Serum markers of angiogenesis and myocardial ultrasonic tissue characterization in patients with dilated cardiomyopathy

BACKGROUND AND AIMS: It has been proven that a disturbance in angiogenesis contributes to the progression of myocardial interstitial fibrosis in idiopathic dilated cardiomyopathy (DCM). This study was designed to evaluate the relationship between serum activity of angiogenic factors and myocardial ultrasonic tissue characterization in patients with DCM. METHODS AND RESULTS: We studied 30 patients with DCM and 15 healthy control subjects. Serum levels of vascular endothelial growth factor (VEGF), interleukin (IL)-4 and IL-13 were measured using enzyme-linked immunosorbent assay. We determined calibrated myocardial integrated backscatter (IB) as the value of myocardial interstitial fibrosis using ultrasonic tissue characterization and also quantified the magnitude of cyclic variations in IB (CV-IB). Serum levels of VEGF and IL-13 were significantly higher in patients with DCM than in control subjects (both P<0.05). Calibrated IB was significantly higher and CV-IB was markedly lower in patients with DCM than in control subjects (both P<0.01). In patients with DCM, the levels of IL-13 significantly correlated with calibrated IB (r=0.520, P=0.018). In addition, there was a significant negative correlation between levels of VEGF and CV-IB (r=-0.611, P=0.007). CONCLUSION: The increase in serum VEGF and IL-13 may be closely related to alterations in myocardial texture in DCM.     

Integrated backscatter for the assessment of myocardial viability

PURPOSE OF REVIEW: Ultrasonic tissue characterization is a non-invasive diagnostic method that uses myocardial integrated backscatter analysis to determine contractile performance and myocardial viability independent of wall motion. This review discusses recent clinical findings regarding the application of ultrasonic tissue characterization for the assessment of myocardial viability. RECENT FINDINGS: As this technique is non-invasive, ultrasonic tissue characterization can be used to predict the patency of infarct-related arteries in patients in the early stage of acute myocardial infarction. Several recent studies have shown that this technique is useful in identifying myocardial contractile reserve. The accuracy of ultrasonic tissue characterization for predicting functional recovery after coronary reperfusion is comparable to dobutamine echocardiography and radionuclide methods. Several studies have suggested that the cyclic variation of myocardial integrated backscatter reflects myocardial viability rather than contractile reserve. The cyclic variation of integrated backscatter is associated with myocardial viability confirmed by the integrity of the microvasculature identified by contrast echocardiography. In addition, the cyclic variation of integrated backscatter better reflects myocardial viability confirmed by the integrity of cellar metabolism than contractile reserve. SUMMARY: Ultrasonic tissue characterization with integrated backscatter is a useful non-invasive method that can provide unique information for the assessment of myocardial viability.     

Sensitive detection of the effects of reperfusion on myocardium by ultrasonic tissue characterization with integrated backscatter

We have shown recently that tissue characterization of myocardium with ultrasound reflects changes associated with contractile function throughout the cardiac cycle. To determine whether ultrasonic tissue characterization can sensitively detect the impact of ischemic injury and reperfusion on contractile properties of the heart, we studied the time course of change of backscatter after 5, 20, and 60 min of coronary occlusion followed by reperfusion in 15 dogs. The time-averaged integrated backscatter (IB) and the amplitude and phase of cyclic variation of IB (phase relative to the left ventricular pressure waveform) were measured. A novel ultrasonic index of acute injury was identified, the phase-weighted amplitude of cyclic variation, and calculated by weighting the amplitude of cyclic variation of IB with respect to the phase. We hypothesized that backscatter variables would change dramatically after occlusion and that their restitution after reperfusion would sensitively reflect the extent and time course of reversibility of ischemic injury. After coronary occlusion, segmental wall thickening decreased from approximately 55% to 5% regardless of the duration of ischemia. Changes in backscatter associated with this decrease included an increase in time-averaged IB of approximately 5 dB, a 5 dB decrease in cyclic variation, an 80 degree phase shift, and a 7 dB decrease in phase-weighted amplitude. Wall thickening after reperfusion immediately after the 5, 20, or 60 min occlusions recovered to 45%, 27%, and 12% of baseline values, respectively. Within 3 hr it recovered to 53%, 44%, and 22%. Time-averaged IB recovered initially by 89%, 61%, and 44% (all p less than .05) and continued to recover subsequently although more slowly. Ultimate recovery was virtually complete. In contrast to the rapid recovery of time-averaged IB, phase-weighted amplitude recovered initially to only 72%, 41%, and -7% of baseline (all p less than .05) and manifested slower and incomplete recovery when ischemia had been present for 20 or 60 min. After reperfusion, the time course of both cyclic variation and phase were reflected by changes in the phase-weighted amplitude. The backscatter variables assessed appear to sensitively delineate the duration, time course of recovery, and reversibility of ischemic injury in response to reperfusion. The results suggest that early recovery of time-averaged IB corresponds in part to the restoration of tissue ultrastructural integrity.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Serial measurement of integrated ultrasonic backscatter in human cardiac allografts for the recognition of acute rejection

Cyclic variation of integrated ultrasonic backscatter (IB) was noninvasively measured in the septum and left ventricular posterior wall using a quantitative IB imaging system to assess the alterations in the acoustic properties of myocardium associated with acute cardiac allograft rejection. The study population consisted of 23 cardiac allograft recipients and 18 normal subjects. In each cardiac allograft recipient, one to eight (mean, four) IB studies were performed, each within 24 hours of right ventricular endomyocardial biopsy performed for rejection surveillance. The magnitude of the cyclic variation of IB in the posterior wall was 5.9 +/- 0.9 dB in normal subjects and 6.2 +/- 1.3 dB in the cardiac allograft recipients without previous or current histological evidence of acute rejection (n = 17, p = NS vs. normal subjects). The magnitude of cyclic variation of IB in the septum was 4.8 +/- 1.1 dB in normal subjects and 3.8 +/- 2.0 dB in the cardiac allograft recipients (n = 15, p = NS vs. normal subjects). A significant decrease in the septal IB measure was observed in cardiac allograft recipients with left ventricular hypertrophy (wall thickness of at least 13 mm) (2.6 +/- 1.7 dB, n = 8, p less than 0.05 vs. normal subjects). IB studies were done before and during moderate acute rejection in 11 recipients (14 episodes). During moderate acute cardiac rejection, the magnitude of the cyclic variation in IB decreased from 6.7 +/- 1.3 to 5.1 +/- 1.4 dB in the posterior wall (n = 14, p less than 0.05) and from 4.2 +/- 2.1 dB to 2.9 +/- 1.8 dB in the septum (n = 12, p less than 0.05). These data suggest 1) the magnitude of the cyclic variation in IB of the septum is different in cardiac allografts with cardiac hypertrophy and normal subjects, possibly reflecting regionally depressed myocardial contractile performance and 2) acute cardiac rejection in humans is accompanied by an alteration in the acoustic properties of the myocardium. This change is detectable by serial measurement of the magnitude of the cyclic variation in IB, both in the septum and in the posterior wall.     

Ultrasonic tissue characterization with integrated backscatter. Acute myocardial ischemia, reperfusion, and stunned myocardium in patients

We have previously shown in studies of experimental animals that myocardium exhibits a cardiac cycle-dependent variation of integrated backscatter that reflects regional myocardial contractile performance and that is blunted promptly after arterial occlusion and recovers after reperfusion. To define the clinical utility of ultrasonic tissue characterization with integrated backscatter for detection of acute myocardial infarction and reperfusion, 21 patients (14 men and seven women) were studied in the cardiac care unit within the first 24 hours (mean time, 11.3 hours; range, 3.5-23.8 hours) after the onset of symptoms indicative of acute myocardial infarction with conventional two-dimensional and M-mode echocardiography and with analysis of integrated backscatter. The magnitude of cyclic variation of integrated backscatter was measured from several sites within acute infarct regions and normal regions remote from the infarct zone for each patient. The average magnitude of cyclic variation among all patients (n = 21) was 4.8 +/- 0.5 dB in normal regions compared with 0.8 +/- 0.3 dB in infarct regions (p less than 0.05) within the first 24 hours after the onset of symptoms. Among the patients who had two studies, 15 (mean, 7.1 days; range, 2-31 days for second study) underwent coronary arteriography to define vessel patency. In patients with vessels with documented patency (n = 10), the magnitude of cyclic variation in infarct regions increased over time from 1.3 +/- 0.6 to 2.5 +/- 0.5 dB from the initial to final study (p less than 0.05). Patients with occluded infarct-related arteries (n = 5) exhibited no significant recovery of cyclic variation (0.3 +/- 0.3-0.6 +/- 0.3 dB). A blinded analysis of standard two-dimensional echocardiographic images revealed no significant recovery of wall thickening in either group over the same time intervals. Ultrasonic tissue characterization promptly detects acute myocardial infarction and may delineate potential beneficial effects of coronary artery reperfusion manifest by restoration of cyclic variation of integrated backscatter in the presence of severe wall motion abnormalities.     

Thrombolytic therapy for a patient with systemic lupus erythematosus and acute myocardial infarction

A young patient with systemic lupus erythematosus was admitted to our hospital because of acute myocardial infarction, and treated by thrombolysis. Coronary angiography revealed a significant stenosis of the left anterior descending artery, together with an intraluminal thrombus. Clotting studies demonstrated an anticoagulant factor suggestive of lupus erythematosus. We conclude that thrombolytic therapy can be useful in patients with systemic lupus erythematosus who present with acute myocardial infarction, although some caution is needed in treatment.     

Mitral valve prolapse in systemic lupus erythematosus

Despite a low incidence of clinical manifestations, autopsy data suggest endocardial and myocardial disease in about 50% of patients with systemic lupus erythematosus. To investigate whether mitral valve prolapse can be considered a clinical manifestation of cardiac involvement in systemic lupus erythematosus, we carried out an echocardiographic study in 51 affected subjects and 102 normals matched for age and sex. Prevalence of mitral valve prolapse was 25% in patients with systemic lupus erythematosus and 9% in healthy controls with a statistically significant difference (p less than 0.01). Neither pericardial effusion nor prolonged (more than 12 months) treatment with corticosteroids were associated with higher prevalence of mitral valve prolapse. Libman-Sacks verrucae on the mitral valve apparatus as well as focal myocardial scars affecting the papillary muscles and adjacent myocardium could be responsible for the development of the valvular dysfunction. We suggest that mitral valve prolapse can be considered a manifestation of cardiac involvement in patients with systemic lupus erythematosus.     

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.     

Silent myocardial infarct as a main manifestation of systemic lupus erythematosus

Myocardial infarction has rarely been reported in patients with systemic lupus erythematosus but may develop late in the disease usually as a result of severe and accelerated atherosclerosis or coronary arteritis. A 32-year-old man with untreated and unrecognized systemic lupus erythematosus, in the absence of conventional coronary risk factors (except family predisposition) and definite extracardiac manifestations of systemic lupus erythematosus had a silent myocardial infarction early in the course of the disease. A coronary arteriogram revealed multiple stenosis of the left anterior descending artery and critical stenosis of the right coronary artery. It is our belief that lupus vasculitis is a likely contributing factor in the development of obstructive coronary disease in this patient.     

Ultrasound integrated backscatter tissue characterization of remote myocardial infarction in human subjects

To determine whether quantitative ultrasound tissue characterization differentiates normal myocardial regions from segments of remote infarction, 32 consecutive patients with a diagnosis of previous myocardial infarction were evaluated. Images were obtained in real time with a modified two-dimensional ultrasound system capable of providing continuous signals in proportion to the logarithm of integrated backscatter along each A line. In 15 patients, adequate parasternal long-axis images that delineated both normal and infarct segments were obtained with standard time-gain compensation. Image data were analyzed to yield both magnitude and delay (electrocardiographic R wave to nadir normalized for the QT interval) of the cyclic variation of backscatter. Cyclic variation was present in 55 of 56 normal myocardial sites, averaging (mean +/- SEM) 3.2 +/- 0.2 dB in magnitude and exhibiting a mean normalized delay of 0.87 +/- 0.03. The magnitude of cyclic variation in infarct segments was significantly reduced to 1.1 +/- 0.2 dB (42 sites), and the delay was markedly increased to 1.47 +/- 0.12 (21 sites) (p less than 0.0001 for both). In 20 of 42 infarct sites, no cyclic variation was detectable. Thus, ultrasound tissue characterization quantitatively differentiated infarct segments from normal myocardium in patients with remote myocardial infarction.     

Factor XII deficiency with systemic lupus erythematosus. Biological implications.

A patient with Factor XII (Hageman) deficiency and fulminant systemic lupus erythematosus is presented. The Factor XII deficiency was noted prior to the onset of clinical systemic lupus erythematosus and persisted throughout the patient's course without associated hemorrhagic manifestations. There was no evidence for a circulating anticoagulant. The patient had a rapidly progressive fatal course unresponsive to corticosteroid therapy. Factor XII levels did not increase during therapy with steroids. Despite absence of Hageman factor, evidence for activation of complement by the classic pathway and thromboembolic phenomenon was observed. The role of Factor XII in coagulation and inflammatory pathways and the influence of the factor deficiency on the course of the patient's illness are discussed.     

Myocardial infarction due to coronary atherosclerosis in three young adults with systemic lupus erythematosus

Three patients, 24, 24 and 25 years of age, with systemic lupus erythematosus had signs of myocardial infarction. Two had serial electrocardiographic changes indicative of infarction without any cardiac symptoms. The third patient had clinical evidence of an acute massive myocardial infarction, which was proved at autopsy to be due to coronary atherosclerosis. This case is presented in detail and the association between systemic lupus erythematosus and myocardial infarction is reviewed. It is postulated that the relation between lupus erythematosus and coronary atherosclerosis is more than coincidental.     

Coronary arteritis in systemic lupus erythematosus.

Acute myocardial infarction in systemic lupus erythematosus may be due to an atheromatous or arteritic process. Confirmation of the latter etiology has previously been made only at postmortem examination. A 45-year-old white woman with known systemic lupus erythematosus developed anginal pain and multiple episodes of acute myocardial infarction. During this period, there was serologic but no other clinical evidence of active systemic lupus erythematosus. Serial coronary angiographic studies were strongly suggestive of an arteritic process based upon (1) a saccular aneurysm with no obstructive lesions in a coronary artery supplying an area of recent transmural myocardial infarction and (2) the development of significant obstructive lesions in a previously normal coronary artery over a period of 18 days. This case illustrates the difficulties in distinguishing between atherosclerosis and arteritis using a single coronary angiographic study. The distinction is significant because of the different therapeutic interventions required.     

Factor xii deficiency with systemic lupus erythematosus

A patient with Factor XII (Hageman) deficiency and fulminant systemic lupus erythematosus is presented. The Factor XII deficiency was noted prior to the onset of clinical systemic lupus erythematosus and persisted throughout the patient's course without associated hemorrhagic manifestations. There was no evidence for a circulating anticoagulant. The patient had a rapidly progressive fatal course unresponsive to corticosteroid therapy. Factor XII levels did not increase during therapy with steroids. Despite absence of Hageman factor, evidence for activation of complement by the classic pathway and thromboembolic phenomenon was observed. The role of Factor XII in coagulation and inflammatory pathways and the influence of the factor deficiency on the course of the patient's illness are discussed.     

The dynamism of cutaneous lupus erythematosus: mild discoid lupus erythematosus evolving into SLE with SCLE and treatment-resistant lupus panniculitis

We present a 47-year-old Caucasian female who initially presented with mild discoid lupus erythematosus that evolved into systemic lupus erythematosus with subacute cutaneous LE and treatment-recalcitrant lupus panniculitis. Conventional therapy with antimalarials, systemic steroids, azathioprine, cyclophosphamide, methotrexate, and pulse doses of methylprednisolone did not control the course of the disease. Cyclosporin-A treatment led to clinical improvement and maintained remission.     

Abnormal Ultrasonic Tissue Characterization of the Myocardium in Children Receiving Doxorubicin for Cancer Therapy

Ultrasonic tissue characterization by integrated backscatter is a sensitive tool to detect myocardial changes related to specific diseases. Cardiotoxicity related to doxorubicin use is well known and remains a major concern. To determine if ultrasonic tissue characterization of the myocardium is abnormal in patients receiving doxorubicin, we studied the myocardium of pediatric patients receiving doxorubicin by a real-time integrated backscatter (IB) imaging system. Three values of IB parameters were averaged from the left ventricular posterior wall at the level of the tip of the mitral valve. In addition to standard echo parameters, we obtained the following IB parameters: peak, nadir, cyclic variation (CV), end-diastole, heart-rate corrected delay of nadir (Delay_c), and the ratio of CV over end-diastole. IB parameters were normalized as Z scores from multiple linear regression equations including echo wall thickness and functional indices from a normal control group of 72 children. We evaluated 27 patients at a median age of 11.6 years (1.6 years to 20.3 years) and median time of 1.7 m (2 days to 7.2 years) after a mean cumulative dose of doxorubicin of 188 ± 120 mg/m² for treatment of neoplasm. Mean (± SD) Z scores for IB variables were as follows: zPeak 0.15 ± 1.07, P = 0.47; zNadir 0.41 ± 1.16, P = 0.08; zCV -0.49 ± 0.95, P = 0.01; zEnd-diastole 0.17 ± 0.94, P = 0.38; zDelay_c 0.33 ± 0.80, P = 0.06, and zCV/Peak -0.59 ± 1.06, P = 0.009. This study shows that ultrasonic IB of the myocardium of children receiving doxorubicin is abnormal and is independent of the cumulative dosage of doxorubicin or the amount of time since the last dose.     

Serotonin content of platelets in inflammatory rheumatic diseases

Significantly decreased platelet serotonin contents were measured in rheumatoid arthritis, systemic lupus erythematosus (SLE), progressive systemic sclerosis, and mixed connective tissue disease. An inverse relationship between platelet serotonin levels and clinical disease activity was observed in both rheumatoid arthritis and systemic lupus erythematosus. SLE patients with multiple organ involvement showed the lowest platelet serotonin values. No correlation was observed between platelet serotonin contents and nonsteroidal antiinflammatory drug treatment, presence of circulating platelet reactive IgG, or the amount of circulating immune complexes. The results are interpreted as indicating platelet release occurring in vivo during inflammatory episodes of the rheumatic disorders investigated.     

Antibodies reacting with ribosomal ribonucleoprotein in connective tissue diseases

Precipitating antibody to an antigen present in cytoplasm was detected in the sera of 7 patients with systemic lupus erythematosus, 1 patient with an overlap syndrome of systemic lupus erythematosus and rheumatoid arthritis, and 1 patient with mixed connective tissue disease. By physicochemical and enzymatic studies, the antigen was shown to have the properties of ribosomal ribonucleoprotein (r-RNP). Cytoplasmic staining in immunofluorescence was observed with all the 9 sera containing antibodies to r-RNP. In certain cases, cytoplasmic staining was associated with nucleolar staining. Antibody to r-RNP is different in immunologic specificity and clinical significance from antibody to nuclear RNP and is present primarily in patients with systemic lupus erythematosus.     

Heart disease in systemic lupus erythematosus: diagnosis and management

Most patients suffering from systemic lupus erythematosus develop secondary heart disease at some time during the course of the primary illness. The most common forms of this type of heart disease are acute fibrinous pericarditis and hypertension. By means of echocardiography, an increased incidence of pericardial effusion has been demonstrated. Although commonly noted at autopsy, myocarditis is often clinically silent. However, endomyocardial biopsy may confirm its presence during life. Libman-Sacks endocarditis, although encountered in 40 to 50% of hearts at autopsy, is rarely diagnosed during life. When significant valve dysfunction such as aortic insufficiency or mitral regurgitation develops during the course of systemic lupus erythematosus, then Libman-Sacks endocarditis should be strongly suspected. Cardiac arrhythmias, first degree AV block, and acquired complete heart block may develop either de novo or in association with lupus pericarditis, myocarditis, vasculitis, etc. Complete congenital heart block has been reported in newborns of mothers with systemic lupus erythematosus, particularly those who have an antibody to a soluble tissue ribonucleoprotein antigen called RO(SS-A). Coronary arteritis and premature coronary atherosclerosis manifesting in either angina pectoris or myocardial infarction in young adults, particularly women suffering from systemic lupus erythematosus, have received attention recently. The development of hypertension and hyperlipidemia while such patients are receiving prolonged corticosteroid therapy has been incriminated as the significant risk factor in premature coronary atherosclerosis. Longstanding hypertension and congestive heart failure have unfavorable prognoses. This report is based on a cumulative review of 50 patients with acute and chronic systemic lupus erythematosus seen at our institution and in private practice during the last 10 years.