Long-term efficacy and safety of pimobendan in moderate heart failure. A double-blind parallel 6-month comparison with enalapril. The Pimobendan-Enalapril Study Group.

In view of growing scepticism as to the efficacy and safety of agents with predominant phosphodiesterase inhibiting properties in heart failure, the clinical efficacy and safety of pimobendan, a calcium-sensitizing and partially phosphodiesterase-inhibiting compound, was compared with enalapril in 242 patients with mild to moderate heart failure (NYHA classification II-III) despite diuretics and digitalis, and abnormal haemodynamics at baseline. Patients were randomly assigned to either pimobendan (average 10.3 mg.day-1, n = 119), or enalapril (average 10.7 mg.day-1, n = 123) in a double-blind fashion for 6 months. Forty-two pimobendan and 37 enalapril patients stopped the treatment, five pimobendan and six enalapril due to worsening of failure without death, whereas 13 and eight patients, respectively, died from cardiac disorders (ns). Other reasons for discontinuation and adverse events not leading to discontinuation were also comparable. Although Holter analysis at 14 days, but not at 6 months, indicated increased ventricular extrasystoles in pimobendan patients, these did not lead to serious clinical events. NYHA classification improved similarly in both groups, from 2.51 to 2.16 (pimobendan) and from 2.40 to 2.06 (enalapril). The number of patients needing a change in background therapy or hospitalization did not differ between the two groups. Haemodynamic variables at rest were improved by both compounds after 6 months. In contrast, only enalapril improved haemodynamics during exercise, and reduced the cardiothoracic ratio. The primary endpoint, exercise capacity, increased significantly during the first 3 months by 45 and 53 s, under pimobendan and enalapril, respectively, but, although unchanged thereafter, the improvement was no longer statistically significant at 6 months in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prinzmetal's variant angina: a case report]. / Variante Prinzmetal-Angina pectoris: ein Fallbericht.

Prinzmetal's angina is a variant of the classic exertion dependent angina pectoris. Typical is the appearance of the symptoms at rest during early morning hours. It is due to spasms in the coronary arteries. Various provocation tests may be used to trigger spasms, among others hyperventilation which leads to vasoconstriction of coronary arteries. The case of a 53-year-old patient with Prinzmetal's angina is described in whom spasms of the right coronary artery could be evoked by hyperventilation. The following pathogenetic mechanisms may be possible in Prinzmetal's angina: disturbed endothelial permeability, endothelial dysfunction, or secretion of vasoconstrictive substances as well as local hypersensitivity of segments disturbed by atherosclerotic lesions to circulating vasoconstrictors.

[Is regression of coronary sclerosis possible?]. / Ist eine Regression der Koronarsklerose möglich?

Randomized studies with sequential coronary arteriographies have clearly documented that aggressive lipid-lowering therapy and change in life style can reduce progression and produce a modest regression of coronary artery lesions. The changes in the extent of a stenosis are determined by the level of cholesterol and LDL cholesterol achieved during treatment. Three of the randomized studies have shown that the lipid-lowering intervention has not only a beneficial influence on the coronary arteriographic lesions, but the number of clinical events is reduced as well. The calcium blockers nifedipine and nicardipine do not influence progression and regression but reduce the de novo appearance of coronary stenoses, either expressed as number of lesions per patient or as percentage of patients with new stenoses.

[Coronary artery size in chronic mitral valve insufficiency before and following mitral valve surgery]. / Koronararterienkaliber bei chronischer Mitralinsuffizienz vor und nach Mitralklappenoperation.

The increase of coronary artery size in myocardial hypertrophy represents an adaptive mechanism to keep coronary blood flow normal. The relationship between coronary cross-sectional area and left ventricular muscle mass was determined angiographically in 10 patients with severe mitral regurgitation before and 28 +/- 15 months after successful mitral valve surgery. 10 subjects with atypical chest pain without coronary artery disease served as controls (C). Left ventricular muscle mass was increased preoperatively in mitral regurgitation (257 g vs C = 129 g; p < 0.001) and decreased postoperatively (205 g; p < 0.01 vs preop. and vs C). The cross-sectional area of the left coronary (= left anterior descending+left circumflex) artery was augmented preoperatively (26.5 vs C = 14.0 mm2; p < 0.001) and decreased postoperatively (22.9 mm2; p < 0.05 vs preop. and vs C). The cross-sectional area of the left coronary artery per 100 g LV muscle mass was not different in the three groups. The cross-sectional area of the right coronary artery was also increased before surgery (12.7 vs C = 8.8 mm2; p < 0.05) and decreased postoperatively (11.3 mm2; p < 0.05 vs preop. ns vs C). Our data show that in mitral regurgitation the size of the left coronary artery increases proportionally to the increase in left ventricular muscle mass. Also, the right coronary artery shows slight enlargement which is probably due to the pressure overload of the right ventricle. After surgery there is regression but not normalization of the size of the coronary arteries.

[Clinical course following mitral valvuloplasty]. / Klinischer Verlauf nach perkutaner Mitralvalvuloplastie.

Percutaneous transvenous mitral valvuloplasty using the double-balloon technique has been attempted in 25 patients (mean age 39 +/- 10 years; 17 women, 8 men) with severe, non-calcified (20 patients) or only slightly calcified (5 patients) mitral stenosis. Valvuloplasty was successful in 22 of the 25 patients. The procedure resulted in a marked increase in mitral valve area from 1.0 +/- 0.2 to 1.9 +/- 0.5 cm2 (p < 0.001) whereas the diastolic transmitral gradient decreased from 11 +/- 4 to 4 +/- 2 mm Hg (p < 0.001). Functional classification according to the New York Heart Association improved from 2.4 +/- 0.6 to 1.7 +/- 0.5 (p < 0.001) and physical working capacity increased from 64 +/- 20 to 76 +/- 17% (p < 0.01). In 3 patients the procedure was not successful: cardiac tamponade and ventricular perforation occurred in 1 patient each and in the third valvuloplasty had to be ended because of lack of cooperation. Follow-up examination was performed 24 +/- 17 months after successful valvuloplasty. In all patients an electrocardiogram, an exercise test and an echocardiogram were obtained after 3, 12, 26 and 40 months. Sinus rhythm was found in 13 and atrial fibrillation in 9 patients before valvuloplasty. After the procedure 3 additional patients could be converted into sinus rhythm. Physical exercise capacity did not change during the follow-up. Mitral valve area determined by Doppler-echocardiography increased from 1.0 +/- 0.1 to 1.7 +/- 0.3 cm2 (p < 0.001) after valvuloplasty and decreased slightly to 1.5 +/- 0.2 cm2 (NS) during the follow-up. Left atrial chamber diameter did not change significantly after the procedure (5.2 vs. 5.0 cm). It is concluded that percutaneous mitral valvuloplasty is successful in 88% of all patients with severe, non calcified mitral stenosis. The clinical result seems to be beneficial and almost all patients had a stable follow-up for two years. Several complications during the procedure occurred in two patients (8%).

[Digital subtraction angiography for the assessment of myocardial perfusion]. / Digitale Subtraktionsangiographie zur Bestimmung der Myokardperfusion.

Coronary angiography does not only permit to evaluate the severity of coronary disease but also to assess coronary flow reserve in various myocardial perfusion areas by digital processing. Use of colour flow mapping allows the assessment of both, density as well as distribution velocity of contrast-medium (= parametric imaging). The advantage of this technique is given by the possibility to assess coronary flow reserve not only at rest but also under physiologic situations such as bicycle ergometry. Clinical investigations have shown that coronary flow reserve determined after papaverine administration does not correlate with physiologic conditions such as physical exercise.

Cutaneous and coronary flow reserve in patients with microvascular angina.

Microvascular angina is characterized by exercise-induced angina in patients with normal coronary arteries and reduced coronary flow reserve. Recently, a generalized disorder of abnormal vascular reactivity in microvascular angina has been postulated. Therefore, coronary flow reserve was determined by the coronary sinus thermodilution technique and compared with the cutaneous flux ratio in 6 control subjects (group 1) and 12 patients with microvascular angina (group 2). Coronary flow reserve was calculated from maximal coronary flow after 0.5 mg/kg of dipyridamole divided by flow at rest. Cutaneous flow ratio was estimated by laser Doppler fluxmetry (right forearm) before and after 4 min of suprasystolic blood pressure occlusion. Coronary flow at rest was identical in the two groups, but after maximal vasodilation with dipyridamole, coronary flow was higher in group 1 than in group 2 (p less than 0.05). Coronary flow reserve differed significantly between the two groups (2.9 in group 1 and 1.3 in group 2; p less than 0.001). Cutaneous Doppler flux at rest was higher in group 1 than in group 2 (p less than 0.05). However, the hyperemic response was identical in both groups. It is concluded that the cutaneous flux ratio in patients with microvascular angina is not impaired. Local peripheral vasomotor tone appears to be increased in patients with microvascular angina because cutaneous flow at rest is reduced. Thus, a generalized disorder of abnormal vascular reactivity cannot be confirmed in patients with microvascular angina.

Left ventricular flow from apex to base during systole and isovolumic relaxation in a patient with hypertrophic cardiomyopathy and midventricular obstruction.

The occurrence of a left ventricular anterograde flow velocity (maximal: 3.9 m.s-1) is demonstrated in a 32-year-old patient with hypertrophic cardiomyopathy and midventricular obstruction, beginning at early systole and persisting throughout the isovolumic relaxation. Cardiac catheterization with simultaneous dual high fidelity pressure measurements in the apical and basal chambers confirmed the presence of the Doppler maximal instantaneous pressure gradient of 60 mmHg. Contrast left ventricular angiography excluded apical dyskinesia. In the two intracavity compartments, isovolumic relaxation time and the time constant of pressure decay (tau) were abnormal whereby tau was more delayed in the apical than in the basal portion. The presence of an apical high pressure zone during systole with impeded and delayed emptying through the midventricular obstacle and the late onset and prolongation of relaxation are thought to be the cause of the intraventricular flow from apex to base lasting from early systole throughout isovolumic relaxation.

Silent myocardial ischemia. How to diagnose? How to treat?

1. The diagnosis of silent ischemia in asymptomatic patients with known coronary artery disease is adequately achieved by stress testing. 24 hour monitoring allows to assess the total ischemic burden which has prognostic implications. 2. The diagnosis of silent ischemia in asymptomatic patients without documented coronary artery disease is difficult. Stress testing should be carried out in selected patients with multiple risk factors. No mass screening by stress tests can be recommended because of the many false positive results and exorbitant costs. 3. Ischemia regardless whether painful or painless is an independent prognostic factor. 4. Drug treatment reduces or abolishes total ischemic burden. Its impact on prognosis is yet unknown but ongoing multicenter studies (TIBET, TIAP) might clarify the issue. 5. Successful PTCA can abolish silent ischemia. 6. In patients with silent ischemia, as in symptomatic patients, survival is better with surgical than with medical treatment in the presence of 3-vessel disease or reduced left ventricular function.

Right ventricular diastolic function during exercise: effect of ischemia.

The effects of exercise on right ventricular diastolic function were evaluated in 14 patients who underwent supine rest and exercise right ventricular angiography. On the basis of coronary anatomy and exercise left ventricular regional wall motion analysis, these patients were classified into two groups: Group 1 (n = 7) had no or only mild coronary artery disease and Group 2 (n = 7) had significant coronary disease and exercise-induced left ventricular wall motion abnormalities suggesting ischemia. Chamber stiffness at rest was higher in Group 2 (48 x 10(-3) ml-1/m2) than in Group 1 (18 x 10(-3) ml-1/m2, p = 0.006). During exercise, right ventricular filling rate in the second half of diastole was significantly lower in Group 2 (126 versus 276 ml/m2 per s, p less than 0.03). The time constant of right ventricular pressure decay decreased significantly in both groups with exercise; however, both groups displayed a parallel upward shift of the pressure-volume curve with exercise. Because ischemia could not be demonstrated in Group 1, it is an unlikely explanation for this shift. Septal shifting was not a significant factor with exercise. Because of an increase in left ventricular end-diastolic volume with exercise and a close correlation between right and left ventricular end-diastolic pressures (r = 0.96 for Group 1 and r = 0.76 for Group 2), pericardial constraint is the most likely cause for this upward shift of the pressure-volume curve. Therefore, an increase in right ventricular end-diastolic pressure may not be a reliable indicator of ischemia during exercise because this pressure is coupled to changes in left ventricular volume and pericardial constraint.

Quantification of aortic regurgitation with amplitude-weighted mean flow 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.

Potential role of coronary vasoconstriction in ischaemic heart disease: effect of exercise.

Coronary vasomotion plays an important role in the regulation of coronary perfusion at rest and during exercise. Normal coronary arteries show coronary vasodilation of the proximal (+20%) and distal (+40%) vessel segments during supine bicycle exercise. However, patients with coronary artery disease show exercise-induced vasoconstriction of the stenotic vessel segments. The exact mechanism of exercise-induced stenosis narrowing is not clear but might be related to a passive collapse of the disease-free vessel wall (Venturi mechanism), elevated plasma levels of circulating catecholamines, an insufficient production of the endothelium-derived vasorelaxing factor or increased platelet aggregation due to turbulent blood flow with release of thromboxane A2 and serotonin. Various vasoactive drugs, such as nitroglycerin and calcium antagonists, prevent exercise-induced stenosis vasoconstriction. An additive effect on coronary vasodilation of the stenotic vessel segment was observed after combination of nitroglycerin with diltiazem. Thus, exercise-induced stenosis narrowing plays an important role in the pathophysiology of myocardial ischaemia during dynamic exercise. The antianginal effect of vasoactive substances can be explained--besides the effect on pre- and afterload--by a direct action on coronary stenosis vasomotion.

Effect of isradipine on left ventricular relaxation and diastolic filling.

The effect of two calcium antagonists on left ventricular (LV) relaxation and diastolic filling was evaluated in 16 randomized patients. Isradipine and nifedipine were administered intravenously in a maximum dose of 60 micrograms/min for isradipine and 63 micrograms/min for nifedipine. Heart rate was increased significantly (p less than 0.01) by both study agents. LV end-diastolic pressure remained unchanged whereas peak systolic pressure decreased significantly (p less than 0.01). The reduction in systolic pressure was significantly greater (p less than 0.05) after isradipine (delta P of 30 mm Hg) than after nifedipine (delta P of 13 mm Hg). The time constant decreased from 65 to 56 ms (p less than 0.05) after isradipine and from 62 to 59 ms (NS) after nifedipine. LV filling remained unchanged. It is concluded that both calcium antagonists are associated with a significant reduction in LV afterload accompanied by a reflex increase in heart rate. Isradipine is a more potent vasodilator than nifedipine at the same infusion rate. A beneficial effect on LV relaxation with isradipine, but not nifedipine, may be due to its less pronounced negative inotropic effect or its more potent afterload-reducing action.

Validation of a new automatic system for biplane quantitative coronary arteriography.

In a collaboration between the University of Texas (software) and the University of Zürich (hardware) a compact, automatic system for biplane quantitative coronary arteriography was developed. The system is based on a 35 mm film projector, a slow-scan CCD-camera (image digitizing) and a computer workstation (Apollo DN 3000, image storage and processing). A new calibration procedure based on two fixed reference points in the center of the image intensifier was used (isocenter technique). Contour detection of coronary arteries was carried out in biplane projection using a geometric-densitometric edge-detection algorithm. The proximal and distal luminal areas, as well as the minimal luminal area of the stenotic vessel segment were determined. Accuracy and precision were determined from precision drilled holes in a plexiglas cube which were filled with 50%, 75% and 100% contrast medium. The diameter of the holes ranged from 0.5 to 5.0 mm. The mean difference and the standard deviation of the differences between the true and the measured diameters were 0.12 +/- 0.14 mm for plane A and 0.26 +/- 0.17 mm for plane B, respectively. After a second order correction the mean difference amounted to 0.02 +/- 0.09 mm for plane A and 0.02 +/- 0.12 mm for plane B, respectively. Intra- and interobserver variability were evaluated in 5 patients (age 60 +/- 10 years) with coronary artery disease using 16 normal and 5 stenotic vessel segments (cross-sectional area ranging from 0.8 to 8.7 mm2). Two independent observers analyzed the same vessel segment twice. Intraobserver variability expressed as the standard error of estimate in percent of the mean angiographic vessel area (SEE) amounted to 2.1% for observer 1 and 4.4% for observer 2, respectively. Interobserver variability expressed as SEE was 4.1% for measurement 1 and 3.6% for measurement 2, respectively.

[Long-term course of hypertrophic cardiomyopathy: drug versus surgical therapy]. / Langzeitverlauf der hypertrophen Kardiomyopathie: medikamentöse versus operative, Therapie.

139 patients with hypertrophic cardiomyopathy (HCM) have been followed up for 1-28 years (mean 8.9 years). Group 1 consisted of 60 patients (mean age 38 years) without indication for septal myectomy (SM) (no pressure gradient at rest in 8, pressure gradient less than 50 mm Hg in 52 cases); group 2 consisted of 79 patients (mean age 36 years) who had SM (pressure gradient at rest 70 mm Hg). Management in group 1 was the following: (1a) propranolol (n = 20) (160 mg/d), (1b) verapamil (n = 18) (360 mg/d) and (1c) no therapy (n = 22). 19 patients died in group 1 (mortality 3.6% year); 17 died in group 2 (mortality 2.4%/year). 10 year survival in group 1b was 80% and in groups 1a und 1c 67% and 65% respectively. Patients of group 1b had a higher survival rate (p less than 0.05) than the other subgroups. Surgery patients treated with verapamil (120-360 mg/d) (n = 17) had a 10-year survival rate of 100% compared to 78% for surgery patients (n = 34) without such treatment (p less than 0.05). In summary, it can be said that the overall survival rate after SM is better than that with medical treatment. Under verapamil, however, survival is not different from that after surgery. The most favorable outcome was observed in surgery patients under long-term therapy with verapamil, probably due to the reduction of systolic pressure overload (SM) and improvement in diastolic function (verapamil).

[Normal values of left ventricular function. Biplanar angiocardiography with reference to sex-specific differences]. / Normalwerte der linksventrikulären Funktion. Biplane Angiokardiographie, unter Berücksichtigung geschlechtsspezifischer Unterschiede.

Normal values of left ventricular function have been determined in 24 patients by means of biplane angiocardiography. Global parameters were chamber volume, ejection fraction and muscle mass. Regional ventricular function was determined by means of an orthogonal and radial axial system. Radial axis shortening parameters showed smaller standard deviations and smaller coefficient of variations than orthogonal parameters. The smallest coefficient of variation elicited regional area reduction methods. Women showed significantly lower chamber volumes and muscle mass than men. There was no difference between the two sexes in the ejection fraction and wall thickness.

[Late potentials and ventricular arrhythmia in patients with chronic coronary heart disease]. / Spätpotentiale und ventrikuläre Rhythmusstörungen bei Patienten mit chronischer koronarer Herzkrankheit.

To assess the value of late potential recordings in predicting complex ventricular arrhythmias in chronic coronary heart disease, signal-averaged ECG and 24-h Holter were performed in 101 consecutive patients following coronary arteriography. In 69 of 101 patients, non-sustained ventricular tachycardia (VT) (22 patients) or monotopic or polytopic ventricular premature beats (VPB) (47 patients) were detected. When the different patient groups (VT, VPB, no arrhythmias) were compared, the parameters defining the late potentials demonstrated broad variability. Patients with non-sustained ventricular tachycardia showed a tendency to increased late potentials, though this tendency was not significant. In patients with pathologic late potentials the predictability of non-sustained ventricular tachycardia was only 38%. - It is therefore concluded that late potentials in patients with chronic coronary heart disease are not directly linked to the extent and severity of arrhythmias recorded in the ambulatory 24-h Holter.

[Initial experiences with thrombolysis in Swiss hospitals. Synopsis of a round-table discussion]. / Erste Erfahrungen mit der Thrombolyse an Schweizer Spitälern. Zusammenfassung des Rundtischgespräches.

Thrombolytic therapy of acute myocardial infarction (AMI) has resulted in significant reduction of mortality, limitation of infarct size and preservation of left ventricular function. Among the panelists there was consensus with respect to the following recommendations for efficient thrombolytic therapy of AMI: the prehospital phase should be considerably shortened, especially by reducing patient delay. This can be achieved by rendering patients aware of symptoms of AMI and the need for immediate hospitalization on their occurrence. After contraindications have been ruled out, intravenous thrombolysis should be started in every case where the time elapsed since the onset of pain is not greater than 3 hours. In patients with large infarctions intravenous thrombolysis is indicated up to 6 hours after onset of pain. Accompanying medication should include heparinization and administration of aspirin. When reperfusion is achieved the patient should be monitored for recurrence of ischemia. Regardless of symptoms recurrence of ischemia requires immediate coronary arteriography with a view to revascularization by PTCA or bypass surgery. Patients without recurrence of spontaneous ischemia should undergo ergometric stress testing before leaving the hospital. Exercise-induced angina or ST segment depression are strong indications for coronary arteriography.