served as a control. The magnitude of cardiac cycle-dependent variation of IB for the posterior wall was 6.0 +/- 0.9 dB in normal subjects, 5.7 +/- 0.8 dB in the patients with uncomplicated pressure-overload hypertrophy, and 6.7 +/- 2.1 dB in the patients with hypertrophic cardiomyopathy. There were no significant differences among any of these groups. In contrast, the magnitude of cardiac cycle-dependent variation of IB for the septum was significantly smaller in the patients with uncomplicated pressure-overload hypertrophy (2.8 +/- 1.3 dB) and in the patients with hypertrophic cardiomyopathy (3.1 +/- 2.3 dB) than in normal subjects (4.9 +/- 1.0 dB). The magnitude of cardiac cycle-dependent variation of IB was smaller as the wall-thickness index increased (r = -0.53, p less than 0.01, n = 82 for all data). This IB measure also correlated with percent-systolic thickening of the myocardium (r = 0.67, p less than 0.01, n = 82). Thus, alteration in the magnitude of cardiac cycle-dependent variation of IB was observed in hypertrophic hearts and showed apparent regional myocardial differences.     

Dynamic assessment of myocardial involvement in patients with end-stage renal disease by ultrasonic tissue characterization and serum markers of collagen metabolism

BACKGROUND: Congestive heart failure is the most common cause of mortality in patients with end-stage renal disease (ESRD). However, noninvasive assessment for cardiac involvement in ESRD has not been established. HYPOTHESIS: Assessment of ultrasonic tissue characterization and serum markers of collagen degradation is useful for defining myocardial involvement in ESRD. METHODS: Cyclic variation of ultrasonic integrated backscatter of the ventricular septum (CV-IBS) and the serum levels of free matrix metalloproteinase-I (MMP-I) and tissue inhibitor of metalloproteinase-I (TIMP-I) were measured in 30 patients with ESRD undergoing routine hemodialysis (HD) and in 40 patients with essential hypertension (HTN). RESULTS: Compared with the group with HTN, ESRD (before HD) showed larger left ventricular (LV) mass index (217 +/- 56 vs. 146 +/- 45 g/m2, p < 0.01), worse LV diastolic function (E/A, 0.6 +/- 0.2 vs. 0.9 +/- 0.3, p < 0.05), smaller CV-IBS (9.0 +/- 1.3 vs. 12.4 +/- 0.9 dB, p < 0.01), and larger TIMP-I/MMP-I (46 +/- 10 vs. 34 +/- 10, p < 0.05), in spite of the comparable ventricular wall thickness. Thus, these indices may possibly reflect myocardial interstitial fibrosis. After HD (after the improvement of myocardial interstitial edema), a negative linear relationship between CV-IBS and TIMP-I/MMP-I was observed (r= -0.52, p < 0.05). CONCLUSIONS: Noninvasive assessment of ultrasonic tissue characterization and serum markers of collagen type I degradation may be a new diagnostic tool for defining myocardial interstitial fibrosis in patients with ESRD and LV hypertrophy.     

Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy

BACKGROUND AND AIMS: Left ventricular (LV) dilation and myocardial remodelling are hallmarks of heart failure in idiopathic dilated cardiomyopathy (DCM). Interstitial collagen is essential for LV integrity and function while degradation of collagen by collagenases, especially matrix-metalloproteinases (MMPs), are suggested to contribute to ventricular dilation. In the present study, serological markers of collagen metabolism were investigated. METHODS AND RESULTS: Serum levels of MMP-1 and its inhibitor (TIMP-1), the markers for collagen degradation type I (collagen carboxyterminal telopeptide (ICTP)) and synthesis (carboxyterminal propeptide of type I procollagen (PICP)) were quantified by ELISA and RIA of 43 patients with DCM and 47 age-matched control subjects. Free MMP-1 serum concentration was significantly increased in the DCM group (5.29+/-0.83 vs. 2.22+/-0.29 ng/ml; P=0.01) as well as the free TIMP-1 concentration (206.54+/-12.65 vs. 181.44+/-8.55 ng/ml; P=0.05). The free MMP-1/TIMP-1-ratio was higher in DCM than in the control group (0.030+/-0.005 vs. 0.012+/-0.001; P=0.01). ICTP was significantly increased (7.60+/-1.21 vs. 3.44+/-0.19 microg/l; P<0.001). PICP was not significantly increased (125.29+/-8.93 microg/l vs. 113.11+/-5.47 microg/l; P=n.s.). Free MMP-1 and MMP-1/TIMP-1-ratio correlated with LV end diastolic diameter [cm/m(2) body surface area (BSA)] (r=0.28; P=0.03 and r=0.34; P=0.01, respectively) as well as with cardiac index (CI) (r=-0.32; P=0.04 and r=-0.33; P=0.04, respectively) in patients with DCM. CONCLUSION: Serum markers of collagen degradation are elevated and might be valuable markers for progression of LV dilation in patients with DCM.     

血管紧张素Ⅱ及转化生长因子在糖尿病心肌病发病机制中的作用

摘要：目的探讨血清血管紧张素Ⅱ（angiotensin1I,Ang-Ⅱ）及转化生长因子α（transfomunggrowthfactorot,TGF-α）浓度在糖尿病（diabetesmellitus,DM）心肌病（diabeticcardiomyopathy．DCM）发病机制中的作用．．方法检测118例DCM患者、40例单纯2型DM患者及50名健康体检者（正常对照组）的血清Ang-Ⅱ及TGF-α浓度,并进行对比分析。DCM患者按心功能分级（纽约心脏学会标准）分为3个亚组：35例心功能正常者设为DCMI组,42例心功能Ⅱ级者设为DCM2组,41例心功能Ⅲ-IV级者设为DCM3组。DCM组及DM组血清Ang-Ⅱ及TGF-仪浓度进行直线相关分析。结果血清Ang-Ⅱ及TGF-α的浓度在DCM各亚组[Ang-Ⅱ：（99．6_＋20．3）、（116．9±26．5）、（137．5±33．7）pg／mL;TGF-α：（62．6±9．8）、（75．3±11．2）、（89．3±13．6）pg／mL]及DM组[Ang-1I：（83．9±17．1）pg／mL;TGF-α：（48．5±8．4）pg／mL]均显著高于正常对照组[Ang-U：（56．2±14．4）pg／mL;TGF-α：（26．8±5．1）pg／mL],差异有统计学意义（P均〈0．05）。DCM各亚组血清Ang-Ⅱ及TGF-α的浓度均屁著高于DM组．差异有统计学意义（P均〈0．05）。DCM组及DM组血清Ang-11与TGF-仪浓度呈正相关（r=0．93,P〈0．05;r=0．90．P〈0．05）。结论血清Ang-Ⅱ及TGF-仅浓度的升高,激活肾素血管紧张素系统,导致心肌纤维化可能是DCM的发病机制之一。     

Interstitial cell infiltrate and myocardial fibrosis in dilated cardiomyopathy: A special type of cardiomegaly corresponding to sequelae of myocarditis

We examined the relationship between interstitial cell infiltration and myocardial fibrosis in patients with clinically diagnosed dilated cardiomyopathy (DCM). Forty-two cases of DCM were divided into two groups, according to the mean number of the interstitial round cells per 10.2 x 10(4) square microns (Nic): the inflammatory group (Nic greater than or equal to 5) and noninflammatory group (Nic less than 5). The 12 cases in the inflammatory group were clinically similar to the 30 cases in the non-inflammatory group, but the inflammatory group exhibited a significantly (P less than 0.001) larger area of myocardial fibrosis (34.8% +/- 12.8% vs 17.5% +/- 8.2%), a significantly (P less than 0.01) higher frequency of diffuse perimyocytic-type fibrosis (83% vs 23%), fewer myocardial cells in the left ventricular wall (170 +/- 70 fibers vs 216 +/- 81 fibers), and significantly (P less than 0.01) greater hypertrophy of the myocytes (18.3 +/- 3.4 vs 15.3 +/- 2.7 microns). In addition, cases exhibiting marked fibrosis (fibrosis area greater than or equal to 25% of the myocardium) had a significantly higher Nic score (8.3 +/- 6.8) compared to cases with the less fibrotic type of DCM (4.0 +/- 5.7). We speculate that persistent or preceding inflammatory cell infiltration induces the myocardial fibrosis, especially the diffuse perimyocytic type, in the fibrosis-predominant type of DCM. Therefore, most of these cases may be a sequela of myocarditis, and more correctly termed post-myocarditic cardiomegaly.     

Oxidative stress and fibrosis in incipient myocardial dysfunction in type 2 diabetic patients

BACKGROUND: The existence of a diabetic cardiomyopathy has been recently supported by epidemiological studies. Increased oxidative stress and myocardial fibrosis has been hypothesized as etiopathogenic mechanisms. We sought to demonstrate the existence of incipient myocardial dysfunction in type 2 diabetes and its relation with markers of oxidative stress and myocardial fibrosis. METHODS: We studied by echocardiography 25 uncomplicated type 2 diabetic patients and 12 sex- and age-matched control subjects. Stress-corrected endocardial and midwall shortening and systolic and early diastolic velocity of the lateral mitral annulus (Doppler tissue) were used as parameters of myocardial function. Serum levels of glutathione peroxidase and procollagen type I carboxy-terminal peptide were used as markers of oxidative stress and myocardial fibrosis, respectively. RESULTS: Diabetics had significant lower values of corrected endocardial shortening than control subjects (P = 0.029). Both systolic and early diastolic mitral annulus velocities were significantly reduced in diabetics as compared to control subjects (P = 0.008 and P = 0.003, respectively). In diabetic patients, corrected endocardial (r = -0.56) and midwall shortening (r = -0.38) correlated with procollagen type I carboxy-terminal peptide, whereas systolic and early diastolic velocities of the mitral annulus correlated with glutathione peroxidase (both r = 0.44). CONCLUSIONS: In a highly selected group of uncomplicated type 2 diabetic patients, we found evidence of systolic and diastolic myocardial dysfunction, especially with the use of pulsed Doppler tissue imaging. The correlations between parameters of myocardial function and glutathione peroxidase and procollagen type I carboxy-terminal peptide support a mechanistic role for the increased oxidative stress and myocardial fibrosis in the myocardial dysfunction of type 2 diabetes.     

Myocardial dna strand breaks are detected in biopsy tissues from patients with dilated cardiomyopathy

Background: Progressive damage of cardiomyocytes with interstitial and replacement fibrosis accompanied by less inflammatory cell infiltration is observed in patients with dilated cardiomyopathy (DCM), suggesting some other mechanisms rather than necrotic cell death. Hypothesis: The aim of this study was to assess the possible involvement of apoptotic process in the pathogenesis of DCM and myocarditis. Methods: Endomyocardial biopsy was performed in patients with DCM (n = 9). myocarditis (n = 4), or atypical chest pain syndrome (as controls; n = 5). The TUNEL method was used for in situ detection of oligonucleosomal DNA strand breaks. Results: The TUNEL-positive cells were observed in three of nine patients with DCM and in all four with myocarditis, but in none of the controls. The TUNEL-positive nuclei were observed exclusively in cardiomyocytes in DCM, whereas in myocarditis they were detected mainly in interstitial cells and in a few myocytes. In DCM, interstitial fibrosis was greater in the TUNEL-positive than in TUNEL-negative patients (p<0.05). In either DCM or myocarditis, electron microscopic examination could not reveal morphologic features of apoptosis of cardiomyocytes. Conclusion: The DNA strand breaks were detected in cardiomyocytes in patients with DCM and mainly in interstitial cells in myocarditis. It is possible that the DNA strand breaks can be involved in mechanisms of progressive loss of functional cardiac units in these myocardial diseases.     

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.     

糖/血小板反应素-1/转化生长因子β1信号传导途径在糖尿病心肌病发病中的作用

目的探讨糖／血小板反应素-1（TSP-1）／转化生长因子（TGF）B。信号传导途径在糖尿病心肌病发病中的作用。方法采用高脂高热量饮食诱导出胰岛素抵抗,加小剂量链脲佐菌素注射建立糖尿病心肌病动物模型,以Masson染色、实时定量逆转录-聚合酶链反应、Western blot技术,检测左室心肌胶原含量、TSP-1、TGFβ1 mRNA和蛋白质表达水平的变化。结果与对照组相比,糖尿病心肌病大鼠左室心肌组织胶原含量明显高,存在心肌间质纤维化;TSP-1 mRNA和蛋白质表达均明显高,TGFβ1 mRNA、活性和非活性TGFβ1蛋白质表达亦明显高;TSP-1、TGFβ1 mRNA水平与空腹血糖、心肌组织胶原含量以及左室舒张功能指标均明显相关,TSP-1、活性TGFβ1蛋白质表达水平与空腹血糖、心肌组织胶原含量以及左室舒张功能指标之间亦存在明显的相关关系,但非活性TGFβ1蛋白质表达水平与空腹血糖、心肌组织胶原含量以及左室舒张功能指标之间无相关性。结论糖／TSP-1／TGFβ1信号传导途径在糖尿病心肌病时心肌间质纤维化发生发展过程中可能起着重要的作用,为临床上糖尿病心肌病的治疗提供了新的靶点。     

Coronary sinus thermography in idiopathic dilated cardiomyopathy: correlation with systemic inflammation and left ventricular contractility

BACKGROUND: Previous studies have demonstrated that patients with heart failure have increased myocardial heat production. Coronary sinus (CS) thermography is a new method for the evaluation of left ventricular heat production. AIMS: We investigated whether the CS blood temperature is increased in patients with idiopathic dilated cardiomyopathy (DCM) compared to a control group and whether the CS blood temperature correlates with ejection fraction and systemic inflammatory activation. METHODS AND RESULTS: We included 25 patients with DCM and 22 healthy subjects. Temperature measurements were performed using a new thermography catheter. Temperature difference (DeltaT) was defined as the difference between the CS and RA blood temperature. The CRP levels were also measured. DeltaT was significantly greater in patients with DCM compared to the controls (0.25+/-0.09 vs 0.14+/-0.07 degrees C, p<0.01). DeltaT and EF were inversely correlated in patients with DCM (R=0.43). We categorized patients with DCM into two groups using a CRP cut-off value of < or =1 mg/dL. DeltaT in patients with high CRP was less (0.21+/-0.06 degrees C) compared to patients with low CRP (0.30+/-0.08 degrees C, p=0.01). CONCLUSIONS: In patients with DCM increased heat production from the myocardium, as estimated from the coronary sinus blood temperature, was demonstrated, interestingly there was no correlation with systemic inflammatory activation.