Long term angiotensin converting enzyme-inhibition in patients after coronary artery bypass grafting reduces levels of soluble intercellular cell adhesion molecule-1.

OBJECTIVE: to examine the effect of angiotensin converting enzyme inhibition (ACEI) on soluble intercellular adhesion molecule 1 (sICAM-1) and C-reactive protein (CRP) in patients requiring coronary artery bypass grafting (CABG). METHOD: subgroup analysis of 42 patients randomised to Quinapril (40 mg daily determined) and 45 to placebo. sICAM-1 and CRP were > or = 4 weeks before and 1 year after surgery. RESULTS: there was no difference in sICAM-1 at baseline (142.2 microg/L vs 136.6 microg/L). There was significant reduction in s-ICAM-1 in patients receiving quinapril (142.2+/-10.8 microg/L vs 125.6+/-9.4 microg/L, p<0.05) but not placebo (136.6+/-10.2 microg/L vs 131.2+/-11.7 microg/L, p=NS). Levels of C-reactive protein remained unchanged in both groups (3.70+/-0.85 vs 2.73+/-0.32 mg/L, 2.85+/-0.48 vs 3.16+/-0.50 mg/L). CONCLUSIONS: ACEI reduces sICAM-1 in patients undergoing CABG. The benefits of ACEI may partly be due to a reduction of the vascular inflammatory response.

Effective prevention of atrial fibrillation by continuous atrial overdrive pacing after coronary artery bypass surgery.

OBJECTIVES: The present study was aimed to evaluate the efficacy of a specific algorithm with continuous atrial dynamic overdrive pacing to prevent atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. BACKGROUND: Atrial fibrillation occurs in 30% to 40% of patients after cardiac surgery with a peak incidence on the second day. It still represents a challenge for postoperative prevention and treatment and may have medical and cost implications. METHODS: Ninety-six consecutive patients undergoing CABG for severe coronary artery disease and in sinus rhythm without antiarrhythmic therapy on the second postoperative day were randomized to have or not 24 h of atrial pacing through temporary epicardial wires using a permanent dynamic overdrive algorithm. Holter ECGs recorded the same day in both groups were analyzed to detect AF occurrence. RESULTS: No difference was observed in baseline data between the two study groups, particularly for age, male gender, history of AF, ventricular function, severity of coronary artery disease, preoperative beta-adrenergic blocking agent therapy or P-wave duration. The incidence of AF was significantly lower (p = 0.036) in the paced group (10%) compared with control subjects (27%). Multivariate analysis showed AF incidence to increase with age (p = 0.051) but not in patients with pacing (p = 0.078). It decreased with a better left ventricular ejection fraction only in conjunction with atrial pacing (p = 0.018). CONCLUSIONS: We conclude that continuous atrial pacing with an algorithm for dynamic overdrive reduces significantly incidence of AF the second day after CABG surgery, particularly in patients with preserved left ventricular function.

Randomized comparison of primary stenting and provisional balloon angioplasty guided by flow velocity measurement. Doppler Endpoints Balloon Angioplasty Trial Europe (DEBATE) II Study Group.

BACKGROUND: Coronary stenting improves outcomes compared with balloon angioplasty, but it is costly and may have other disadvantages. Limiting stent use to patients with a suboptimal result after angioplasty (provisional angioplasty) may be as effective and less expensive. METHODS AND RESULTS: To analyze the cost-effectiveness of provisional angioplasty, patients scheduled for single-vessel angioplasty were first randomized to receive primary stenting (97 patients) or balloon angioplasty guided by Doppler flow velocity and angiography (523 patients). Patients in the latter group were further randomized after optimization to either additional stenting or termination of the procedure to further investigate what is "optimal." An optimal result was defined as a flow reserve >2.5 and a diameter stenosis <36%. Bailout stenting was needed in 129 patients (25%) who were randomized to balloon angioplasty, and an optimal result was obtained in 184 of the 523 patients (35%). There was no significant difference in event-free survival at 1 year between primary stenting (86.6%) and provisional angioplasty (85.6%). Costs after 1 year were significantly higher for provisional angioplasty (EUR 6573 versus EUR 5885; P:=0.014). Results after the second randomization showed that stenting was also more effective after optimal balloon angioplasty (1-year event free survival, 93.5% versus 84.1%; P:=0. 066). CONCLUSIONS: After 1 year of follow-up, provisional angioplasty was more expensive and without clinical benefit. The beneficial value of stenting is not limited to patients with a suboptimal result after balloon angioplasty.

Adaptive mechanisms of arterial and venous coronary bypass grafts to an increase in flow demand.

OBJECTIVE: To compare the mechanisms by which arterial and venous grafts increase their flow during pacing induced tachycardia, early and later after coronary bypass surgery. DESIGN: 43 grafts (13 epigastric artery, 15 mammary artery, 15 saphenous vein) evaluated early (9 (3) days (mean (SD)) after bypass surgery were compared with 41 other grafts (15 epigastric, 11 mammary, 15 saphenous vein) evaluated later after surgery (mean 23 months, range 6 to 168 months) by quantitative angiography and intravascular Doppler velocity analysis during atrial pacing. Controls were 17 normal coronary arteries. RESULTS: Baseline graft flow tended to be lower later after surgery than early (41 (16) v 45 (21) ml/min, NS). Blood flow increased during pacing by 30 (16)% early after surgery, less than later after surgery (+46 (18)%, p < 0.001) and less than in normal coronary arteries (+54 (27)%, p < 0.001 v early grafts; NS v late grafts). There was no difference between venous and arterial grafts. No significant vasodilatation was observed during pacing early after surgery in arterial and venous grafts. Later after surgery, significant vasodilatation was observed only in arterial grafts (mammary and epigastric grafts), from 2.41 (0.37) to 2.53 (0. 41) mm (+5.1% v basal, p < 0.001). Early after surgery and in venous grafts later after surgery, the increase in flow was entirely due to an increase in velocity. In later arterial grafts, the relative contribution of the increase in velocity to the increase in flow during pacing was lower in arterial grafts (70 (22)%) than in venous grafts (102 (11)%, p < 0.001) and similar to normal coronary arteries (68 (28)%). CONCLUSIONS: Early and later after surgery, arterial grafts and venous grafts both increase their flow similarly during pacing. Early arterial grafts and venous grafts increase their flow only through an increase in velocity. Later after surgery, arterial grafts act as more physiological conduits and increase their flow in the same way as normal coronary arteries, through an increase in velocity and calibre mediated by the endothelium.

Noninvasive functional assessment of left internal mammary artery grafts by transcutaneous Doppler echocardiography.

A noninvasive method to assess left internal mammary artery (LIMA) patency and function would be useful because this vessel is frequently used for revascularization of the left anterior descending coronary artery. The purpose of this study was to assess the feasibility of measuring changes in LIMA velocities by transcutaneous Doppler during dipyridamole-induced vasodilation. Twenty-five patients with a LIMA graft anastomosed to the left anterior descending coronary artery were studied at least 1 month after surgery by the use of a 5 MHz transducer placed in the left supraclavicular fossa. Doppler velocity parameters were measured at baseline and after intravenous administration of dipyridamole. Dipyridamole increased mean velocity by 127% +/- 54% (p < 0.001), systolodiastolic velocity time integral by 89% +/- 31% (p < 0.001), and diastolic-to-systolic peak velocity ratio from 0.7 +/- 0.3 to 1.2 +/- 0.4 (p < 0.001). The dipyridamole-to-baseline mean velocity ratio was 2.3 +/- 0.5. We conclude that it is possible to measure dipyridamole-induced changes in LIMA flow velocities and thus obtain an index of LIMA blood velocity reserve by transcutaneous Doppler echocardiography.

Evaluation in vivo of the endothelial function of the native gastroepiploic artery.

The endothelial function of a coronary bypass graft is an important aspect, contributing not only to its patency but to its functional performance. To evaluate this aspect in vivo, we studied 16 patients who underwent selective catheterization of the native gastroepiploic artery (GEA). Quantitative angiography of the GEA was performed at baseline, after 2 minutes' infusion of acetylcholine in three ascending doses, and after 2 mg isosorbide dinitrate injection directly into the GEA. Mean GEA diameter was 2.02 +/- 0.38 mm at baseline. We observed dose-dependent vasodilation during acetylcholine infusion: The mean diameter increased slightly to 2.11 +/- 0.32 mm (+6%, not significant) with the second dosage and, more significantly, with the highest dosage, to 2.32 +/- 0.33 mm (+18%, p < 0.001). More important vasodilation was observed after administration of nitrates (+36%, p < 0.001). We found no difference between patients with and without coronary artery disease and no relationship with risk factors for atherosclerosis. A positive correlation was seen between the vasodilation observed after nitrate administration and the highest dose of acetylcholine (r = 0.728, p = 0.002). In conclusion, the GEA demonstrates a notable vasodilatory response to nitrates (non-endothelium-dependent) and a dose-related dilator response to acetylcholine, reflecting preserved endothelial function. This sensitivity should affect favorably the hemodynamic performance of grafts performed with GEA, as well as these grafts' long-term patency rate.

Flow-mediated vasodilation during pacing of the free epigastric artery bypass graft early and late postoperatively.

OBJECTIVES: The free epigastric artery bypass graft is proposed as an alternative conduit to the saphenous vein graft, known for its high rate of attrition. The aim of our study was to assess its endothelial function in vivo. BACKGROUND: The endothelium of arterial bypass grafts plays a role in both the performance and the patency of such grafts. METHODS: We studied 73 epigastric grafts early (mean +/- SD 10 +/- 3 days) and 36 late (12 +/- 5 months) after coronary bypass surgery with quantitative angiography at rest, after 2 min of atrial pacing (130 beats/min) and after injection of isosorbide dinitrate (1 to 2 mg) into the graft. RESULTS: At rest, mean epigastric graft diameter was lower in the late than in the early postoperative period (2.26 +/- 0.39 vs. 2.61 +/- 0.49 mm, p < 0.001). Early after operation, epigastric grafts with a small or an intermediate runoff, but not those with a large runoff, were capable of vasodilation with nitrates (+0.09 +/- 0.10 mm). Late after operation, vasodilation after administration of isosorbide dinitrate was similar in epigastric grafts with a large runoff and in those with a small or intermediate runoff (+ 0.23 +/- 0.09 vs. +0.23 +/- 0.18 mm). Significant vasodilation during pacing was observed late (+4 +/- 9%, p < 0.01) but not early postoperatively, except in a subset of patients with grafts capable of vasodilation after nitrates. A correlation between the response to nitrates and the response during pacing was observed early (r = 0.579, p < 0.001) and late postoperatively (r = 0.530, p = 0.02). CONCLUSIONS: Flow-mediated vasodilation during pacing was observed in most epigastric grafts late, but not early, after operation. This endothelium-dependent dilation was correlated with the importance of the vasodilation observed with nitrates (endothelium-independent), which was related to the importance of the runoff only in the early postoperative period. The ability of epigastric grafts late postoperatively to dynamically adapt their dimensions to an acute increase in demand could contribute to the good functional results of this new alternative arterial graft.

Revascularization of the circumflex artery with the pedicled right internal thoracic artery: clinical functional and angiographic midterm results.

Retroaortic crossing of the pedicled right internal thoracic artery for revascularization of the circumflex artery used in combination with a pedicled left internal thoracic artery anastomosed to the left anterior descending artery and its branches is an attractive technique to achieve an extensive arterial revascularization of the left ventricle. However, there is a suspicion that pulling the right internal thoracic artery through the transverse sinus could compromise its blood flow capacity and patency. Between January 1990 and July 1994 this technique was applied in 256 patients (202 men, 54 women; average age 62 years, range 31 to 80 years). Sixty-one patients had two-vessel disease and 195 had three-vessel disease. Seventeen patients were undergoing a reoperation. Twenty-two had a left ventricular ejection fraction of 40% or less. Thirty had diabetes. Twenty-eight had morbid obesity. The right internal thoracic artery was directed to the circumflex artery (259 anastomoses) through the transverse sinus and the left internal thoracic artery was anastomosed to the left anterior descending artery and its branches (375 anastomoses) in all patients. The 195 patients with three-vessel disease received additional coronary artery bypass grafts to the right coronary artery (93 saphenous vein grafts, 89 free inferior epigastric artery grafts, 12 pedicled right gastroepiploic artery grafts). In total, the 256 patients received 833 distal anastomoses (average 3.2, maximum 5 per patient) and 634 distal anastomoses were internal thoracic artery anastomoses (average 2.4, maximum 4 per patient). Three patients died early and eight had a nonfatal myocardial infarction. Seven patients needed postoperative intraaortic balloon pump support. Six patients underwent early reoperation because of excessive bleeding. Sternal dehiscence occurred in four patients. One of these four patients died of the complication 10 months after the operation. No patient was lost to follow-up (average 33 months). During follow-up, two sudden deaths and six noncardiac deaths occurred. Two patients had a nonfatal myocardial infarction and 12 had recurrence of angina. There were no late reoperations. One patient underwent a successful percutaneous balloon angioplasty of a native left anterior descending artery. Seventy-four patients, enrolled in prospective angiographic studies, underwent a postoperative recatheterization (average 13.2 months, range 6 to 58 months). Seventy-three of the 74 right internal thoracic artery grafts were patent. In comparison, 74 of 74 of the left internal thoracic artery grafts (106/107 anastomoses) were patent. Maximal stress thallium-201 scintigraphy results, obtained in 25 of those patients, did not reveal ischemia in the area of the circumflex artery.(ABSTRACT TRUNCATED AT 400 WORDS)

Functional evaluation of internal mammary artery bypass grafts in the early and late postoperative periods.

OBJECTIVES: We sought to determine whether internal mammary artery grafts adapt to an increase in myocardial flow demand and whether they restore maximal flow reserve. BACKGROUND: Although mammary grafts are now considered the graft of choice for coronary artery bypass surgery, there is still controversy about whether they can provide adequate flow at periods of peak myocardial demand. METHODS: Of 28 patients with a mammary graft anastomosed to the left anterior descending coronary artery, 15 were studied early (mean [+/- SD] 8 +/- 2 days) and 13 late (19 +/- 15 months) after operation by quantitative angiography and selective intravascular Doppler analysis at baseline, during pacing and after injection of papaverine and isosorbide dinitrate into the graft. Eleven patients with a normal left anterior descending artery served as control subjects. RESULTS: At baseline, mean graft diameter (2.39 +/- 0.41 vs. 2.42 +/- 0.45 mm) and bypass flow (38 +/- 22 vs. 30 +/- 12 ml/min) were similar in the early and late postoperative periods. Significant and similar vasodilation was observed in mammary grafts after administration of papaverine (+6 +/- 5% vs. +9 +/- 6%) and nitrates (+14 +/- 7% vs. +16 +/- 9%) both early and late after bypass surgery. Graft diameter increased during pacing late (+6 +/- 3%, p < 0.05) but not early after operation. Bypass flow increased similarly during pacing in both groups, but maximal flow reserve induced by papaverine was significantly lower in mammary grafts studied early (2.70 +/- 0.62) than those studied late (3.66 +/- 0.81, p < 0.01) and in normal coronary arteries (4.05 +/- 0.96, p < 0.001). CONCLUSIONS: An increase in myocardial blood flow induced by pacing resulted in vasodilation of mammary grafts in the late but not in the early postoperative period. Significant vasodilation of mammary grafts after papaverine and isosorbide dinitrate administration was observed both early and late after operation. However, bypass flow reserve after papaverine injection was significantly lower in the early postoperative period but normalized over time. This finding seems unrelated to the conduit; rather, it appears to be related to the periphery and could be the result of injury to the microvasculature during operation.

Coronary artery bypass grafting with the inferior epigastric artery. Midterm clinical and angiographic results.

Between December 1988 and September 1993, 157 patients (141 men, 16 women, average age 60.2 years, range 37 to 78 years) underwent a complete myocardial revascularization with 157 inferior epigastric artery grafts and 285 internal mammary artery grafts (281 in situ, 4 free grafts). A total of 543 distal arterial anastomoses (average 3.4, range two to five per patient) were constructed, 376 with the internal mammary artery and 167 with the inferior epigastric artery. The inferior epigastric artery grafts were anastomosed to two left anterior descending, 5 diagonal, 34 circumflex, and 126 right coronary arteries. The indications for the use of the inferior epigastric artery were the unavailability of conventional conduits in 56 patients and a favorable anatomy or a young age in 101 selected patients. The clinical follow-up averages 31.8 months (range 6 to 62 months). Four patients died early, and there were three perioperative nonfatal myocardial infarctions. Eight patients required early reoperation for thoracic bleeding (2) or drainage of an abdominal parietal collection (6). There were four late deaths (2 sudden deaths, 2 noncardiac causes) and one nonfatal myocardial infarction. Angina recurred in nine patients, of whom one required reoperation and three underwent successful percutaneous balloon angioplasty of a native coronary artery (2) or an old saphenous vein graft (1). An early recatheterization was obtained before discharge (average 11 days) in 135 patients: 132 of 135 inferior epigastric artery grafts were patent. Seventy-seven patients underwent a second angiographic restudy 6 to 43 months after the operation. Forty-four of the 48 inferior epigastric artery grafts restudied within the first postoperative year (average 8.5 months) were patent, but eight showed a diffuse narrowing. Twenty-eight of the 29 inferior epigastric artery grafts examined angiographically between 13 and 43 months (average 25 months) were open, and among those 29, 25 were widely patent, perfectly matching the receiving coronary artery. Most of the occluded or narrowed inferior epigastric artery grafts were grafted onto coronary arteries with mild stenosis at restudy. Five patients underwent a third angiographic reexamination up to 60 months after the operation (average 39 months). All five inferior epigastric artery grafts were widely patent. The early attrition rate of the inferior epigastric artery, as for any free arterial graft, is probably the result of both the loss of a true pedicle and the need for constructing an additional proximal anastomosis. The fact that the patency rate of the inferior epigastric artery graft seems to remain stable beyond 1 year could suggest a good durability in the future.

Peroperative hemodynamic study of left internal mammary artery grafts.

The present study was undertaken to analyse hemodynamic features of an arterial graft and to determine parameters which influence primarily flow and velocity. A total of 284 consecutive patients having isolated coronary bypass surgery underwent peroperative hemodynamic assessment by pulsed Doppler ultrasonics of a left internal mammary artery bypass graft implanted onto the left anterior descending artery. Internal mammary artery free flow was 109.2 +/- 3.7 ml/min and flow in the internal mammary artery measured after completion of the distal anastomosis was 70.9 +/- 2.7 ml/min. All values quoted are mean +/- standard error of the mean. Mean velocity was 21.2 +/- 0.6 cm/sec, internal diameter was 2.65 +/- 0.04 mm and pulsatility index was 2.24 +/- 0.12. Resistance was expressed as mmHg/(ml . min-1) and averaged 1.65 +/- 0.13 for total resistance, 0.87 +/- 0.05 for graft resistance, and 0.73 +/- 0.13 for coronary resistance. From a set of 35 variables, stepwise multiple regression analysis selected two parameters influencing independently flow in internal mammary artery (R2 = 0.8762): flow velocity (p < 10(-4)) and internal diameter (p < 10(-4)). Variables influencing velocity (R2 = 0.3071) were: pulsatility index, which is a dimensionless expression of peripheral resistance (p < 10(-4)), and free internal mammary artery flow (p = 0.0007). Furthermore, a significant correlation between internal diameter and total resistance was observed (R = -0.5363, p < 10(-4), Y = 1.676X-1.545), and the exponentially fitted regression line was characterized by a marked increase of resistance at diameters less than 2 mm.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative angiographic follow-up study of the free inferior epigastric coronary bypass graft.

BACKGROUND: Attempts to improve late results of bypass coronary surgery have focused on the use of arterial conduits because of the high attrition rate of venous grafts. METHODS AND RESULTS: In our institution, 150 patients received an inferior epigastric artery (EPIG) as a free bypass graft, anastomosed to the right coronary artery in 73% and to a marginal branch in 20% of cases. These patients were followed prospectively by qualitative and quantitative angiography. Angiographic studies were performed in 122 patients (81%) early after surgery (11 +/- 5 days), and in 72 cases, a late evaluation (11 +/- 6 months) was also obtained. Quantative angiography (basal and after isosorbide dinitrate [ISDN]) was performed on the in situ EPIG in a large subset of these patients, as well as in 59 patients before bypass surgery. The patency rate was 98% at early control and remained high (93%) at late control. However, at late control, 14 EPIGs were occluded or threadlike, but of these 14, eight were grafted on a coronary artery with a moderate stenosis (< or = 60%) and with good anterograde perfusion. Mean basal EPIG diameter increased from 2.23 +/- 0.42 mm before surgery to 2.57 +/- 0.52 mm at 11 days (P < .01) but decreased to 2.20 +/- 0.47 mm in late study (P < .01 versus 11 days and P = NS versus before surgery). Vasodilation of EPIG with ISDN was observed before surgery (+0.34 +/- 0.20 mm, P < .001) and at late control (+0.20 +/- 0.17 mm, P < .001) but not in the early postoperative period for the whole group. Early after surgery, basal diameter was not different from native EPIG dimensions after ISDN (2.57 +/- 0.52 versus 2.56 +/- 0.39 mm), suggesting maximal dilation. However, vasodilation with ISDN was observed in a subgroup of patients at this time. These responder patients (n = 51) had a smaller basal diameter (2.47 +/- 0.49 versus 2.67 +/- 0.54 mm, P < .05) and a smaller runoff (P < .001) than nonresponder patients. CONCLUSIONS: EPIG grafts have a good early patency rate. The mid-term patency rate remains high and seems to depend, at least partially, on flow through the native coronary artery. EPIGs initially increase their lumen size, probably to meet the increased blood flow due to myocardial requirements. Over time, EPIG diameters decrease mainly as a result of a higher basal vasomotor tone. Long-term angiographic follow-up (eg, 5 to 10 years) is needed to assess late patency rate and the relation with these early findings and will define the place of this new coronary bypass conduit.

Natural history and patterns of current practice in heart failure. The Studies of Left Ventricular Dysfunction (SOLVD) Investigators.

A total of 6,273 consecutive relatively unselected patients with heart failure or left ventricular dysfunction, or both (mean age 62 +/- 12 years, mean ejection fraction 31 +/- 9%), were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) Registry over a period of 14 months. All patients were followed up for vital status and hospital admissions at 1 year. Ischemic heart disease was the underlying cause of failure or dysfunction in approximately 70% of patients, whereas hypertensive heart disease was considered to be primarily involved in only 7%. There were striking differences in the etiology of heart failure among blacks and whites: 73% of whites had an ischemic etiology of failure versus only 36% of blacks; 32% of blacks had a hypertensive condition versus only 4% of whites. The total 1-year mortality rate was 18%; 19% of patients had hospital admissions for heart failure and 27% either died or had a hospital admission for congestive heart failure during the 1st year of follow-up. Factors related to 1-year mortality or hospital admission for congestive heart failure included age, ejection fraction, diabetes mellitus, atrial fibrillation and female gender. There was no difference in mortality associated with congestive heart failure among blacks and whites, but hospital admissions for heart failure were more frequent in blacks. Digitalis and diuretic agents were the drugs most often used in these patients, who were often taking many medications in relation to severity of congestive heart failure symptoms and ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of the mechanisms underlying the changes in left ventricular filling dynamics during oral nisoldipine therapy in patients with anterior myocardial infarction.

The aim of this study was to clarify the mechanisms responsible for the increase in early filling rate observed during oral nisoldipine therapy in patients with ischaemic left ventricular (LV) dysfunction. For that purpose, the global and regional LV function was analysed before and after 2 months of double-blind monotherapy with nisoldipine (10 mg twice daily) or a placebo, in 17 patients with a previous anterior myocardial infarction. The baseline LV ejection fraction ranged from 34-51% and no patient had heart failure. Compared to the placebo, nisoldipine significantly lowered LV systolic pressure and end-diastolic pressure (-3 mmHg vs +6 with the placebo; P less than 0.01) and the LV pressure at the time of mitral opening (-2.0 +/- 3.4 mmHg vs +3.5 +/- 3.0; P less than 0.01). Despite this reduction in driving pressure, the global LV early peak filling rate improved with nisoldipine only and this improvement was related to a selective increase in expansion rate of the anterior areas, from 1010 +/- 360 to 1339 +/- 496 mm2.s-1 (P less than 0.001). The time to regional peak filling rate (-8%; P less than 0.01), the asynchrony of diastolic wall motion and the regional ejection fraction (33 +/- 10 to 38 +/- 12%; P less than 0.001) also improved in the anterior areas with nisoldipine but not with the placebo. In contrast, in the inferior, control zones, the regional ejection fraction and filling rate remained unchanged, both when compared to baseline and to the placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of prolonged nisoldipine administration on the "hibernating" myocardium.

To assess the effects of nisoldipine on chronically underperfused myocardial areas ("hibernating myocardium"), the global and regional left ventricular (LV) function was analyzed before and after 2 months of double-blind monotherapy with nisoldipine (10 mg twice daily) or placebo in 17 patients with a previous anterior myocardial infarction. The baseline LV ejection fraction ranged from 34 to 51%, and no patient had heart failure. Compared to placebo, nisoldipine significantly lowered the LV systolic pressure and end-diastolic pressure (-3 vs. +6 mmHg with placebo; p < 0.01) and the LV pressure at the time of mitral valve opening (-2.0 +/- 3.4 vs. +3.5 +/- 3.0 mm Hg; p < 0.01). Despite this reduction in driving pressure, the global LV early peak filling rate improved only with nisoldipine and this improvement was related to a selective increase in the expansion rate of the anterior areas, from 1,010 +/- 360 to 1,339 +/- 496 mm2/s (p < 0.001). The time to regional peak filling rate (-8%; p < 0.01), the asynchrony of diastolic wall motion, and the regional ejection fraction (33 +/- 10 to 38 +/- 12%; p < 0.001) also improved in the anterior areas with nisoldipine but not with placebo. In contrast, in the inferior control zones, the regional ejection fraction and filling rate remained unchanged, both when compared to baseline and to placebo. In conclusion, prolonged nisoldipine therapy had no significant effect on the normal myocardium but improved systolic and diastolic function in hypokinetic areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of benazeprilat on left ventricular systolic and diastolic function and neurohumoral status in patients with ischemic heart disease.

The effects of the intravenous administration of the angiotensin converting enzyme inhibitor benazeprilat on left ventricular function were examined in 18 patients with ischemic heart disease. Twenty minutes after drug infusion (0.3-10 mg), heart rate (78 +/- 17 to 71 +/- 16 beats/min, p less than 0.0003), left ventricular systolic pressure (-9 mm Hg, p less than 0.0004), and plasma norepinephrine concentration all decreased significantly. The isovolumic indexes of inotropic state also decreased slightly (-10% in dP/dtmax, p less than 0.001), whereas the ejection fraction (39 +/- 16% to 41 +/- 16%, p less than 0.08) and the end-systolic volume (-6%, p less than 0.04) tended to improve, probably because of the afterload reduction (-13% in mean systolic wall stress, p less than 0.05). After benazeprilat administration, the left ventricular end-diastolic pressure was unchanged at the group level, but there was a consistent downward shift of the diastolic pressure-volume relation during rapid filling, and the mean diastolic wall stress decreased from 99 +/- 73 to 69 +/- 42 kdyne/cm2 (p less than 0.007). These data indicate that the acute administration of benazeprilat has a dual action on left ventricular pump function, which is that the negative inotropic effect of bradycardia and reduced sympathetic drive are compensated by afterload reduction. The drug also improved left ventricular diastolic distensibility and significantly reduced wall stress during diastole. The beneficial effects on diastolic function were noted both in patients with mild left ventricular dysfunction and in patients with heart failure.

Effects of the beta 1-adrenergic receptor partial agonist xamoterol on left ventricular diastolic function. An evaluation after 1-6 years of oral therapy.

Acute intravenous administration of the new beta 1-adrenergic receptor partial agonist xamoterol lowers left ventricular end-diastolic pressure and improves the isovolumic indexes of inotropic state and relaxation. To determine if these hemodynamic changes were maintained after prolonged administration, the dose-response relation to cumulative doses of xamoterol was determined in a group of 14 patients with mild (n = 6)-to-serve (n = 8) ischemic left ventricular dysfunction. These patients had been treated with xamoterol (200 mg, b.i.d.) for a mean of 51 +/- 17 months, and the drug had been stopped for 72 hours before testing the responsiveness to xamoterol. In these patients, xamoterol administration still induced dose-dependent decreases in left ventricular end-diastolic pressure from 21.4 +/- 8.2 to 15.8 +/- 7.7 mm Hg (p less than 0.01, vs. baseline and vs. the control data 51 +/- 17 months before). Peak positive dP/dt and dP/dt normalized to a developed pressure of 40 mm Hg [( dP/dt]/DP40) increased by 14% and 23%, respectively (p less than 0.01), whereas the rate of isovolumic pressure decrease improved by 12% (p less than 0.01). It is concluded that the myocardial response to xamoterol is maintained after years of continuous therapy, and that in patients with heart failure, this response was expressed mainly as a reduction in left ventricular end-diastolic pressure.

Effects of alinidine on metabolic response to high-demand myocardial ischemia.

Alinidine is a new bradycardic agent that interferes with ion channels and the if pacemaker current. To determine if alinidine had antiischemic effects unrelated to its bradycardic action, myocardial metabolism was studied during a pacing-stress test in 20 patients with coronary artery disease and angina pectoris, before and after intravenous infusion of alinidine (10 mg, n = 10; 50 mg, n = 10). When compared to the control pacing-stress test, the low dose of alinidine had no significant effect on aortic pressure, coronary sinus flow (-3%, NS), myocardial oxygen extraction, or myocardial lactate uptake. After the high dose of alinidine, aortic pressure and coronary sinus flow remained unchanged but the arteriocoronary sinus difference in oxygen content increased (12.2 +/- 1.3 to 12.7 +/- 1.4 ml/100 ml; p less than 0.0002) above the values observed during the control pacing-stress test, while both the chemical lactate extraction fraction (-19 +/- 30 to 15 +/- 21%; p less than 0.025) and the L-[1-14C]lactate extraction fraction increased. Accordingly, the net myocardial lactate uptake (corrected for production) had increased from 14 +/- 32 during the control pacing-stress test to 29 +/- 24 mumol/min during the pacing repeated after the high dose of alinidine (p less than 0.05). After the high dose of alinidine, the free fatty acid uptake also rose slightly (+23%; NS) and the alanine production was reduced in 7 of 10 patients (-3.6 +/- 1.7 to -1.4 +/- 0.6 mumol/min; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Focus on diastolic dysfunction: a new approach to heart failure therapy.

1. Although heart failure is commonly associated with depressed systolic function, there is increasing evidence that impaired diastolic performance is also universally present and might be a key determinant of symptoms, physical capacity and even survival in some subsets of patients. 2. Reduced diastolic distensibility increases cardiac filling pressure not only at rest, but even more during exercise when diastolic filling time is reduced. The increases in filling pressure and diastolic wall stress lead to pulmonary congestion and subendocardial ischaemia, it also triggers myocardial hypertrophy and a detrimental remodelling of the ventricular cavity. Perhaps even more importantly, impaired ventricular distensibility limits the use of the Frank-Starling mechanism, impairing systolic pump function and cardiac output adaptation during exercise. Therapies able to improve the distensibility of the ventricle are, therefore, desirable in heart failure. 3. Nitrates, angiotensin converting enzyme (ACE) inhibitors and diuretics may indirectly increase left ventricular chamber compliance by their effects on the right side of the heart. Cardiac glycosides do not improve myocardial relaxation and may even cause diastolic contracture at toxic doses. The new beta 1-adrenoceptor partial agonist, xamoterol, on the other hand, consistently lowers left ventricular filling pressure at rest and during exercise, and produces an increase in left ventricular dynamic compliance through the direct lusitropic effect of beta 1-adrenoceptor stimulation. These beneficial effects are maintained during prolonged therapy and also appear sufficient to slow the remodelling of the ventricular cavity. The improvement in symptoms and in exercise tolerance observed during xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) therapy might, therefore, be related to the improvement in left ventricular diastolic distensibility induced by this drug.

Effects of intracoronary infusion of nicardipine during silent ischaemia on myocardial metabolism and function.

The effects of an intracoronary infusion of nicardipine (0.2 mg over 10 min) on myocardial substrate uptake and function were studied in 16 patients with coronary artery disease and angina pectoris. Silent ischaemia, demonstrated by myocardial lactate production, was induced twice by pacing below anginal threshold. Nicardipine or saline was randomly infused during the first or second pacing. During pacing with nicardipine, no systemic effect was noted but coronary sinus flow increased (+ 18%; P less than 0.015) and myocardial oxygen uptake decreased by 12% (P less than 0.025). Transcardiac lactate production did not improve (-8 to -10 mumol min-1; NS) but net lactate uptake, estimated from radiolabelled lactate uptake, tended to rise and the glutamine uptake increased from 1.8 to 5.5 mumol min-1 (P less than 0.04). During recovery after pacing, lactate production decreased faster and LV peak (+) dP/dt and relaxation rate were significantly better after nicardipine infusion than after saline. Thus, during silent ischaemia induced by an increased oxygen demand, intracoronary nicardipine did not prevent lactate release but allowed a faster metabolic and functional recovery. These beneficial effects of nicardipine could be explained by an improved myocardial perfusion or by an effect on intracellular calcium homeostasis.