Ryuji Nohara

Baroreflex Sensitivity and Heart Rate Variability in the Identification of Patients at Risk for Life-Threatening Arrhythmias

BACKGROUND: The need for accurate risk stratification is heightened by the expanding indications for the implantable cardioverter defibrillator. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) focused interest on patients with both depressed left ventricular ejection fraction (LVEF) and the presence of nonsustained ventricular tachycardia (NSVT). Meanwhile, the prospective study Autonomic Tone and Reflexes After Myocardial Infarctio (ATRAMI) demonstrated that markers of reduced vagal activity, such as depressed baroreflex sensitivity (BRS) an heart rate variability (HRV), are strong predictors of cardiac mortality after myocardial infarction. METHODS AND RESULTS: We analyzed 1071 ATRAMI patients after myocardial infarction who had data on LVEF, 24-hour ECG recording, and BRS. During follow-up (21 +/- 8 months), 43 patients experienced cardiac death, 5 patients had episodes of sustained VT, and 30 patients experienced sudden death and/or sustained VT. NSVT, depressed BRS, or HRV were all significantly and independently associated with increased mortality. The combination of all 3 risk factor increased the risk of death by 22x. Among patients with LVEF<35%, despite the absence of NSVT, depressed BRS predicted higher mortality (18% versus 4.6%, P = 0.01). This is a clinically important finding because this grou constitutes 25% of all patients with depressed LVEF. For both cardiac and arrhythmic mortality, the sensitivity of lo BRS was higher than that of NSVT and HRV CONCLUSIONS: BRS and HRV contribute importantly and additionally to risk stratification. Particularly when LVEF is depressed, the analysis of BRS identifies a large number of patients at high risk for cardiac and arrhythmic mortalit who might benefit from implantable cardioverter defibrillator therapy without disproportionately increasing the number of false-positives.

Effect of clarithromycin on renal excretion of digoxin: Interaction with P‐glycoprotein

We present a digoxin‐clarithromycin interaction in two patients in whom digoxin concentrations were unexpectedly increased. The ratio of renal digoxin clearance to creatinine clearance in one patient was lower during the concomitant administration of clarithromycin (0.64 and 0.73) than that after cessation of clarithromycin administration (1.30 ± 0.20; mean ± SD). Because P‐glycoprotein could play an important role in the renal secretion of digoxin, we hypothesized that clarithromycin decreases renal digoxin excretion by inhibiting P‐glycoprotein‐mediated transport. Digoxin transport was evaluated with use of a kidney epithelial cell line, which expresses the human P‐glycoprotein on the apical membrane by transfection with MDR1 complementary deoxyribonucleic acid. Clarithromycin inhibited the transcellular transport of digoxin from the basolateral to the apical side in a concentration‐dependent manner and concomitantly increased the cellular accumulation of digoxin. These results suggest that clarithromycin may inhibit the P‐glycoprotein‐mediated tubular secretion of digoxin, and this interaction mechanism may contribute to an increase in the serum digoxin concentration.

Prediction of reversible ischemia after revascularization: perfusion and metabolic studies with positron emission tomography

BACKGROUND Accurate noninvasive determination of myocardial viability is of paramount importance for the clinical identification of patients who will benefit most from revascularization. The preserved metabolic activity in the myocardium, as studied with positron emission tomography (PET), has been considered a gold standard for this purpose. However, recent reports show that moderate hypoperfusion or stress-induced ischemia may represent reversible ischemia. The present study was undertaken to compare the value of perfusion and metabolic studies with PET for predicting improvement in wall motion after revascularization. METHODS AND RESULTS Of 61 patients who had regional asynergy and underwent PET before revascularization, 43 patients who had successful revascularization were included in the study. Each patient underwent rest-stress 13N-ammonia perfusion scans and 18F-fluorodeoxyglucose (FDG) scan at rest while in a fasting state. Reversible ischemia was considered to be present when the resting perfusion was > or = 50% of the peak value, stress-induced hypoperfusion was present, or an increase in FDG uptake was observed. Of 130 asynergy segments, 51 segments had improved wall motion after revascularization. The positive and negative predictive values for improvement in asynergy were 48% and 87% by the rest perfusion study, 63% (P = .05 versus the rest value) and 87% by the rest-stress perfusion study, and 76% (P < .01 versus the rest value) and 92% by the FDG study. CONCLUSIONS FDG PET provided the best predictive value for improvement in wall motion after revascularization. On the other hand, 13N-ammonia PET is useful for predicting nonreversible myocardial scarring when it shows severe hypoperfusion at rest or hypoperfusion without stress-induced ischemia.

Prognostic value of an increased in flourine-18 deoxyglucose uptake in patients with myocardial infarction: Comparision with stress thallium imaging

OBJECTIVES This study was undertaken to evaluate the prognostic value of an increase in fluorine (F)-18 deoxyglucose uptake compared with clinical, angiographic and stress thallium findings in patients with myocardial infarction. BACKGROUND Positron emission tomography (PET) imaging using F-18 deoxyglucose has been applied to assess tissue viability in patients with coronary artery disease. We hypothesized that patients with a myocardial segment with augmented F-18 deoxyglucose uptake are at high risk for a future cardiac event. METHODS One hundred fifty-eight consecutive patients with myocardial infarction referred for F-18 deoxyglucose PET and stress thallium scans were studied. Follow-up was obtained in 84 patients at a mean interval of 23 months to investigate prognostic implications of radionuclide studies. RESULTS Seventeen patients had a cardiac event during the follow-up interval. Univariate analysis showed that an increase in F-18 deoxyglucose uptake was the best predictor of a future cardiac event (p = 0.0006), followed by the number of stenosed vessels (p = 0.008). In the multivariate analysis, when an increase in F-18 deoxyglucose uptake was entered into the model, only angiographic variables had an independent prognostic value, whereas no other radionuclide variables showed significant prognostic value. Among patients who did not show redistribution, a future cardiac event was observed more often in patients with than in those without an increase in F-18 deoxyglucose uptake (p < 0.05). CONCLUSIONS Thus, an increase in F-18 deoxyglucose uptake seemed to be the best predictor of a future cardiac event among all clinical, angiographic and radionuclide variables in this study of stable patients with myocardial infarction. Even when a stress thallium-201 scan does not show redistribution, those patients who have an increase in F-18 deoxyglucose uptake in a PET study may be at risk for a future cardiac event, and these patients may need aggressive treatment to prevent a future cardiac event.

Regional myocardial perfusion and glucose metabolism in experimental left bundle branch block.

BackgroundSeveral authors have reported cases in which 201TI scintigraphy demonstrated perfusion abnormality in the septum of patients with left bundle branch block (LBBB) and normal coronary arteriogram. The mechanism of this abnormality, however, remains to be clarified. Methods and ResultsTo determine whether LBBB itself induces abnormal myocardial perfusion and ischemia and to elucidate its mechanism, we used an in vivo animal model. LBBB was induced by right ventricular pacing in 17 open-chest dogs. We examined myocardial perfusion and glucose uptake using 201T1 and 18F-labeled 2-fluoro-2-deoxy-D-glucose. 201T1 activity in the septum was reduced to 74.7±14.5% of its maximal activity, and mean activity was 86.5±5.3% in the free wall (p<0.05). 18F activity in the septum was also reduced compared with that in the free wall (67.4±12.1% versus 88.0plusmn;5.2%, p<0.05). Regional myocardial blood flow was significantly reduced in the septum compared with the free wall, averaging 0.53±0.18 ml/min/g versus 0.84±0.14 ml/min/g, respectively (p<0.01). Systolic thickening in the septum was reduced from 1.36±0.20 to 0.98±0.04 (p<0.01) after the induction of LBBB, and the intramyocardial pressure in the septum in diastolic phase, in which the major flow of left anterior descending coronary artery (LAD) exists, increased from 26.6±10.5 to 57.8±22.2 mm Hg (p<0.02). Mean aortic pressure, IAD flow, and lactate extraction rate showed no significant change. ConclusionsLBBB itself may reduce myocardial perfusion and glucose uptake in the septum because of impaired systolic thickening and augmented intramyocardial pressure in the septum; however, this is not necessarily related to septal ischemia.

Detection and evaluation of tricuspid regurgitation using a real-time, two-dimensional, color-coded, Doppler flow imaging system: Comparison with contrast two-dimensional echocardiography and right ventriculography

To detect and evaluate regurgitant flow in tricuspid regurgitation (TR) with a newly developed, realtime, 2-dimensional (2-D), color-coded, Doppler flow imaging system (Doppler 2-D echo), 27 patients (18 with suspected TR and 9 normal subjects) were examined and the findings were compared with those obtained using contrast 2-D echocardiography (contrast 2-D echo) and right ventriculography. In 16 of 18 patients with suspected TR, Doppler 2-D echo easily visualized the color-coded regurgitant flow in the right atrium and estimated the severity of TR from the distance of the visible TR jet. On the basis of the QRS synchronized appearance of contrast in the inferior vena cava by the subxiphoid approach or of the negative contrast effect above the tricuspid valve just after the contrast entered the right ventricle with its subsequent back-and-forth movements across the tricuspid valve, Doppler 2-D echo was more sensitive and specific in detecting TR (100% and 100%) than contrast 2-D echo (75% and 82% in the subxiphoid view, 56% and 100% in the 4-chamber view) when the fast Fourier transformation frequency analysis was used as the standard of TR, and it was more sensitive in detecting TR (85%) than contrast 2-D echo (69% in the subxiphoid approach, 46% in the 4-chamber view) when right ventriculography was used as the standard of TR. Additionally, the severity of TR as shown by Doppler 2-D echo correlated fairly well with that shown by right ventriculography. Thus, Doppler 2-D echo is clinically useful for detecting and evaluating TR.

Elevated basic fibroblast growth factor in pericardial fluid of patients with unstable angina

BACKGROUND Collateral growth is induced by chemical signals from the ischemic myocardium. We hypothesized that angiogenic growth factors are produced by cardiac tissue; they are diffusible, more concentrated in pericardial fluids, and are increased by myocardial ischemia. METHODS AND RESULTS With the use of an enzyme-linked immunosorbent assay, we measured the concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in pericardial fluids of 12 patients with unstable angina (group 1) and of 8 patients with nonischemic heart diseases (group 2). The levels of protein in pericardial fluids were quite comparable between the two groups (34 +/- 2 versus 32 +/- 4 mg/mL). The concentration of bFGF in pericardial fluids in group 1 was 2036 +/- 357 pg/mL, significantly (P < .001) higher than the 289 +/- 72 pg/mL in group 2. The amount of bFGF per milligram of protein was also significantly (P < .05) higher in group 1 than in group 2 (67 +/- 15 versus 12 +/- 4 pg/mg). The concentration of VEGF in pericandial fluids tended to be higher in group 1, but the difference was statistically insignificant (39 +/- 7 versus 22 +/- 6 pg/mL). The amount of VEGF per milligram of protein was 1.2 +/- 0.3 pg/mg in group 1, similar to the 0.8 +/- 0.4 pg/mg in group 2. CONCLUSIONS This finding provides new evidence that bFGF plays an important role in mediating collateral growth in humans.

Stress scintigraphy using single-photon emission computed tomography in the evaluation of coronary artery disease

Twenty-seven patients with angina pectoris, 24 with postmyocardial infarction angina and 7 with normal coronary arteries were examined by exercise thallium-201 emission computed tomography (SPECT) and planar scintigraphy. Exercise SPECT was compared with the reperfusion imaging obtained approximately 2 to 3 hours after exercise. The sensitivity and specificity of demonstrating involved coronary arteries by identifying the locations of myocardial perfusion defects were 96 and 87% for right coronary artery, 88 and 89% for left anterior descending artery (LAD) and 78 and 100% for left circumflex artery (LC). These figures are higher than those for planar scintigraphy (85 and 87% for right coronary artery, 73 and 89% for LAD and 39 and 100% for LC arteries). In patients with 3-vessel disease, sensitivity of SPECT (100, 88 and 75% for right coronary artery, LAD and LC, respectively) was higher than planar imaging (88, 63 and 31%, respectively), with a significant difference for LC (p less than 0.05). In 1, 2 and 0-vessel disease the sensitivity and specificity of the 2 techniques were comparable. Multivessel disease was more easily identified as multiple coronary involvement than planar imaging with a significant difference in 3-vessel disease (p less than 0.05). In conclusion, stress SPECT provides useful information for the identification of LC lesions in coronary heart disease, including 3-vessel involvement.

Collateral function in early acute myocardial infarction

The role of the collateral circulation less than 6 hours after the onset of acute myocardial infarction (MI) was evaluated in 34 consecutive patients without previous MI. There were 19 patients with and 15 without collaterals. The group was subdivided into those with nonjeopardized collaterals (group A, 14 patients) and those with jeopardized collaterals (group B, 5 patients), and the group without collaterals into those with partially obstructed coronary arteries (group C, 5 patients) and those with totally obstructed coronary arteries (group D, 10 patients). These groups had similar sites of coronary stenoses and MI. Eleven of 14 collaterals in group A were poor, but MI mass measured by peak creatine kinase (CK) was smaller in group A than in group B (p less than 0.01) or group D (p less than 0.01), and cardiac function was significantly better in group A than in group D (cardiac index, p less than 0.05; stroke index, p less than 0.01; ejection fraction, p less than 0.01; regional wall motion, p less than 0.01). Group C was not statistically different from group A in myocardial function and CK. Group B was similar to group D in MI mass and cardiac function (cardiac index, stroke index, ejection fraction and regional wall motion). Thus, patients with nonjeopardized collaterals and those with partially obstructed coronary arteries had less myocardial damage and better cardiac function than did those with jeopardized collaterals and those with totally obstructed coronary arteries. A nonjeopardized collateral circulation may play a role in limiting MI mass and preserving myocardial function in the early stages of acute MI.

Detection of coronary artery disease with 13N-ammonia and high-resolution positron-emission computed tomography

In order to evaluate the detectability of coronary artery disease (CAD) with positron-emission computed tomography (PET), we performed 13N-ammonia myocardial PET scanning at rest and with exercise loading in 20 normal subjects and 40 patients with CAD, by means of a high-resolution, multi-slice, whole-body PET scanner. Myocardial PET scanning was performed 3 minutes after injection of 13N-ammonia at rest and during exercise. The circumferential profile analysis of resting PET images revealed regional hypoperfusion in 96% of CAD patients with previous myocardial infarction and in 29% of those without infarction. Exercise PET studies showed high sensitivity (93%) in detecting CAD without myocardial infarction, whereas no abnormal hypoperfusion was detected in normal subjects. Segmental analysis of regional myocardial perfusion with exercise stress identified 67 of 75 stenosed vessels (89%). We conclude that 13N-ammonia myocardial PET with exercise loading provides high-quality tomographic images of regional myocardial perfusion and is a valuable technique for detecting CAD.