Tomoyuki Murakami

Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin.

To study the vasomotility of normal and diseased coronary arteries during dynamic exercise, symptom-limited supine bicycle exercise during cardiac catheterization was performed by 18 patients with classic angina pectoris. The cardiovascular response was assessed by hemodynamic measurements and computer-assisted determination of normal and stenotic coronary artery luminal areas from biplane coronary angiograms made before, during, and after exercise. After baseline measurements were recorded, 12 patients (group 1) performed bicycle exercise for 3.4 min (mean), reaching a maximum workload of 81 W (mean); at the end of exercise they received 1.6 mg sublingual nitroglycerin. After measurements at rest in six other patients (group 2), 0.1 mg intracoronary nitroglycerin was given, followed by exercise (3.8 min, 96 W; NS) and sublingual nitroglycerin as in group 1. During exercise in group 1, luminal area of the coronary stenosis decreased to 71% of resting levels (p less than .001), while area of the normal coronary artery increased to 123% of control (p less than .001). After sublingual nitroglycerin at the end of exercise, area of the normal vessel further increased to 140% of control (p less than .001), while luminal area of the stenosis dilated to 112% of resting levels (p less than .001 vs exercise, NS vs rest). Pretreatment with intracoronary nitroglycerin increased both normal (121%; p less than .05) and stenotic (122%; p less than .05) luminal areas, while preventing the previously observed narrowing of stenosis during exercise (114%; NS). Exercise resulted in a similar heart rate-systolic pressure product and caused angina pectoris in two-thirds of the patients in each group. However, patients pretreated with intracoronary nitroglycerin (group 2) had a lower mean pulmonary arterial pressure during maximum exercise (35 mm Hg) than those patients (group 1) not receiving pretreatment (47 mm Hg; p less than .001). Group 2 patients reached a percentage of their predicted work capacity (65%) that was about the same as that during previous upright bicycle exercise (71%; NS), while group 1 patients had a significantly lower work capacity (51% of predicted) than that before catheterization (82%; p less than .001). Hence, narrowing of coronary artery stenosis during dynamic exercise is attributable to active vasoconstriction due to its reversibility by preexercise intracoronary nitroglycerin. Patients who did not experience narrowing of stenosis during exercise (group 2) had less evidence of myocardial ischemia (lower mean pulmonary arterial pressure) and maintained their work capacity.(ABSTRACT TRUNCATED AT 400 WORDS)

Diastolic filling dynamics in patients with aortic stenosis.

Left ventricular filling dynamics were investigated in 24 patients with aortic stenosis (AS). Biplane cineangiography was performed with simultaneous micromanometry in these 24 patients and in six control subjects. Twelve of the patients with AS had moderate hypertrophy with a left ventricular muscle mass index of less than 180 g/m2 (ASI group) and 12 had severe hypertrophy with an index of 180 g/m2 or more (AS2 group). Filling dynamics were also evaluated postoperatively in eight patients in the AS1 and six patients in the AS2 group. Preoperatively, end-diastolic and end-systolic volume indexes were larger and ejection fraction was lower in the AS2 compared with the control or AS1 group. Percent volume increase during the first half of diastole (%V1) was smaller in the AS1 than in the AS2 group. Peak filling rate in the first half of diastole (PFR 1) was higher in the AS2 than in the control or in AS1 group, while peak filling rate in the second half of diastole (PFR2) was considerably greater in the AS1 group than in the other two groups. The time constant of left ventricular pressure decline, an index of the rate of relaxation, was prolonged in the AS2 group. In contrast, mitral valve opening pressure (MVOP) was significantly higher in this group than in the other two groups. The constant of left ventricular chamber stiffness was slightly but not significantly greater in both AS groups than in the control subjects. After surgery in patients in the AS1 group, preoperatively reduced %V1 had increased and preoperatively enhanced PFR2 had decreased. In patients in the AS2 group, excluding one with a persistent low ejection fraction after surgery, preoperatively enhanced PFR1 decreased in association with a decrease in MVOP. Thus, left ventricular filling dynamics vary in patients with AS depending on the degree of left ventricular hypertrophy and systolic function. In patients with AS and moderate hypertrophy %V1 is slightly reduced but is compensated for by a forceful atrial contraction. In those with severe hypertrophy and systolic dysfunction increased driving pressure allows %V1 to remain within normal limits, despite prolonged left ventricular relaxation and decreased elastic recoil. Both changes in left ventricular filling dynamics tend to normalize after surgery in association with a reduction in left ventricular hypertrophy and/or an improvement of systolic function.

Prostacyclin therapy in patients with congestive heart failure

The acute hemodynamic effects of intravenous prostacyclin (PGI2), in doses of 22 +/- 11 ng/kg per min were studied in nine patients with severe congestive heart failure refractory to digitalis and diuretic drugs. After prostacyclin infusion, mean (+/- standard deviation) pulmonary capillary wedge pressure decreased from 21.0 +/- 7.9 to 15.0 +/- 6.6 mm Hg (p less than 0.001), mean arterial pressure from 98.9 +/- 12.8 to 76.2 +/- 7.0 mm Hg (p less than 0.001), systemic vascular resistance from 2,574 +/- 384 to 1,368 +/- 283 dynes s cm-5 (p less than 0.001), pulmonary vascular resistance from 1,008 +/- 451 to 443 +/- 135 dynes s cm-5 (p less than 0.001) and pulmonary arteriolar resistance from 330 +/- 111 to 189 +/- 73 dynes s cm-5 (p less than 0.001). Heart rate increased from 78 +/- 21 to 82 +/- 24 beats/min (p = not significant [NS]), cardiac index from 2.0 +/- 0.37 to 3.2 +/- 0.59 liters/min per m2 (p less than 0.001) and stroke index from 27.6 +/- 8.69 to 42.0 +/- 0.62 cc/m2 (p less than 0.001). With prostacyclin, moreover, coldness of the limbs and face disappeared, and patients felt warmth and mild flushing of the face. After prostacyclin, plasma norepinephrine levels, renin activity and aldosterone concentrations rose from 824 +/- 375 to 880 +/- 468 pg/ml (NS), 0.68 +/- 1.36 to 0.95 +/- 1.21 ng/ml per h (NS), and 6.64 +/- 2.50 to 6.38 +/- 2.88 ng/dl (NS), respectively, while plasma epinephrine increased from 140 +/- 80 to 250 +/- 154 pg/ml (p less than 0.025).

Left ventricular passive diastolic properties in chronic mitral regurgitation.

BackgroundIn chronic mitral regurgitation, the myocardium responds to the increased filling volume by geometric alteration and eccentric hypertrophy. This study was designed to evaluate the effects of a pure volume overload on left ventricular diastolic chamber and myocardial properties and to assess the relation of passive diastolic function to systolic ejection performance. Methods and ResultsBy use of simultaneous cineangiography and left ventricular micromanometry, left ventricular passive diastolic stiffness was evaluated in nine normal controls (group 1), 14 patients with chronic mitral regurgitation and a normal ejection fraction (.57%, group 2), and 13 patients with mitral regurgitation and a reduced ejection fraction (<57%, group 3). Passive diastolic function was evaluated by using a three-constant elastic model. Left ventricular chamber properties were represented by the relation of pressure to volume; myocardial properties were evaluated by relating myocardial midwall stress to midwall strain. The constant of left ventricular chamber stiffness was decreased in group 2 compared with controls (p<0.05) but it was normal in group 3. The constant of myocardial stiffness was increased in group 3 compared with groups 1 and 2 (p<0.01). Among patients with mitral regurgitation, there was a significant inverse relation between ejection fraction and the constant of myocardial stiffness (r= −0.83). ConclusionsThe chronic adaptation to volume overload in chronic mitral regurgitation tends to decrease left ventricular chamber stiffness. Patients with mitral regurgitation and a depressed ejection fraction demonstrated diastolic myocardial dysfunction. Compromised diastolic function in patients with chronic mitral regurgitation and reduced systolic performance may contribute to the clinical manifestations of congestive heart failure. (Circulation 1991;83:797–807)

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.

Does verapamil improve left ventricular relaxation in patients with myocardial hypertrophy

A beneficial effect of verapamil on left ventricular relaxation has been reported in patients with hypertrophic cardiomyopathy. The effect of 0.1 mg/kg intravenous verapamil on left ventricular relaxation and diastolic mechanics was studied in 10 patients with hypertrophic cardiomyopathy and 13 patients with aortic stenosis. M mode echocardiograms and left ventricular high-fidelity pressure measurements were obtained simultaneously in patients at rest and 10 to 15 min after verapamil. The time constant of left ventricular pressure decay (T; in msec) and the pressure intercept (PB; in mm Hg) were calculated from left ventricular pressure and negative dP/dt during isovolumetric relaxation with the use of a linear regression analysis. Left ventricular early and mean diastolic filling rates as well as diastolic pressure-diameter relationships before and after verapamil were determined from simultaneous echocardiographic and pressure measurements. After verapamil heart rate, left ventricular peak systolic pressure, and maximum and minimum dP/dt remained unchanged in both groups. Left ventricular end-diastolic pressure increased significantly from 15 to 17 mm Hg (p less than .02) in patients with aortic stenosis but did not change in those with hypertrophic cardiomyopathy. However, the time constant T decreased significantly from 79 to 60 msec (p less than .001) in patients with hypertrophic cardiomyopathy but increased significantly from 53 to 68 msec (p less than .025) in those with aortic stenosis. Parallel to the decrease in time constant, early (5.3 vs 7.3 cm/sec, p less than .05) and mean (3.0 vs 4.3 cm/sec, p less than .06) diastolic lengthening rate increased in patients with hypertrophic cardiomyopathy after verapamil. In contrast, early (7.7 vs 7.6 cm/sec, p = NS) and mean (4.3 vs 4.2 cm/sec, p = NS) diastolic lengthening rate remained unchanged in patients with aortic stenosis. The diastolic pressure-diameter relationship did not change in either group after verapamil. Cycle efficiency of the left ventricular pressure-diameter loop was significantly decreased in patients with hypertrophic cardiomyopathy when compared with that in those with aortic stenosis (71% vs 80%; p less than .01), but improved significantly from 71% to 77% (p less than .02) in patients with hypertrophic cardiomyopathy and remained unchanged in those with aortic stenosis (80% vs 80%) after verapamil. We conclude that verapamil improves left ventricular relaxation in patients with hypertrophic cardiomyopathy but delays relaxation in those with aortic stenosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of coronary artery reperfusion on relation between creatine kinase-MB release and infarct size estimated by myocardial emission tomography with thallium-201 in man.

The quantitative relations between serum creatine kinase-MB isoenzyme (CK-MB) release and the final infarct size estimated by myocardial emission computed tomography with thallium-201 was assessed in 37 patients with a first acute transmural myocardial infarction who underwent intracoronary thrombolysis using urokinase 4.6 +/- 1.9 hours after the onset of symptoms. Serial CK-MB determinations were used to calculate the accumulated release of CK-MB (sigma CK-MB). Myocardial emission tomography with thallium-201 was performed 4 weeks after the onset, and infarct volume was measured from reconstructed tomographic images by computerized planimetry. The results are presented for two groups of patients: 11 patients with unsuccessful thrombolysis (group A) and 26 patients with successful thrombolysis (group B). An excellent linear relation was found for group A (sigma CK-MB = 6.4 X infarct volume + 47.7, r = 0.91), whereas a different linear relation was observed for group B (sigma CK-MB = 10.5 X infarct volume + 89.1, r = 0.80). Moreover, serum CK-MB activity reached a peak at 21.1 +/- 2.2 hours after the onset in group A and reached an earlier peak at 12.5 +/- 2.9 hours in group B (p less than 0.001). These data suggest that acute coronary recanalization alters the kinetics of CK-MB release, resulting in greater CK-MB release into the serum for equivalent infarct volume estimated by myocardial emission tomography with thallium-201. Thus, serum CK-MB time-activity curves after acute myocardial infarction may be influenced considerably by acute reperfusion, which is an important factor that should be incorporated in the interpretation of enzymatic estimates of infarct size in human patients.

Coordinate interaction between ATP-sensitive K+ channel and Na+, K+-ATPase modulates ischemic preconditioning

BACKGROUND We reported that digoxin abolishes the infarct size (IS)-limiting effect of ischemic preconditioning (IPC). Because ATP-sensitive K+ (KATP) channels are involved in IPC, we studied whether Na+,K+-ATPase and KATP channels functionally interact, thereby modulating IPC. METHODS AND RESULTS Rabbits received 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. IPC was elicited by 5 minutes of occlusion followed by 10 minutes of reperfusion. The IS, expressed as a percentage of the area at risk, was 40.2+/-2.8% in control and 39.8+/-5.0% in digoxin pretreatment rabbits. Both IPC and pretreatment with cromakalim, a KATP channel opener, reduced IS to 11.8+/-1.8% and 13.4+/-2.6% (P<0. 05 versus control). Digoxin abolished the reduction in IS induced by IPC (33.5+/-3.3%), whereas it did not change that induced by cromakalim (18.8+/-3.0%). In patch-clamp experiments, digoxin was found to inhibit the opening of KATP channels in single ventricular myocytes in which ATP depletion had been induced by metabolic stress. In contrast, digoxin had little effect on the channel opening induced by cromakalim. Moreover, the inhibitory action of digoxin on channel activities was dependent on subsarcolemmal ATP concentration. CONCLUSIONS The IS-limiting effect of IPC is modulated by an interaction between KATP channels and Na+,K+-ATPase through subsarcolemmal ATP.

Induction of coronary artery spasm by intracoronary acetylcholine: Comparison with intracoronary ergonovine

To investigate the mechanism of coronary spasm, we compared the action of acetylcholine with that of ergonovine in 11 patients with vasospastic angina (group 1) and in 15 patients with chest pain (group 2). Coronary arteriography was performed immediately after the patients received intracoronary injections of titrated increments of each agent. In the patients in group 1 occlusive or near-occlusive (99% luminal narrowing) coronary spasm associated with angina and ischemic electrocardiographic ST changes was noted in nine of 11 patients receiving acetylcholine and in all 11 patients receiving ergonovine. The region and the degree of the most severe coronary spasm on coronary arteriograms evoked by the two agents were the same in nine of the 11 patients in group 1. In the other two patients in group 1, spontaneous focal coronary spastic stenosis in the baseline coronary arteriogram was relieved by the intracoronary injection of acetylcholine, and a focal coronary occlusive spasm in the same region was induced repeatedly by the subsequent intracoronary injection of ergonovine (paradoxic phenomenon). In contrast, occlusive or near-occlusive coronary spasm was not induced by either agent in any patient in group 2. These results suggest that the two provocative tests for coronary spasm that involve acetylcholine and ergonovine are clinically useful in the diagnosis of vasospastic angina, but testing with intracoronary ergonovine is needed when a spontaneous focal coronary spasm is relieved by the intracoronary injection of acetylcholine. The results also indicate that in many patients with vasospastic angina, nonspecific hypersensitivity to acetylcholine or ergonovine in a definite region of the coronary arteries generally plays an important role in the induction of coronary spasm.(ABSTRACT TRUNCATED AT 250 WORDS)

Doppler echocardiographic transmitral peak early velocity does not directly reflect hemodynamic changes in humans : importance of normalization to mitral stroke volume

Doppler echocardiographic transmitral peak early velocity normalized to the time-velocity integral during diastole is equivalent to volumetric peak filling rate normalized to stroke volume. To compare the pathophysiologic validity of normalized and nonnormalized peak early flow velocity, pulsed Doppler echocardiography with simultaneous high fidelity left ventricular pressure measurements was performed in 52 patients with coronary artery disease. Left ventricular loading conditions were changed by intravenous administration of norepinephrine in 15 patients and synthetic atrial natriuretic polypeptide in 15 others. Norepinephrine increased nonnormalized and normalized peak early flow velocities in association with significantly elevated end-diastolic, peak systolic and mitral valve opening pressures and decelerated the time constant of left ventricular isovolumetric pressure decline. Atrial natriuretic polypeptide did not change either nonnormalized or normalized peak early flow velocity, despite significant reductions in end-diastolic, peak systolic and mitral valve opening pressure and an accelerated time constant. Normalized peak early flow velocity showed the highest univariate correlation with long-term change in mitral valve opening pressure (n = 52, r = 0.67, p less than 0.0001). It provided a modest univariate correlation (n = 30, r = 0.74, p less than 0.0001) with immediate change in mitral valve opening pressure during norepinephrine infusion, whereas this correlation was lower (n = 30, r = 0.57, p less than 0.001) during polypeptide infusion. However, multivariate regression analysis relating normalized peak velocity with long- and short-term changes in end-diastolic, peak systolic and mitral valve opening pressures, time constant and constant of left ventricular chamber stiffness improved the correlation coefficients (r = 0.80 to 0.85, all p less than 0.0001). In contrast, neither univariate nor multivariate correlations of nonnormalized velocity with long- and short-term changes in these hemodynamic variables were satisfactory. Thus, nonnormalized peak early flow velocity does not directly reflect underlying hemodynamic changes in humans. Normalization to mitral stroke volume clarifies the dependence of peak early flow velocity on the determinants of early diastolic filling. When left ventricular early diastolic filling is evaluated by Doppler echocardiography, normalized peak early flow velocity should be taken into consideration.