Toshiyuki Noda

Plasma Fas Ligand, an Inducer of Apoptosis, and Plasma Soluble Fas, an Inhibitor of Apoptosis, in Patients With Chronic Congestive Heart Failure

OBJECTIVES This study sought to examine plasma levels of soluble Fas/APO-1 receptor (sFas), an inhibitor of apoptosis, and soluble Fas ligand (sFas-L), an inducer of apoptosis, and their relation to each other and to other clinical variables, such as New York Heart Association functional class, tumor necrosis factor (TNF) and interleukin-6 (IL-6) in congestive heart failure (CHF). BACKGROUND It has been recently reported that apoptotic cell death occurs in myocytes of dogs with CHF. Hypoxia is frequently seen in advanced CHF and can stimulate Fas/APO-1 receptors (Fas) to induce apoptosis in cultured myocytes. Fas and Fas ligand (Fas-L) are cell-surface proteins and representative apoptosis-signaling molecules. Fas on the cell membrane induces apoptosis when it binds Fas-L or sFas-L. However, plasma sFas, a molecule lacking the transmembrane domain of Fas, blocks apoptosis by inhibiting binding between Fas and Fas-L or sFas-L on the cell membrane. At present, it is unknown whether plasma sFas-L and plasma sFas increase in the presence of cardiac disease. METHODS The study included 70 patients (mean [+/-SEM] age 65 +/- 2 years, range 21 to 93) with chronic CHF (coronary artery disease in 28, dilated cardiomyopathy in 27, valvular heart disease in 15) and 62 age- and gender-matched normal control subjects. Plasma levels of sFas, sFas-L, TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assays using monoclonal anti-human antibodies. RESULTS There was no significant difference in sFas-L levels between normal subjects and patients in functional classes I to IV; however, sFas increased with severity of functional classification, independent of the underlying disease. sFas levels were significantly higher even in patients in functional class II than in normal subjects and those in functional class I, and were highest in patients in functional class IV (normal subjects; 2.2 +/- 0.1 ng/ml; functional class I: 2.2 +/- 0.2 ng/ml; functional class II: 3.1 +/- 0.2 ng/ml; functional class III: 3.9 +/- 0.3 ng/ml; functional class IV: 5.1 +/- 0.6 ng/ml). Plasma sFas levels were significantly higher in patients with elevated pulmonary artery wedge pressure and a decresed cardiac index than in those with values in the normal range. In patients in functional class IV, there was no significant difference in plasma sFas levels between the survivors and non-survivors during 6-month follow-up. However, plasma levels of sFas tended to decrease in nine patients with clinical improvement (baseline sFas: 5.2 +/- 0.8 ng/ml; 6-month sFas: 4.3 +/- 0.5 ng/ml, p = 0.07) but were similar in patients with no change in functional class. TNF-alpha and IL-6 were increased significantly only in patients in functional class IV, as previously reported, but were not related to sFas. CONCLUSIONS We found elevated levels of plasma sFas and no increase in plasma sFas-L in human CHF. The increase in sFas may play an important role in the pathophysiologic mechanisms of CHF.

Noninvasive quantitative tissue characterization and two-dimensional color-coded map of human atherosclerotic lesions using ultrasound Integrated backscatter comparison between histology and Integrated backscatter images

OBJECTIVES The purpose of the present study was to define clinicopathologically whether integrated backscatter (IB) combined with conventional two-dimensional echo (2DE) can differentiate the tissue characteristics of calcification (CL), fibrosis (FI), lipid pool (LP) with fibrous cap, intimal hyperplasia (IH) and thrombus (TH) and can construct two-dimensional tissue plaque structure in vivo. BACKGROUND It is difficult to characterize the components of plaque using conventional 2DE techniques. METHODS Integrated backscatter values of plaques were measured in the right common carotid and femoral arteries (total 24 segments) both during life and after autopsy in 12 patients (age 68 to 84 years, 10 men and two women). Integrated backscatter values were determined using a 5-12 MHz multifrequency transducer, setting the region of interests (ROIs) (11 x 11 pixels) on the echo tomography of the entire arterial wall (55 +/- 10 ROI/segment) and comparing it with histologic features in the autopsied arterial specimens. RESULTS Corrected IB values obtained before death and at autopsy were significantly correlated (r = 0.93, p < 0.01). Corresponding to the histologic features, corrected IB values on the rectangle ROIs obtained during life were divided into five categories: category 1 (TH) 4 < IB < or = 6; category 2 (media and IH or LP in the intima) 7 < IB < or = 13; category 3 (FI) 13 < IB < or = 18, category 4 (mixed lesion) 18 < IB < or = 27 and category 5 (CL) 28 < IB < or = 33. In category 2, media and intima were differentiated using conventional 2DE. Under the above procedures, color-coded maps constructed with IB-2DE obtained during life precisely reflected the histologic features of media and intima. CONCLUSIONS Integrated backscatter with 2DE represents a useful noninvasive tool for evaluating the tissue structure of human plaque.

Considerable Time From the Onset of Plaque Rupture and/or Thrombi Until the Onset of Acute Myocardial Infarction in Humans Coronary Angiographic Findings Within 1 Week Before the Onset of Infarction

BackgroundIt has been thought that the thrombi and bleeding in plaques that occur after plaque rupture or endothelial damage from vessels with mild stenosis suddenly occlude the lumen and cause acute myocardial infarction (AMI). However, our hypothesis is that thrombi and bleeding may not suddenly occlude the lumen. Methods and ResultsThe study group consisted of 20 patients who had coronary angiograms performed within 1 week (3±3 days) before AMI and 20 control patients who had coronary angiograms performed 6 to 18 months (282±49 days) before AMI. The features of infarct-related coronary segments (IRCS) at 3 days before AMI were the presence of a significant stenosis of >50% (95% in incidence and 71±12% diameter stenosis) and Ambrose’s type II eccentric lesions (plus multiple irregularities), an indicator of plaque rupture and/or thrombi (60% [70%]), and the features at 1 year before AMI were mild stenosis of <50% (95% incidence and 30±18% diameter stenosis) with rare Ambrose’s type II eccentric lesions (plus multiple irregularities) (10% [10%]). The same relation was observed in each of the 4 subgroups with Q-wave infarction, non–Q-wave infarction, preceding effort angina within 1 month before AMI, and no preceding effort angina. ConclusionsThe appearance of marked progression and Ambrose’s type II eccentric lesion on coronary angiograms 3 days before AMI suggests the presence of a considerable time from the onset of plaque rupture and/or thrombi until the onset of AMI. These features may be predictors of AMI. The concept provides new insight into the mechanism and prevention of human AMIs.

Process of progression of coronary artery lesions from mild or moderate stenosis to moderate or severe stenosis: A study based on four serial coronary arteriograms per year.

BACKGROUND The process of progression in coronary artery disease is unknown. METHODS AND RESULTS The subjects were 36 patients with 36 objective vessels with clinically significant progression of coronary artery disease (>/=15% per year) in whom 4 serial coronary arteriograms (CAGs) were performed at intervals of approximately 4 months in a 1-year period. The degree of progression of percent stenosis between each of 2 serial CAGs was classified as marked (M: >/=15%), slight (S: 5% to 14%), and no progression (N: <5%). From the pattern of progression, the 36 vessels were classified as 14 type 1 vessels with marked progression (N-->N-->M in 13 vessels and S-->S-->M in 1 vessel) and 22 type 2 vessels without marked progression (S-->S-->S in 18 vessels, N-->S-->S in 4). Percent stenosis at the first, second, third, and final CAGs was 44+/-14%, 46+/-13%, 46+/-13%, and 88+/-10% (P<0.05 versus first CAG) in type 1 vessels and 44+/-11%, 50+/-9%, 59+/-9%, and 67+/-9% in type 2 vessels (P<0.05 for second, third, and final CAGs versus first CAG). Type 1 vessels featured the sudden appearance of severe stenosis due to marked progression, angina pectoris, or myocardial infarction (71%) and Ambrose type II eccentric lesions indicating plaque rupture or thrombi (57%). Type 2 vessels featured continuous slight progression of stenosis with smooth vessel walls; angina pectoris (14%) occurred when the percent stenosis reached a severe level. An increase in serum C-reactive protein was observed only in the type 2 vessel group, which suggests a relation between continuous slight progression and inflammatory change. CONCLUSIONS Two types of stenosis progression provide a new insight into the mechanism of coronary artery disease.

Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease.

OBJECTIVES This study focused on 1) the determination of the optimal preconditioning (PC) duration, and 2) the protective effect of nicorandil (NC), a hybrid nitrate with a KATP channel opening effect, during a percutaneous transluminal coronary angioplasty (PTCA) model in humans. BACKGROUND The ischemic PC effect is induced in 180 s ischemia, but not in 120 s ischemia in rabbit hearts. However, the duration of ischemia that induces PC effect and the role of the KATP channel in the PC effect in humans are still unclear. METHODS Forty-six patients with stable angina were randomly allocated to four groups: the duration of the first inflation as PC ischemia was 60 s in the PC60 group (n = 12), and 180 s in the PC180 group (n = 12). In the other groups, NC (80 microg/kg) was intravenously given for 1 min in the NC group (n = 12), and isosorbide dinitrate (ISDN) (40 microg/kg) was given in the ISDN group (n = 10). Five minutes after first inflation or drug administration, a second inflation was conducted for 120 s in each group. In the ECG, the lead with the largest shift in ST segment (deltaST max), and the sum of elevated ST levels in all leads (sigmaST) were determined. RESULTS In the PC60 group, no significant difference was observed in either deltaST max or sigmaST between the first and second inflation. However, the second inflation in the PC180 group showed significantly lower levels of deltaST max and sigmaST compared with those of the first inflation. In the NC group, both deltaST max and sigmaST measured at 30 s and 60 s after balloon inflation were significantly lower than those of the first inflation in the PC60 and PC180 control groups. In the ISDN group, no significant difference was observed in deltaST max or sigmaST. CONCLUSION In human PTCA models, a PC effect is observed in 180 s ischemia, but not in 60 s ischemia. A pharmacological PC effect is induced by NC, a KATP channel opener with a nitrate-like effect but not ISDN. This suggests that the opening of KATP channels plays an important role in the protecting effect of NC.

Marked expression of plasma brain natriuretic peptide is a special feature of hypertrophic obstructive cardiomyopathy

OBJECTIVES We examined whether plasma brain natriuretic peptide levels are abnormally elevated in hypertrophic obstructive cardiomyopathy compared with other cardiac diseases. BACKGROUND We previously reported that plasma brain and atrial natriuretic peptide levels were elevated in hypertrophic cardiomyopathy. METHODS We compared plasma concentrations of brain and atrial natriuretic peptide and hemodynamic and echocardiographic data in 50 patients with hypertrophic obstructive cardiomyopathy (n = 15, mean [+/-SD] intraventricular pressure gradient 37 +/- 16 mm Hg), hypertrophic nonobstructive cardiomyopathy (n = 15), aortic stenosis (n = 10, mean pressure gradient 41 +/- 18 mm Hg) and hypertensive heart disease (n = 10, mean systolic/diastolic blood pressure 203 +/- 16/108 +/- 11 mm Hg, respectively) and 10 normal subjects. RESULTS Plasma brain natriuretic peptide levels were higher in the hypertrophic obstructive cardiomyopathy group (397.1 +/- 167.8 pg/ml*) than in the hypertrophic nonobstructive cardiomyopathy (60.0 +/- 48.1 pg/ml*), hypertensive heart disease (53.9 +/- 31.4 pg/ml*), aortic stenosis (75.4 +/- 54.3 pg/ml*) and normal groups (9.8 +/- 6.4 pg/ml [*p < 0.05 vs. normal group, p < 0.05 vs. hypertrophic obstructive cardiomyopathy group]). Although plasma atrial natriuretic peptide levels were higher in the hypertrophic obstructive cardiomyopathy group than the other patient groups, the brain/atrial natriuretic peptide ratio in the hypertrophic obstructive cardiomyopathy group was higher (4.5 +/- 2.3) than those in the other three patient groups (1.1 to 1.4) and the normal group (0.7 +/- 0.5). Left ventricular end-diastolic pressure and left ventricular end-diastolic volume index were similar among the four patient groups. The interventricular septal thickness and the ratio of interventricular septal thickness to left ventricular posterior wall thickness were similar between the hypertrophic obstructive and nonobstructive cardiomyopathy groups. CONCLUSIONS Abnormal elevations of plasma brain natriuretic peptide levels are difficult to explain on the basis of hemodynamic and echocardiographic data and are a special feature of hypertrophic obstructive cardiomyopathy.

Evidence for the delayed effect in human ischemic preconditioning: Prospective multicenter study for preconditioning in acute myocardial infarction☆

OBJECTIVES This study aimed to investigate prospectively the protective effect of a first preinfarction angina attack against acute myocardial infarction (AMI) in human hearts without significant collaterals. BACKGROUND Several retrospective studies and the prospective studies have demonstrated the existence of the preconditioning (PC) effect in humans. However, collaterals were not examined in the prospective studies. In animal models, the PC effect on myocardial infarct size appears soon after PC reperfusion (classic) but disappears within 1 to 2 h. It then reappears 24 to 48 h after reperfusion (the delayed PC effect). Meanwhile, the PC effect on stunning appears 12 h after PC reperfusion (the delayed PC effect). The concept of the classic and delayed PC effects has not been investigated in human AMI studies. If the above concept is also correct in humans, the infarct size and/or impairment of the left ventricular function should be inversely correlated with the time interval between the first preinfarction angina attack and the onset of AMI when that time interval is limited to between 2 and 48 h. METHODS The subjects were 25 patients with first AMI of the proximal left anterior descending artery who underwent successful direct percutaneous transluminal coronary angioplasty (PTCA) 2 to 6 h after the onset and with no (or poor) collateral circulation (grade 0 or 1). They were divided into two groups: preinfarction angina (PA)(+) group: 11 patients with new onset preinfarction angina from 2 to 48 h before the onset, PA(-) group: 14 patients without angina before infarction. Peak creatine kinase (CK) and cumulative CK were examined, and the left ventricular ejection fraction (LVEF) and the regional wall motion (RWM) were determined from the left ventriculograms during the acute (immediately after the coronary reperfusion) and chronic (four weeks after the onset of AMI) phases. The RWM index (RWMI) was then calculated as the mean motion of chords (standard deviation [SD]/chord) lying in the area of chords of RWM < or = -2 SD in the acute phase (ischemic risk area). RESULTS The increase in the RWMI between the acute and chronic phases was significantly larger in the PA(+) group than in the PA(-) group (1.55 +/- 1.32 and 0.69 +/- 0.75, p < 0.05, respectively) although no significant difference in the enzymatic infarct size was seen between the two groups. The increases in the LVEF and the RWMI were significantly correlated with the time interval from the first preinfarction angina attack to the onset of AMI (r = 0.622, p < 0.05 and r = 0.646, p < 0.05, respectively), but the enzymatic infarct size was not. CONCLUSIONS The beneficial effect of preinfarction angina on left ventricular wall motion, independently of collateral flows, indicates the existence of the PC effect in humans. The greater protective effect of a longer time interval between angina pectoris and AMI suggests that the protection is due to a delayed PC effect.

Left atrial function assessed by speckle tracking echocardiography as a predictor of new-onset non-valvular atrial fibrillation: results from a prospective study in 580 adults

AIMS The aim of this prospective study was to evaluate left atrial (LA) function for the prediction of increased risk of new-onset non-valvular atrial fibrillation (AF). Risk stratification for new-onset AF based on LA remodelling may have a major public health impact. Although left atrial volume (LAV) or LA dimension have been proposed as predictors of AF, other predictive parameters of LA function have not yet been fully examined. METHODS AND RESULTS LA emptying function (EF), strain rate (SR), and LAV were evaluated in the apical four-chamber view by speckle tracking echocardiography in 580 consecutive adults (age 64 ± 17, 303 men) without a history of atrial arrhythmias. During a follow-up period of 28 months, 32 subjects (age 73 ± 9, 18 men) developed electrocardiographically confirmed AF. Subjects with new-onset AF had lower LA active EF (16 ± 5 vs. 28 ± 8%, P< 0.001) and lower LA SR at atrial contraction (-0.9 ± 0.2 vs. -1.4 ± 0.5 S(-1), P< 0.001), but larger maximum LAV index (59 ± 12 vs. 46 ± 16 mL/m(2), P< 0.001) compared with non-AF subjects at baseline. In multivariate logistic regression analysis, LA active EF was the only independent predictor of new-onset AF. Using an LA active EF cut-off of ≤20%, the sensitivity and specificity for new-onset AF based on receiver operator characteristic curve analysis were 88 and 81%, respectively (area under the curve: 0.92). CONCLUSION Reduced LA active EF (booster pump function) assessed by speckle tracking echocardiography independently predicts the risk of new-onset AF, suggesting a stronger association between LA functional remodelling and AF than between LA size and AF.

Left atrial global and regional function in patients with paroxysmal atrial fibrillation has already been impaired before enlargement of left atrium: velocity vector imaging echocardiography study.

AIMS Left atrial volume (LAV) has been proposed as a predictor of atrial fibrillation (AF) and LA function has been investigated by velocity vector imaging (VVI) echocardiography. The aim of this study was to determine whether LA function was associated with the existence of AF. METHODS AND RESULTS We examined emptying function (EF) as a global function and strain rate (SR) as a regional function of LA function during three phases of the cardiac cycle (reservoir, conduit, and booster pump phase). The parameters were measured (apical four-chamber view) by VVI in 302 subjects [126 sinus rhythm, 91 paroxysmal AF (PAF), and 85 chronic AF]. Global and regional LA function were significantly lower in PAF patients during sinus rhythm (LA total EF: 35 ± 8%; SR at atrial contraction: -0.8 ± 0.3s(-1)) and much lower in chronic AF patients (LA total EF 22 ± 8%) than in subjects with sinus rhythm (LA total EF: 47 ± 7%; SR at atrial contraction: -1.4 ± 0.4s(-1)). In multivariate logistic regression analysis, LA active EF and SR at atrial contraction were independent features of PAF. CONCLUSION LA function, particularly LA active relaxation and contraction, was lower in PAF patients than in subjects with sinus rhythm, regardless of LA size and age. LA functional impairment was observed regardless of hypertension before LA enlargement in patients with PAF. Reduced LA function, as assessed by VVI, is an important feature of AF as well as LA structure.

Quantitative validation of left atrial structure and function by two-dimensional and three-dimensional speckle tracking echocardiography: a comparative study with three-dimensional computed tomography.

BACKGROUND The aim of this study was to validate the accuracy of three-dimensional (3D) speckle tracking echocardiography (STE) and two-dimensional (2D)-STE for the assessment of left atrial (LA) volume and function by comparison with 3D-computed tomography (CT) performed on the same day as STE. METHODS LA phasic volume and emptying function (EF) were measured in 28 patients with paroxysmal atrial fibrillation undergoing catheter ablation (62±11 years old) using both 3D-STE and 2D-STE during sinus rhythm. LA phasic volume and function measured by 3D-STE and 2D-STE were validated using 3D-CT as a gold standard. RESULTS The intraobserver correlation coefficient and variability in maximum LA volume assessed by 3D-STE were 0.99 and 1.4±6.0%, respectively. The interobserver correlation coefficient and variability in maximum LA volume assessed by 3D-STE were 0.99 and 0.2±4.5%, respectively. There were strong correlations between LA phasic volume measured by 3D-CT and those measured by 3D-STE (r=0.98, p<0.001). There were correlations between LA phasic function measured by 3D-CT and those measured by 3D-STE (r=0.85-0.88, p<0.001). There was a better agreement between 3D-CT and 3D-STE in the assessment of LA phasic volumes and function than between 3D-CT and 2D-STE in apical 2- and 4-chamber view. CONCLUSIONS 3D-STE allows more accurate measurement of LA volume and function than 2D-STE and has high reproducibility.