Joerg Grimm

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)

Effect of coronary occlusion during percutaneous transluminal angioplasty in humans on left ventricular chamber stiffness and regional diastolic pressure-radius relations

The effect of repeated (3 to 10 second) and transient (15 to 75 second) abrupt coronary occlusion on the global and regional chamber stiffness was studied in nine patients undergoing angioplasty of a single proximal left anterior descending coronary artery stenosis. The left ventricular high fidelity pressure and volume relation was obtained before and after the procedure as well as during coronary occlusion, after 20 seconds (n = 9) and after 50 seconds (n = 5). During ischemia, there was an upward shift of the pressure-volume relation. The nonlinear simple elastic constant of chamber stiffness increased from 0.0273 +/- 0.017 before angioplasty (mean +/- SD) to 0.0621 +/- 0.026 after 20 seconds of occlusion (p less than 0.05) and 0.0605 +/- 0.015 after 50 seconds of occlusion (p less than 0.01). In five patients, the postangioplasty value remained higher than the control value, but at the group level the mean value (0.0529 +/- 0.037) was not statistically different. The regional stiffness was determined from the changes in the length of six segmental radii during diastole, from the lowest diastolic to the end-diastolic pressure. The regional constant of elastic stiffness was unaffected in the nonischemic zone. In the adjacent and ischemic zones, the regional stiffness was increased during occlusion (p less than 0.05). These regional abnormalities in diastolic function persisted at the time of postangioplasty measurements, 12 minutes after the end of the procedure. This suggests that recovery of normal diastolic function after repeated ischemic injuries is delayed after restoration of normal blood flow and systolic function.

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.

Myocardial relaxation and passive diastolic properties in man.

We have developed a model for assessing the influence of the decaying contractile systolic tension on diastolic wall dynamics and the passive properties of left ventricular muscle. Total measured left ventricular diastolic pressure and stress (sigma T) are determined by two overlapping processes: the decay of actively developed pressure and stress (sigma A) and the buildup of passive filling pressure and stress (sigma*). The decaying contractile stress sigma A is formulated in terms of a relaxation pressure with a time constant (T) assessed during the isovolumic relaxation interval. By subtracting the contribution of sigma A from sigma T we obtain sigma*. With micromanometry, echocardiography, and cineangiography, total and passive stress-strain relations and strain rates were evaluated over the entire filling period in six normal control subjects and in seven patients with aortic stenosis. Elastic stiffness constants (k), the slopes of the linear passive stiffness vs sigma* relations, did not differ in the two groups over a common lower stress range (6/6 normal, k = 9.37 +/- 1.23; 7/7 aortic stenosis, k = 9.34 +/- 1.08). Over a higher sigma* range, transition into a much steeper linear region occurred, and k values were much larger (4/7 aortic stenosis, k = 28.76 +/- 2.02). When diastolic stress levels are elevated, passive stiffness-stress relations can be better described as bilinear, with a much greater wall stiffness constant in the higher than in the lower stress range. Dynamic effects of decaying systolic contractile wall stress components are important in the rapid filling phase in normal hearts as well as in those with aortic stenosis.

Abnormal coronary vasomotion during exercise in patients with normal coronary arteries and reduced coronary flow reserve.

A reduced coronary flow reserve has been reported in patients with ischemialike symptoms and normal coronary arteries. In 13 such patients, both coronary vasomotion and flow reserve were studied. The luminal area of the proximal and distal third of the left anterior descending and left circumflex artery were determined by biplane quantitative coronary arteriography using a computer-assisted system. Patients were studied at rest, during submaximal supine bicycle exercise (4.0 minutes, 116 W), and 5 minutes after sublingual administration of 1.6 mg nitroglycerin. Heart rate, mean pulmonary pressure, and mean aortic pressure as well as the percent change of both proximal and distal luminal area were determined. In 10 of the 13 patients, coronary sinus blood flow was measured by coronary sinus thermodilution technique at rest and after dipyridamole infusion (0.5 mg/kg in 15 minutes) 10 +/- 5 days after quantitative coronary arteriography. Coronary flow ratio (dipyridamole/rest) and coronary resistance ratio (rest/dipyridamole) were determined in these patients. Patients were divided into two groups according to the behavior of the coronary vessels during exercise (vasodilation, group 1; vasoconstriction, group 2). Coronary vasodilation of the proximal (luminal area +26%, p less than 0.001) and distal (+45%, p less than 0.001) artery was observed in seven patients (group 1) during exercise and after sublingual nitroglycerin (+46%, p less than 0.001; and +99%, p less than 0.001, respectively). In group 2 (n = 6), however, there was coronary vasoconstriction of the distal vessel segments (-24%, p less than 0.001) during exercise, whereas the proximal coronary artery showed vasodilation (+26%, p less than 0.001) during exercise. After sublingual nitroglycerin, both vessel segments elicited vasodilation (distal coronary, +44%, p less than 0.001; proximal coronary artery, +47%, p less than 0.001). Coronary flow ratio amounted to 2.5 in group 1 and 1.2 in group 2 (p less than 0.05) and coronary resistance ratio to 2.7 in group 1 and to 1.2 in group 2 (p less than 0.05), respectively. Thus, among patients with ischemialike symptoms and normal coronary arteries, there is a group of patients (group 2) with an abnormal dilator response of the distal coronary arteries to the physiologic dilator stimulus of exercise and a reduced dilator capacity of the resistance vessels after dipyridamole (abnormal coronary vasodilator syndrome). The nature of this exercise-induced distal coronary vasoconstriction is not clear but might be due to an abnormal neurohumoral tone that may cause or contribute to the blunted vascular response during exercise.

Effect of aortic valve stenosis (pressure overload) and regurgitation (volume overload) on left ventricular systolic and diastolic function

In secondary hypertrophy from chronic pressure or volume overload, or both, systolic as well as diastolic abnormalities of left ventricular (LV) function have been described, but their relation has not been defined. In 58 patients with aortic valve disease (28 with aortic valve stenosis, and 30 with aortic regurgitation) and in 11 control subjects, LV biplane cineangiography was performed simultaneously with LV high-fidelity pressure measurements. LV ejection performance was assessed by ejection fraction, and diastolic function by the time constant of LV pressure decay, the early and late peak filling rates, and the constants of chamber (pressure-volume relation) and myocardial stiffness (stress-strain relation). In the entire cohort (n = 69), ejection fraction was inversely related to the time constant of LV relaxation (r = -0.58, p less than 0.001) and to the constant of myocardial stiffness (r = -0.62, p less than 0.001). Despite preserved systolic contractile function (as evaluated from the ejection fraction-mean systolic stress relation), abnormalities in LV diastolic function were present in 9 of 18 patients with pressure overload and 20 of 22 with volume overload. None of the 58 patients with aortic valve disease had a reduced early peak filling rate, whereas a reduction in late peak filling rate was observed in 3 with aortic stenosis, but in none with aortic regurgitation. This, it appears that abnormalities of relaxation and passive diastolic myocardial stiffness precede alterations in myocardial contractility. Assessment of peak filling rates is not helpful to detect diastolic dysfunction in patients with aortic valve disease.

Diastolic simple elastic and viscoelastic properties of the left ventricle in man.

The intrapatient comparison of the simple elastic and viscoelastic stress-strain relationship showed a significantly better curve fitting (r = 0.93 vs 0.96) for the viscoelastic model. The correction by the viscoelastic model occurred mainly during the highly filling-rate dependent early diastole, whereas the correction during atrial filling was low. Early diastolic deviations from the simple elastic stress-strain relationship were especially pronounced in the patients with myocardial hypertrophy. The viscoelastic constants of myocardial stiffness, B and K, were significantly different from the corresponding simple elastic constants, b and k, indicating that the simple elastic stiffness constants include both elastic and viscous forces.

Effect of intravenous propranolol on coronary vasomotion at rest and during dynamic exercise in patients with coronary artery disease.

Coronary vasomotion was studied at rest and during bicycle exercise with biplane quantitative coronary arteriography in 28 patients with coronary artery disease. Patients were divided into two groups; the first 18 patients served as controls (group 1), and the next 10 patients were treated with propranolol 0.1 mg/kg, which was infused intravenously before exercise (group 2). Luminal area of a normal and a stenotic vessel segment was determined at rest, during supine bicycle exercise, and 5 minutes after sublingual administration of 1.6 mg nitroglycerin after exercise. In group 1, the normal vessel showed vasodilation (+16%, p less than 0.001) during exercise, whereas the stenotic vessel segment showed vasoconstriction (-31%, p less than 0.001). After sublingual administration of nitroglycerin, there was coronary vasodilation of both normal (+36%, p less than 0.001 vs. rest) and stenotic (+20%, p less than 0.001) vessel segments. Patients with angina pectoris during supine exercise (n = 10) had significantly (p less than 0.05) more vasoconstriction (-36%) than patients without angina (-23%). In group 2, intravenous administration of propranolol at rest was associated with a decrease in luminal area of both normal (-24%, p less than 0.001) and stenotic (-43%, p less than 0.001) vessel segments; however, during subsequent exercise, both normal (-2%, p = NS vs. rest) and stenotic (-3%, p = NS vs. rest) vessel segments dilated when compared with the measurements after propranolol. Administration of nitroglycerin further increased luminal area of both vessel segments (normal segment, +23%, p less than 0.001; stenotic segment, +46%, p less than 0.001 vs. rest). It is concluded that dynamic exercise in patients with coronary artery disease is associated with coronary vasodilation of the normal and vasoconstriction of the stenotic coronary arteries. Patients with exercise-induced angina had significantly more stenosis vasoconstriction than patients without angina although minimal luminal area at rest was similar. Intravenous administration of propranolol is accompanied by a significant decrease in coronary luminal area of both normal and stenotic vessel segments at rest, which is overridden by dynamic exercise and sublingual nitroglycerin. The reduction in myocardial oxygen consumption and the prevention of exercise-induced stenosis vasoconstriction might explain the beneficial effect of beta-blocker treatment in most patients with coronary artery disease.

Quantification of mitral regurgitation with amplitude-weighted mean velocity from continuous wave Doppler spectra.

Aortic regurgitant fraction (RFao) was quantified by estimating the ratio of the forward blood flow through the aortic (Qao) and pulmonary (Qp) valve: RFao = 100(Qao - Qp)/Qao. Aortic and pulmonary flow were measured by the systolic time integrals of the amplitude-weighted mean velocity from continuous wave Doppler spectra recorded over the aortic and pulmonary valves. Thus, measurements are independent of the left and right ventricular outflow tract area. In 20 normal subjects, aortic regurgitant fraction ranged between -2.9% and +12.0% (mean +4.3%), the physiologic value being +2%. In 20 patients with pure aortic regurgitation, aortic regurgitant fraction obtained by Doppler spectra (y) was compared with that calculated from biplane left ventriculography and cardiac output determined with the Fick method (x). The correlation was r = 0.94, (SEE = 5.4%, which is 10.6% of the angiography-Fick mean value). The regression line was y = 0.87x + 6.6 (mean y = 51.2%, mean x = 51.1%). It is concluded that determination of aortic regurgitant fraction in pure aortic regurgitation by using the amplitude-weighted mean velocity from continuous wave Doppler spectra is accurate and allows easy noninvasive evaluation of the regurgitant fraction in routine clinical applications.

Prevention of coronary vasoconstriction by diltiazem during dynamic exercise in patients with coronary artery disease

Whether exercise-induced vasoconstriction of coronary artery stenoses is modified by the administration of calcium antagonists was examined in 14 patients with classic angina pectoris. In this group the effect of intracoronary diltiazem (2 to 3 mg) on luminal area was evaluated in normal and stenotic segments of epicardial coronary arteries during symptom-limited supine exercise. The luminal area of a normal and a stenotic coronary artery segment was determined by quantitative coronary arteriography with a computer-assisted system. Patients were studied at rest, 6 min after 2 to 3 mg of intracoronary diltiazem, during supine bicycle exercise (96 W) and 5 min after sublingual administration of 1.6 mg nitroglycerin. Heart rate, mean pulmonary and aortic pressure as well as the percent change of both normal and stenotic luminal area were determined. Intracoronary administration of diltiazem was associated with mild dilation of both normal (19%, p less than 0.01) and stenotic coronary luminal area (11%, p less than 0.05). During subsequent exercise, luminal area of the stenotic vessel segment increased by 23% (p less than 0.001) and that of the normal vessel segment by 24% (p less than 0.001), whereas in a previously reported control group, luminal area of the stenotic vessel segment decreased by 29% during exercise. After sublingual administration of nitroglycerin, the luminal area of both the normal and the stenotic vessel segment increased further by 19% (p less than 0.01) and 22% (p less than 0.01), respectively, compared with the values after intracoronary administration of diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)