Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study

OBJECTIVES: We conducted a pilot study to evaluate the feasibility of transendocardial delivery of autologous bone marrow (ABM) strategy in patients with severe symptomatic chronic myocardial ischemia not amenable to conventional revascularization. BACKGROUND: Transendocardial injection of ABM cells appears to enhance perfusion of ischemic porcine myocardium. METHODS: Ten patients underwent transendocardial injection of freshly aspirated and filtered unfractionated ABM using left ventricular electromechanical guidance. Twelve injections of 0.2 ml each were successfully delivered into ischemic noninfarcted myocardium pre-identified by single-photon emission computed tomography perfusion imaging. RESULTS: Autologous bone marrow injection was successful in all patients and was associated with no serious adverse effects; in particular, there was no arrhythmia, evidence of infection, myocardial inflammation, or increased scar formation. Two patients were readmitted for recurrent chest pain. At three months, Canadian Cardiovascular Society angina score significantly improved (3.1 +/- 0.3 vs. 2.0 +/- 0.94, p = 0.001), as well as stress-induced ischemia occurring within the injected territories (2.1 +/- 0.8 vs. 1.6 +/- 0.8, p < 0.001). Treadmill exercise duration, available in nine patients, increased, but the change was not significant (391 +/- 155 vs. 485 +/- 198, p = 0.11). CONCLUSIONS: This study provides preliminary clinical data indicating feasibility of catheter-based transendocardial delivery of ABM to ischemic myocardium.     

Comparison of late outcome in patients with versus without angina pectoris having reversible perfusion abnormalities during dobutamine stress technetium-99m sestamibi single-photon emission computed tomography

The aim of this study was to assess the prognostic significance of reversible perfusion abnormalities in patients without angina during dobutamine stress technetium-99m sestamibi single-photon emission computed tomography (SPECT). The study comprised 224 patients (age 60 +/- 11 years, 144 men) with completely or partially reversible perfusion abnormalities during dobutamine stress sestamibi SPECT. Follow-up end points were hard cardiac events (cardiac death and nonfatal myocardial infarction). Angina occurred in 93 patients (42%) during the dobutamine stress test (symptomatic ischemia group). The 131 patients without dobutamine-induced angina represented the silent ischemia group. There was no significant difference between patients with and without angina with regard to summed stress perfusion score (5.3 +/- 2.5 vs 5.2 +/- 2.2, p = 0.9) or summed ischemic score (3.1 +/- 1.7 vs 3.2 +/- 1.4, p = 0.7). During a median follow-up of 7.2 years, cardiac death occurred in 14 patients (15%) with and in 21 patients (16%) without angina. Nonfatal myocardial infarction occurred in 8 patients (9%) with and in 13 patients (10%) without angina. In a multivariate analysis model of clinical and perfusion data, independent predictors of cardiac events were age (hazard ratio 1.02, confidence intervals [CI] 1.01 to 1.05 per year increment), diabetes mellitus (hazard ratio 1.9, CI 1.2 to 3.4), and ischemic perfusion score (hazard ratio 2.1, CI 1.3 to 3.8). Patients with silent ischemia defined as reversible perfusion abnormalities without associated angina during dobutamine stress sestamibi SPECT imaging had similar incidences of ischemia and similar cardiac event rates compared with patients with symptomatic ischemia. Therefore, the absence of angina in association with reversible perfusion abnormalities should not be interpreted as a sign of a more benign prognosis.     

Usefulness of intramyocardial injection of autologous bone marrow-derived mononuclear cells in patients with severe angina pectoris and stress-induced myocardial ischemia

Bone marrow cell transplantation has been proposed as a novel therapeutic option for patients with coronary artery disease. This study investigated whether autologous bone marrow-derived mononuclear cell injection into the ischemic myocardium of patients with severe angina pectoris could safely reduce anginal symptoms, improve myocardial perfusion, and increase left ventricular (LV) function. In a total of 20 patients (63 +/- 10 years old; 16 men) with angina pectoris, myocardial segments with stress-induced ischemia as assessed by gated single-photon emission computed tomography were injected with 30 to 100 million mononuclear cells. Anginal symptoms, Canadian Cardiovascular Society class, and quality of life were assessed at 3 and 6 months of follow-up. At baseline and 3 months of follow-up, an exercise test, gated single-photon emission computed tomography, and magnetic resonance imaging were performed to assess exercise capacity, myocardial perfusion, and LV function. Intramyocardial injection of autologous bone marrow-derived mononuclear cells was safe. The Canadian Cardiovascular Society class improved from 3.5 +/- 0.5 at baseline to 2.4 +/- 0.6 after 3 months (p <0.01) and 2.4 +/- 0.6 after 6 months (p <0.01). The quality-of-life score improved from 52 +/- 10% to 71 +/- 10% at 3 months (p <0.01) to 73 +/- 15% at 6 months (p <0.01). The exercise capacity increased from 79 +/- 31% to 84 +/- 29% (p <0.05). Magnetic resonance imaging revealed an increased LV ejection fraction from 51 +/- 11% to 54 +/- 10% (p <0.01) and a reduced LV end-systolic volume from 97 +/- 50 to 88 +/- 42 ml (p <0.01). The wall motion score index improved from 0.36 +/- 0.32 to 0.24 +/- 0.28 (p <0.01). The number of segments with stress-induced ischemia decreased from 5.1 +/- 3.2 to 2.3 +/- 2.6 (p<0.01). In conclusion, autologous bone marrow-derived mononuclear cell injection in patients with ischemia is safe, reduces anginal symptoms, improves myocardial perfusion, and increases LV function.     

Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia

OBJECTIVES: We tested the hypothesis that intramyocardial injection of autologous bone marrow (ABM) promotes collateral development in ischemic porcine myocardium. We also defined, in vitro, whether bone marrow (BM) cells secrete vascular endothelial growth factor (VEGF) and macrophage chemoattractant protein-1 (MCP-1). BACKGROUND: The natural processes leading to collateral development are extremely complex, requiring multiple growth factors interacting in concert and in sequence. Because optimal angiogenesis may, therefore, require multiple angiogenic factors, we thought that injection of BM, which contains cells that secrete numerous angiogenic factors, might provide optimal therapeutic angiogenesis. METHODS: Bone marrow was cultured four weeks in vitro. Conditioned medium was assayed for VEGF and MCP-1 and was added to cultured pig aortic endothelial cells (PAEC) to assess proliferation. Four weeks after left circumflex ameroid implantation, freshly aspirated ABM (n = 7) or heparinized saline (n = 7) was injected transendocardially into the ischemic zone (0.2 ml/injection at 12 sites). Echocardiography to assess myocardial thickening and microspheres to assess perfusion were performed at rest and during stress. RESULTS: Vascular endothelial growth factor and MCP-1 concentrations increased in a time-related manner. The conditioned medium enhanced, in a dose-related manner, PAEC proliferation. Collateral flow (ischemic/normal zone X 100) improved in ABM-treated pigs (ABM: 98 +/- 14 vs. 83 +/- 12 at rest, p = 0.001; 89 +/- 18 vs. 78 +/- 12 during adenosine, p = 0.025; controls: 92 +/- 10 vs. 89 +/- 9 at rest, p = 0.49; 78 +/- 11 vs. 77 +/- 5 during adenosine, p = 0.75). Similarly, contractility increased in ABM-treated pigs (ABM: 83 +/- 21 vs. 60 +/- 32 at rest, p = 0.04; 91 +/- 44 vs. 36 +/- 43 during pacing, p = 0.056; controls: 69 +/- 48 vs. 64 +/- 46 at rest, p = 0.74; 65 +/- 56 vs. 37 +/- 56 during pacing, p = 0.23). CONCLUSIONS: Bone marrow cells secrete angiogenic factors that induce endothelial cell proliferation and, when injected transendocardially, augment collateral perfusion and myocardial function in ischemic myocardium.     

Greater diagnostic sensitivity of treadmill versus cycle exercise testing of asymptomatic men with coronary artery disease.

Maximal hemodynamic and ventilatory responses using cycle and treadmill ergometer were compared in 52 asymptomatic patients with angiographically proved coronary artery disease. Moreover, test sensitivity with respect to ST-segment depression and typical angina pectoris were compared between exercise modes used. Exercise tests were performed on different days in randomized order. In 42 patients, exercise-induced myocardial ischemia, expressed as a fraction of left ventricular circumference, was assessed by thallium-201 scintigraphy. The main finding of this study was a significantly higher maximal oxygen uptake (1.87 +/- 0.4 vs 2.2 +/- 0.5 liters/min; p less than 0.001), heart rate (148 +/- 19 vs 158 +/- 18 beats/min; p less than 0.001) and rate-pressure product (28.3 +/- 5 x 10(3) vs 30.7 +/- 5 x 10(3); p less than 0.001) during treadmill walking than during cycling. Therefore, stress-induced myocardial ischemia was significantly more extensive after treadmill walking (31 +/- 37 degrees vs 45 +/- 40 degrees; p less than 0.001). Moreover, there were significantly more patients with signs of myocardial ischemia (ST-segment depression or typical angina pectoris, or both) during treadmill than during cycle ergometry (35 vs 25 patients; p less than 0.05). However, lactate levels measured at peak exercise (4.07 +/- 2.0 vs 4.38 +/- 1.9 mmol/liter) and 3 minutes into the recovery period (5.60 +/- 2.2 vs 5.80 +/- 2.2 mmol/liter) were comparable between both methods, indicating no significant difference in anaerobic energy production. These findings suggest that walking on a treadmill represents an exercise method with a greater ability than cycling to detect coronary artery disease.     

Frequency and significance of early postoperative silent myocardial ischemia in patients having peripheral vascular surgery

Coronary disease causes the majority of perioperative complications after peripheral vascular surgery. Twenty-four patients with stable coronary disease undergoing peripheral revascularization were studied using continuous electrocardiographic monitoring to determine the incidence of perioperative asymptomatic myocardial ischemia and its relation to postoperative clinical ischemic events. Patients were monitored preoperatively (17 +/- 1 hours), intraoperatively and postoperatively (29 +/- 2 hours) using 4-channel calibrated amplitude-modulated units. Fifteen patients (63%) had early postoperative silent ischemia; 3 also had preoperative silent ischemia and 5 intraoperative transient ischemia. Patients with and without silent ischemia had similar clinical characteristics, perioperative antianginal medications and postoperative episodes of hemodynamic instability. However, 8 of 15 patients (53%) with silent ischemia had postoperative clinical ischemic events (2 had myocardial infarction, 2 had new congestive heart failure and 4 had new rest angina), versus only 1 of 9 patients (11%) without silent ischemia who had angina (p less than 0.05). Early postoperative silent myocardial ischemia occurs frequently after vascular surgery and is associated with postoperative clinical ischemic events.     

Prognostic significance of silent ischemia in the exercise test in patients with coronary disease

To evaluate the prognostic significance of silent ischemia during exercise testing, 152 consecutive patients (143 males, 9 females) with a mean SD of 55 +/- 7 years (age range 32-73) who underwent exercise testing and coronary arteriography within 3 months were studied. All patients had the following characteristics: 1) a positive electrocardiographic exercise test response; 2) significant coronary artery disease on the arteriography; 3) uninterrupted clinical follow-up for a minimum of 6 months. The 152 patients were divided in 2 groups: group I: 56 patients (37%) with ischemic ST-segment depression during exercise testing without angina (silent ischemia); group II: 96 patients (63%) with ischemic ST-segment depression and angina (symptomatic ischemia). Patients in group I and group II showed similar time to ST-segment depression (3.6 +/- 1.5 min vs 3.2 +/- 1.4 min; p = NS), maximal ST-segment depression and peak heart rate-systolic pressure product (21,151 +/- 7,124 vs 20,456 +/- 6,024; p = NS). Exercise duration was longer in group I than in group II (5.6 +/- 2.1 min vs 4.8 +/- 1.5 min; p less than 0.001). The extent of coronary artery disease defined by the number of significant narrowed coronary vessels, left ventricular end diastolic pressure and ejection fraction were similar in the 2 groups. Sixty six patients who underwent coronary bypass surgery were not included in the analysis. The remaining 86 patients (40 in group I and 46 in group II) were medically treated. The mean follow-up period was 43,5 +/- 25 months (range 6-101).2+ myocardial ischemia during exercise testing.     

Electrophysiological and arrhythmogenic effects of intramyocardial bone marrow cell injection in patients with chronic ischemic heart disease

BACKGROUND: Bone marrow cell injection has been introduced to treat patients with ischemic heart disease. However, focal application of bone marrow cells may generate an arrhythmogenic substrate. OBJECTIVES: To assess the electrophysiological and arrhythmogenic effects of intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia. METHODS: Bone marrow was aspirated in 20 patients (65+/-11 years, 19 male) with drug-refractory angina and myocardial ischemia. Electroanatomical mapping (NOGA, Biosense-Webster, Waterloo, Belgium) was performed during mononuclear cell isolation. Areas for cell injection were selected based on the localization of ischemia on SPECT. These areas were mapped in detail to evaluate local bipolar electrogram duration, amplitude and fragmentation. Mononuclear cells were injected in the ischemic area with the NOGA system. SPECT and electroanatomical mapping were repeated at 3 months. Holter monitoring was repeated at 3 and 6 months. RESULTS: SPECT revealed a decrease in the number of segments with ischemia (3.5+/-2.5 vs. 1.1+/-1.0 at 3 months; P<0.01) and an increased left ventricular ejection fraction (44+/-13% vs. 49+/-17% at 3 months; P=0.02). The number of ventricular premature beats remained unchanged (10+/-24x10(2)/24h vs. 8+/-23x10(2)/24h at 3 months (P=NS) and 12+/-30x10(2)/24h at 6 months (P=NS)). At 3 months follow-up, bone marrow cell injection did not prolong electrogram duration (15.9+/-4.6 ms vs. 15.6+/-4.0 ms; P=NS), decrease electrogram amplitude (3.8+/-1.5 mV vs. 3.8+/-1.5 mV; P=NS), or increase fragmentation (2.0+/-0.5 vs. 1.9+/-0.4; P=NS). CONCLUSION: Intramyocardial bone marrow cell injection does not increase the incidence of ventricular arrhythmias and does not alter the electrophysiological properties of the injected myocardium.     

Systemic neurohumoral activation and vasoconstriction during pacing-induced acute myocardial ischemia in patients with stable angina pectoris

To identify the effect of myocardial ischemia on systemic neurohormones and vascular resistance, 32 untreated, normotensive patients with coronary artery disease underwent incremental atrial pacing until angina. Arterial and coronary venous lactate and arterial values of catecholamines and angiotensin II were determined at control, at maximal pacing rates, and at 1, 2, 5 and 30 minutes after pacing. Based on pacing-induced ST-segment depression (greater than or equal to 0.1 mV) or myocardial lactate production, or both, patients were selected as ischemic (n = 25) or nonischemic (n = 7). Baseline clinical and hemodynamic data were comparable. During pacing, chest pain was similar (20 ischemic vs 7 nonischemic patients). Also, hemodynamic measurements were comparable, except for contractility, which did not improve, and left ventricular end-diastolic pressure, which significantly increased in ischemic patients. Moreover, during ischemia arterial pressures increased significantly (13%) and systemic resistance increased from 1,470 +/- 60 (control) to 1,632 +/- 76 dynes.s.cm-5 5 minutes after pacing (p less than 0.05) in ischemic but not in nonischemic patients. Pacing did not affect neurohormones in nonischemic patients. In contrast, norepinephrine in ischemic patients increased significantly from 1.7 +/- 0.2 (control) to 2.6 +/- 0.3 (maximal pacing) and to 3.0 +/- 0.4 nmol/liter (1 minute after pacing), whereas angiotensin II levels increased from 6.2 +/- 1.4 (control) to 9.3 +/- 2.1 pmol/liter (1 minute after pacing, p less than 0.05). Epinephrine only increased during maximal rates (0.9 +/- 0.1 vs 0.6 +/- 0.1 nmol/liter at control, p less than 0.05). Thus, myocardial ischemia activates circulating catecholamines and angiotensin II, accompanied by systemic vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ischemia at rest is independent of the extent of ventricular dysfunction and arrhythmias in patients with coronary artery disease

To assess the relation between myocardial ischemia, ventricular arrhythmias (VA), and left ventricular (LV) dysfunction, we evaluated 74 patients with coronary artery disease (CAD) using radionuclide angiography (to determine the resting ejection fraction [EF]), resting thallium-201 scintigraphy (to ascertain the extent of resting ischemia), and 24-hour Holter monitoring (to assess VA). Thirty patients had resting ischemia, 26 had resting EF less than 30%, and 27 had repetitive VA. Patients with and without ischemia had similar EFs (36 +/- 14 vs 38 +/- 14, p = NS). Further, patients with and without repetitive forms of VA had a similar number of resting ischemic segments (1.1 +/- 1.7 vs 1.1 +/- 2.2, p = NS). Patients with EFs less than 30 had more VA than patients with EFs greater than or equal to 30 (Holter class 4.3 +/- 2.3 vs 3.0 +/- 1.8, p less than 0.01) but a similar extent of ischemia (1.4 +/- 2.2 vs 1.0 +/- 1.7, p = NS). Thus, while patients with lower EFs have more repetitive forms of VA, ischemia at rest is independent of VA and EF. These data suggest that prognostic stratification of patients with CAD for intervention studies should include a separate consideration of ischemia.     

Prevalence, time course and malignancy of ventricular arrhythmia during spontaneous ischemic ST-segment depression

Ventricular arrhythmias during transient myocardial ischemia were studied in 60 patients with spontaneous angina and greater than or equal to 1 ischemic attack with ST-segment depression during 24-hour ambulatory electrocardiography. The patients were divided into 2 groups: group 1, 10 patients (17%) who developed ventricular arrhythmias during 26 of 92 (28%) ischemic attacks; and group 2, 50 patients who did not show this phenomenon. Daily ischemic attacks, total ischemic time and the proportion of symptomatic ischemic attacks were significantly greater (p less than 0.01) in group 1 versus group 2. In group 1 patients, ischemic attacks were found to have twice the duration in the presence of arrhythmias than in their absence (20.4 +/- 11.9 vs 9.1 +/- 8.4 minutes, p less than 0.01); arrhythmias were more common during symptomatic than during silent ischemic attacks (39 vs 13%, p less than 0.02). Arrhythmias occurred at the onset or peak of ST-segment depression (ischemia phase) in 6 cases (60%), during the resolution of ST-segment depression (recovery phase) in 2 cases (20%) and during both phases of ischemic attacks in the remaining 2 (20%). When compared to recovery phase arrhythmias, ischemia phase arrhythmias were characterized by a later onset time (173 +/- 144 vs 58 +/- 54 seconds, p less than 0.01) and a longer duration (105 +/- 107 vs 41 +/- 22 seconds, p less than 0.01). During the ischemia phase, 16 of 353 ventricular premature complexes initiated ventricular tachycardia, while during the recovery phase only 1 of 161 ventricular premature complexes resulted in ventricular tachycardia (4.5 vs 0.6%, p less than 0.02). Thus, ventricular arrhythmias may accompany spontaneous ischemic ST-segment depression, when the latter is recurrent, prolonged and symptomatic; arrhythmias are characterized by a greater frequency, duration and malignancy during the ischemia phase than during the recovery phase of ischemic attacks.     

Estimation of jeopardized left ventricular myocardium in symptomatic and silent ischemia as determined by iodine-123 phenylpentadecanoic acid rotational tomography

Whether patients with silent myocardial ischemia have a lesser mass of ischemic myocardium than patients with symptomatic ischemia is controversial. Forty-five patients with angiographic coronary artery disease (greater than or equal to 70% luminal diameter narrowing) were studied. All patients had ischemic patterns of myocardial uptake and clearance of the long-chain fatty acid perfusion/metabolic imaging agent iodine-123 phenylpentadecanoic acid after maximal exercise. Single-photon emission computed tomography was performed and 25 myocardial segments were analyzed using circumferential activity profile curves. The 21 patients with silent treadmill ischemia exercised longer than the 24 patients with painful treadmill ischemia (430 +/- 137 vs 337 +/- 96 seconds, p less than 0.01) and to a higher heart rate (138 +/- 21 vs 125 +/- 18 beats/min, p less than 0.05). Patients with treadmill silent ischemia had the same number of abnormally perfused myocardial segments as patients with painful treadmill ischemia (8.6 +/- 4.5 vs 6.5 +/- 4.1 segments, difference not significant) and the same number of reversibly ischemic myocardial segments (4.0 +/- 1.4 vs 4.2 +/- 3.0 segments, difference not significant). The angiographic severity and extent of coronary artery disease were similar in the 2 groups. Thus, in this selected group of patients, those with silent treadmill ischemia appear to have at least as great an extent of ischemic myocardium as patients with painful exertional ischemia.     

Efficacy of pentoxifylline in patients with stable angina pectoris

Pentoxifylline, a methyl xanthine derivative, improves symptoms of peripheral vascular disease probably by reducing whole blood viscosity. The authors assessed the value of this agent in treating myocardial ischemia in 11 patients with angiographically documented coronary artery disease and stable angina pectoris. Maximal, symptom limited treadmill exercise stress tests were performed before and after six weeks of therapy with 1200 mg of pentoxifylline per day. Clinical symptoms proved in 9 [82%] of patients; none developed drug side effects. After therapy, mean total exercise time [7.7 +/- 1.3 vs 10.1 +/- 1.2 minutes], time to onset of angina [5.5 +/- 0.9 vs 7.9 +/- 1.0 minutes], heart rate at onset of angina [93.4 +/- 6.7 vs 112.0 +/- 10.5 beats/min] and rate at onset of ST depression [94.0 +/- 5.8 vs 115.9 +/- 7.4 beats/min] all increased significantly [p less than 0.05]. Mean maximum ST segment depression also decreased [1.6 +/- 0.3 vs 1.2 +/- 0.4mm], but the difference was not significant. Thus, pentoxifylline increases exercise performance in patients with angina pectoris and increases exercise capacity before development of of myocardial ischemia. It may, therefore, be a useful agent for treating ischemic heart disease.     

Role of perceptive threshold in myocardial infarction patients without previous angina

The purpose of this study is to clarify the mechanism of sudden onset myocardial infarction (MI) without previous angina and the relationship of MI without previous angina to the mechanism of onset of postinfarction asymptomatic myocardial ischemia. The mean initial time of ischemic pain in the upper arm under the tourniquet test was significantly prolonged in the MI patients without previous angina, compared with that for the MI patients with previous angina and normal control subjects, although there are some overlapping cases (74 +/- 37 sec versus 52 +/- 20 sec (p less than 0.01), and versus 56 +/- 15 sec (p less than 0.05), respectively). The tolerance time for ischemic pain also was similarly prolonged. There was no significant difference between the groups of MI patients (with and without previous angina) with respect to age, frequency of complications of diabetes mellitus, severity of coronary artery lesions or site of MI. The incidence of post-infarction myocardial ischemia was 50% for the previous angina group and 39.5% for the group without previous angina, but the frequency of asymptomatic ischemia was significantly higher in patients without previous angina, at 66.7%, than in those with previous angina, 32.3% (p less than 0.05). These results suggest that there is a close relationship between the mechanism of MI with sudden onset and that of asymptomatic myocardial ischemia during the pre- and post-infarction periods in patients with low sensitivity to pain.     

Direct minimally invasive intramyocardial injection of bone marrow-derived AC133+ stem cells in patients with refractory ischemia: preliminary results

BACKGROUND: Bone marrow-derived stem cells (BMSC) may represent a viable option for patients with myocardial ischemia refractory to conventional treatments. MATERIAL AND METHODS: In 5 patients (4 males and 1 female, mean age 64 +/- 8 years) with untreatable angina pectoris (Canadian Cardiovascular Society Class III/IV), myocardial segments with stress-induced ischemia as assessed by gated single-photon emission computed tomography were injected with 4 to 12 million CD133+ BMSC. Cells were injected into the myocardium (2 anterior, 2 lateral, 1 inferior wall) through minimally invasive approaches (left minithoracotomy [n = 4] and subdiaphragmatic approach [n = 1]). At baseline, at 6 months and at 1 year of follow-up, an exercise test, gated single-photon emission computed tomography (SPECT), 2-D echocardiography and coronary angiography were performed to assess exercise capacity, myocardial perfusion, LV function and coronary anatomy. RESULTS: Intramyocardial injection of autologous CD133+ BMSC cells was safe. No early or long-term complications were observed. After an average of 3.8 weeks from cell inoculation, all patients experienced a significant improvement of CCS class (from 3.8 to 1.8 at 6 months) and serial SPECT documented improvements of rest and stress perfusion in the injected territories at 6 months from operation. In 3 cases, coronary angiography showed an increase in the collateral score of the target areas. Clinical improvements still persist unchanged in 4 out of 5 cases at a mean of 36.5 months postoperatively. CONCLUSIONS: After stand-alone BMSC transplantation for refractory myocardial ischemia, we observed long-term clinical and perfusion improvements in the absence of adverse events.     

Low molecular weight heparin decreases rebound ischemia in unstable angina or non-Q-wave myocardial infarction: the Canadian ESSENCE ST segment monitoring substudy

OBJECTIVES: The goal of this study was to determine whether enoxaparin was more effective than heparin in reducing recurrent ischemic episodes. BACKGROUND: Continuous ST segment monitoring is a simple tool for assessment of ischemia and identifies patients with a worse prognosis. Little is known about the impact of low molecular weight heparin on ST segment shift. METHODS: Patients were randomized to receive enoxaparin or heparin (mean 3.4 days). Three-lead ST segment monitoring was performed for the first 48 h (n = 220) and an additional 48 h (n = 174) after intravenous study drug discontinuation (mean 1.9 days later). RESULTS: During initial monitoring, ischemia rates were similar among the heparin and enoxaparin groups (27.2% vs. 22.6%, p = 0.44); however, the time to first ischemic episode was earlier among heparin-treated patients (11 +/- 11 vs. 25 +/- 18 min, p = 0.001). After drug discontinuation, ischemic episodes occurred more frequently (44.6% vs. 25.6%, p = 0.009), and the total ischemic duration was greater among heparin patients (18 +/- 39 vs. 5 +/- 12 min/24 h, p = 0.005). Recurrent ischemia occurred more frequently after discontinuation in the heparin (46% vs. 31%, p = 0.043), but not the enoxaparin, group (18.4% vs. 25%, p = 0.33). Regardless of treatment, patients with ischemia were more likely to die or experience (re)infarction at one year (18.4% vs. 8.3%, p = 0.023). CONCLUSIONS: ST segment shift occurs frequently in unstable angina/non-Q-wave myocardial infarction despite antithrombotic therapy and is associated with worse one-year prognosis. Enoxaparin is a more effective antithrombotic treatment than unfractionated heparin and leads to greater prevention of rebound ischemia.     

Urokinase plus heparin versus aspirin in unstable angina and non-Q-wave myocardial infarction

The pivotal role of thrombosis in unstable angina and non-Q-wave myocardial infarction has been established recently. To assess the value and safety of thrombolytic therapy compared to conventional antithrombotic therapy (aspirin) in arresting progression in this setting to recurrent ischemic end-points, 25 patients presenting with unstable angina and an electrocardiogram showing subendocardial ischemia were randomized to receive either aspirin 325 mg daily, or urokinase 3 x 10(6) U intravenously, over 30 minutes followed by heparin. Incidence of endpoints (intractable ischemia requiring mechanical intervention, new myocardial infarction or death) was determined over 7 days. Coronary arteriography was performed at 24 to 72 hours to determine extent of coronary artery disease and morphologic severity of the culprit lesion, graded by a semiquantitative scoring system ranging from 4+ (definite thrombosis) to 0 (chronic lesion). In the first 24 hours, 7 of 13 aspirin versus 1 of 12 urokinase patients exhibited ischemia progression (p less than 0.05). By 7 days, progression to a primary ischemic endpoint occurred in 8 of 13 aspirin patients (3 myocardial infarctions and 5 intractable ischemias) versus 3 of 12 urokinase patients (2 intractable ischemias and 1 death) (p = 0.18). The apparent benefit of urokinase followed by heparin compared to conventional aspirin therapy in arresting early progression of unstable angina or non-Q-wave myocardial infarction was not associated with enhanced culprit lesion morphology (mean lesion severity score 2.7 +/- 1.5 vs 2.8 +/- 1.6 in aspirin-treated patients). Large scale, randomized trials to assess the clinical utility of urokinase for unstable angina are warranted.     

Anti-ischemic effects of atenolol versus nifedipine in patients with coronary artery disease and ambulatory silent ischemia

The anti-ischemic effects of atenolol and nifedipine were compared in a randomized double-blind crossover manner in 24 patients with stable exertional angina and transient silent ischemia during ambulatory electrocardiographic (ECG) monitoring. Both atenolol and nifedipine were effective (p less than 0.005) in reducing the average number and duration of transient ischemic events, but therapy with atenolol was associated with a significantly greater reduction in the mean number (p less than 0.05) and duration (p less than 0.01) of silent ischemic events. Analyses of the silent ischemic activity during the morning hours revealed that only therapy with atenolol produced a significant reduction in the average duration per patient (139 +/- 54 vs. 1,609 +/- 468 s, p less than 0.01) and in the average duration of silent ischemia per event between 6 AM and 12 noon (62 +/- 21 vs. 208 +/- 24 s, p less than 0.005). There were fewer adverse experiences during therapy with atenolol. These results show that although both atenolol and nifedipine are effective in reducing silent ischemic events, treatment with atenolol is associated with significantly greater efficacy, particularly on the morning surge of silent myocardial ischemia.     

Impact of daily life myocardial ischemia in patients with chronic reversible and irreversible myocardial dysfunction.

Repetitive myocardial ischemia during daily life has been suggested as the underlying mechanism of reversible myocardial dysfunction, which may progress into a hibernating state. Thirty-seven patients with ischemic cardiomyopathy (ejection fraction 35 +/- 7%) underwent positron emission tomography (N-13 ammonia and 18-F-fluoro-2-deoxy-glucose [FDG]) and exercise testing before coronary artery bypass grafting (CABG) and 48- hour ambulatory electrocardiographic monitoring to detect ischemia before CABG and 6 months postoperatively. Reversibility of regional myocardial dysfunction was detected by echocardiographic follow-up at 5 days, 2 months, and 6 months after the operation. Preoperatively, ischemic episodes during daily activities were more common (2 [25th to 75th percentiles 0 to 4] vs 0 episodes, p <0.01) and duration of ischemia longer (9 [25th to 75th percentiles 0 to 37] vs 0 [25th to 75th percentiles 0 to 1] minutes, p <0.02) in patients with reversible dysfunction (n = 15) than in patients with irreversible dysfunction (n = 22). The number of ischemic episodes per patient correlated with the numbers of reversibly dysfunctional segments (p = 0.003), viable segments as seen by positron emission tomography (p <0.05), and flow-metabolic mismatch segments (p <0.05). CABG eliminated ambulatory ischemic episodes in patients with reversible dysfunction (0 episodes, p <0.05 vs before CABG). Preoperatively, all patients with reversible dysfunction had a positive exercise test (14 of 15 patients), whereas daily life ischemia was present in 60% of patients. Reversibly dysfunctional segments in patients with ambulatory ischemia had faster recovery of function (15 of 28 patients vs 2 of 12 patients recovered at 5 days, p <0.05), higher FDG uptake (0.86 +/- 0.19% vs 0.71 +/- 0.24%, p <0.05) than in patients without ambulatory ischemia, whereas perfusion was similar (0.63 +/- 0.20 and 0.62 +/- 0.19 ml/g/min). Thus, exercise-induced myocardial ischemia is associated with reversibility of myocardial dysfunction, but not all patients with reversible ischemic cardiomyopathy have ischemic attacks during daily life.     

Continuous monitoring of coronary sinus oxygen saturation during pacing loading in patients with syndrome X

To determine whether patients with syndrome X suffer from myocardial ischemia, coronary sinus oxygen saturation was continuously measured during pacing loading in 31 patients. Subjects were categorized by groups as syndrome X (11 patients), effort angina (14), and old myocardial infarction and valvular heart disease (6). Pacing loading induced evidence of ischemia in all syndrome X patients and in eight of the 11 patients with effort angina, while there was no such evidence in those with old myocardial infarction and valvular heart disease. Coronary sinus oxygen saturation in syndrome X decreased significantly from 44.2 +/- 5.8% to 33.5 +/- 4.4% (p less than 0.01), and it decreased from 47.0 +/- 4.9% to 31.2 +/- 4.0% (p less than 0.01) in effort angina with induced ischemic evidence, indicating that a significant reduction in coronary sinus oxygen saturation reflects the presence of myocardial ischemia. In the group with old myocardial infarction and valvular heart disease, coronary sinus oxygen saturation remained nearly unchanged during pacing. The pattern of depression of coronary sinus oxygen saturation during pacing was steeper in effort angina than in syndrome X. Therefore, we conclude that, although syndrome-X may not be a homogeneous group of patients, most of them may develop myocardial ischemia due to reduced vasodilator reserves of the small coronary artery.