The sensitivity of intracoronary injection of acetylcholine in inducing coronary spasm differs in patients with stable and unstable angina.

In an attempt to clarify the role of coronary artery spasm in the pathogenesis of unstable angina, acetylcholine (20 and 50 micrograms) was injected directly into the coronary arteries of 19 patients with unstable effort angina (group 1), 30 patients with unstable spontaneous angina (group 2), and 15 patients with stable effort angina due to coronary artery organic stenosis (greater than or equal to 75%) (group 3). Coronary spasm was defined as severe vasoconstriction (greater than or equal to 90% of luminal diameter) with chest pain and/or ischemic ST-segment changes. Intracoronary injection of acetylcholine induced spasm of at least one coronary artery in 19 patients (100%) of group 1 and 28 (93%) of group 2 but only 3 (20%) of group 3 (p less than 0.01). When acetylcholine was injected into the left and right coronary arteries separately, multivessel spasm (spasm of both coronary arteries) was induced in 5 of 12 (42%) patients of group 1 and in 9 of 23 (39%) patients of group 2. In contrast, intracoronary acetylcholine did not cause multivessel coronary spasm in any of 15 patients of group 3 (0%). These results suggest that coronary arteries in patients with unstable effort angina as well as spontaneous angina are susceptible to spasm and that coronary artery spasm may be responsible at least in part for the genesis of attacks in these patients.     

Ventricular-load optimization by inotropic stimulation in patients with heart failure

To evaluate the effects of inotropic stimulation on ventriculo-arterial coupling, we determined both the slope of the end-systolic pressure-volume relationship (ventricular elastance) and the slope of end-systolic pressure-stroke volume relationship (arterial elastance) at rest and during dobutamine infusion (5 micrograms/kg/min). We also determined stroke work, end-systolic potential energy and the ventricular work efficiency defined as stroke work per pressure volume area (stroke work + potential energy). In the resting state, ventricular elastance was lower than arterial elastance and work efficiency was about 59.7 +/- 9.3% (mean +/- SD). This condition is remote from the point where stroke work or mechanical efficiency is optimal. Enhanced ventricular elastance by 41% with dobutamine resulted in a significant reduction in both left ventricular end-diastolic and end-systolic volumes and was accompanied by the reduction in arterial elastance by 23%. Consequently, the ratio of arterial elastance to ventricular elastance decreased from 1.43 +/- 0.57 to 0.82 +/- 0.47, which resulted in an increase in stroke work, a decrease in potential energy and hence a marked increase in work efficiency. Thus, inotropic stimulation of depressed hearts could modulate ventriculo-arterial coupling towards optimization of either stroke work or mechanical efficiency.     

Ventriculo-arterial coupling during aerobic and anaerobic exercise in normal subjects

Physiological differences in aerobic and anaerobic exercise were assessed within the coupling framework between the left ventricle and the arterial system. In 10 normal men, the anaerobic threshold was estimated using sequential breath gas analysis during incremental ergometer tests. Direct arterial pressure and left ventricular echocardiograms were simultaneously recorded as its pressure was changed by phenylephrine or nitroprusside, and the slope (Ees) and volume axis intercept (Vo) of the end-systolic pressure (ESP)-volume relationship were determined. The effective arterial elastance (Ea) was expressed by the slope of the ESP-stroke volume relationship. Assuming that the Vo was unchanged from the resting state, the Ees and Ea were determined during exercise at aerobic and anaerobic work levels for each subject. During aerobic exercise, an increase in left ventricular end-diastolic volume and the tendency to decrease in ESP caused a significant fall in Ea by 30%. There was no significant change in Ees. Consequently, Ea/Ees which correlates inversely with left ventricular pump efficiency, decreased by 35%. During anaerobic exercise, Ea remained the same as during aerobic exercise, but Ees rose substantially by 89%. This caused a further reduction in Ea/Ees (-54%). Thus, ventriculo-arterial coupling during exercise is characterized by a decrease in Ea/Ees, indicating an augmentation of pump efficiency. This is primarily mediated by changes in loading conditions (decrease in Ea) during aerobic exercise, and by enhanced contractility (increase in Ees) during anaerobic exercise.     

Acute hemodynamic effects of a new positive inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212), in conscious and anesthetized dogs

The acute hemodynamic effects of a new cardiotonic agent, OPC-8212 (a 1H-quinolinone derivative), were studied in six conscious and 11 anesthetized dogs using a pair of ultrasonic crystals to measure the left ventricular segment length and a micromanometer to measure the left ventricular pressure. In six anesthetized dogs subjected to aortic constriction, the ascending aortic flow (AoF) was measured before and after intervention. In the anesthetized state bolus injections of OPC-8212 increased the ejection indices dose dependently. Maximum effects were observed at 1 min, the mean velocity of the circumferential fiber shortening (mean Vcf) being augmented by 6.6% with 0.3 mg, by 39.7% with 1 mg, and by 67.2% with 3 mg. These changes were not accompanied by any significant alteration in heart rate. With aortic constriction, the left ventricular wall shortening was significantly reduced. Depressed pump function was dramatically improved with injection of 3 mg of OPC-8212, the dP/dt was elevated by 98%, the AoF by 46%, and the mean Vcf by 78%. In the conscious state the same doses induced the same type of changes in hemodynamics and dimensions, but the amplitude of the response was significantly less; increase in the mean Vcf was by 36% and that of dP/dt by 52%. Thus, OPC-8212 has a potent inotropic effect. The effect was greater in the anesthetized state, or in dogs with depressed ventricular function, than in the conscious state.     

Improvement of oxygen metabolism in ischemic myocardium as a result of enhanced external counterpulsation with heparin pretreatment for patients with stable angina

Enhanced external counterpulsation (EECP) is noninvasive, safe, and effective for stable angina. We have reported that the development of functional collateral vessels is one of the mechanisms of EECP therapy using ammonia positron emission tomography (PET). The efficacy of heparin treatment on collateral growth is shown in several clinical studies. We evaluated whether EECP combined with intravenous heparin injection is effective for exercise capacity and oxygen metabolism of ischemic myocardium in stable angina. Eleven patients with stable angina were treated with conventional EECP therapy (C group). Seven patients with stable angina were treated with EECP therapy with 5000IU heparin pretreatment (H group). At baseline and after the completion of treatment H, 7 patients underwent [¹¹C] acetate PET to examine the change in regional myocardial oxygen metabolism. Although the total treadmill exercise time was prolonged after treatment in both groups, the extent of the improvements was significantly greater in the H group compared with the C group. Although k mono, the index of regional myocardial oxygen metabolism, in the nonischemic region remained unchanged, k mono in the ischemic region increased significantly (P 0.05) from 0.038 ± 0.004 to 0.053 ± 0.007. In conclusion, EECP with heparin pretreatment appears to be a new treatment remedy for patients with stable angina.     

Regional work of the human left ventricle calculated by wall stress and the natural logarithm of reciprocal of wall thickness

Regional left ventricular work is a more precise indicator of function than is simple shortening fraction. Regional work of the ventricle normalized to a unit volume of myocardium (RWM) is given by the following equation: RWM = - intergral of sigma d[ln(1/H)], where sigma is the mean wall stress and ln(1/H) is the natural logarithm of reciprocal of wall thickness. This method has been previously validated in animal experiments and it is now extended to the clinical setting for the first time. In 10 normal subjects and 6 patients with anteroseptal myocardial infarction, ventricular minor axis and wall thickness were measured by echocardiography and recorded simultaneously with high fidelity left ventricular pressure. Then, regional work of the interventricular septum and of the posterior wall of the left ventricle was calculated from the measured pressure and dimension data. In normal subjects, regional work of the septum and posterior wall was 6.1 +/- 1.7 and 7.0 +/- 1.8 mJ/cm3, respectively; the average of the septal and posterior wall regional work multiplied by the left ventricular myocardial volume correlated well (r = 0.93) with the total mechanical work done by the entire left ventricle. In patients with anteroseptal infarction, septal regional work was greatly reduced (0.6 +/- 1.7 mJ/cm3), compared with posterior wall regional work in the same patients (6.1 +/- 1.8 mJ/cm3). This simple method can be applied clinically in assessing the functional state of different regions of the myocardium.     

Inotropic agents and immune modulation

Since depression of myocardial contractility forms the basis for the development of heart failure, many attempts have been made to enhance the inotropic state of the failing heart by cardiotonic agent as the therapeutic modality. However, large scale clinical trials conducted in the Western societies revealed excess mortality in patients with heart failure received long-term treatment with inotropic agent. Therefore, all of these agents are now regarded as unsuitable for chronic heart failure treatment. In contrast, some inotropic agents with phosphodiesterase inhibitory properties exhibited potential benefits in Japanese patients. In Japan mortality due to heart disease is substantially lower than that found in all other Western countries. Thereby, chronic treatment with inotropic agent may be justified as the optimal care in the context of relief of symptoms and an improved quality of life. The salutary effects of these phosphodiesterase inhibitorsappear to be related to anticytokine and immunomodulating effects as well as their cardiotonic action. These findings support the recent new concept that immune responses mediated by cytokines play an important role in the pathogenesis of heart failure.     

Ultimobranchial glands in the teleost (Plecoglossus altivelis ryukyuensis): special references to changes of gland volume with maturation.

In lower vertebrates, the bone-mineralizing hormone "calcitonin" is secreted from ultimobranchial glands, which assume various shapes, e.g., follicles, cellular masses, or cell strands. Histological observations support the view that in some teleosts, the glands increase in size when females maturate. We determined the exact volume of the gland in juveniles and adult males and females of a teleost, Ryukyuayu (Plecoglossus altivelis ryukyuensis). Furthermore, we examined plasma Ca, Na and K levels. In this species, the gland was fundamentally composed of a single follicle. The gland volume was converted to numerical data under a certain condition. It thus became clear that the value of the follicle wall was significantly increased only in maturing and mature females with high plasma Ca levels and that the value of the lumen did not show any statistically significant changes during growth and maturation.     

Optimal doses of paclitaxel and carboplatin combination chemotherapy for ovarian cancer: a phase I modified continual reassessment method study

Background. A multicenter, phase I study of combination therapy with paclitaxel and carboplatin for epithelial ovarian cancer was conducted to determine the safety and recommended dosages for Japanese women. Methods. Paclitaxel was administered intravenously over a 3-h period, followed by carboplatin administered intravenously over a 1.5-h period. A modified continual reassessment method (mCRM) was used in two treatment arms to establish the maximum tolerated dose (MTD) and recommended doses of the combination. In group A, the dose of paclitaxel (175 mg/m²) was constant and the dose of carboplatin was increased from 4 to 7 in terms of the target area under the plasma concentration-versus-time curve (AUC). In group B, the dose of carboplatin was constant (AUC 6) and paclitaxel was administered at two dose levels (160 and 175 mg/m²). In both groups, the carboplatin dose was limited to a maximum of 800 mg/body for each administration. Results. Because the calculated probability of toxicity was greatest at a dose of paclitaxel 175 mg/m² and carboplatin AUC 7, this dose was designated the MTD in group A. Based on this result, treatment in group B was initiated at doses of paclitaxel of 160 mg/m² and carboplatin AUC 6. While the dose of paclitaxel was escalated to 175 mg/m², the safety of the combination was confirmed. The most frequent adverse effect was neutropenia, which resolved promptly with the appropriate use of granulocyte-colony stimulating factor (G-CSF). No other severe hematologic or nonhematologic toxicities were observed. Conclusions. Our study demonstrated that the recommended dose for this combination regimen should be paclitaxel 175 mg/m² plus carboplatin AUC 6 (maximum dose, 800 mg/body). Received: March 5, 2001 / Accepted: September 6, 2001