Marcus F. Stoddard

Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.

BACKGROUND c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. METHODS In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461. FINDINGS This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). INTERPRETATION These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. FUNDING University of Louisville Research Foundation and National Institutes of Health.

Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: A transesophageal echocardiographics tudy

Objectives. The objective of this study was to determine the frequency of left atrial thrombus in patients with acute atrial fibrillation. Background. It is commonly assumed but unproved that left atrial thrombus in patients with atrial fibrillation begins to form after the onset of atrial fibrillation and that it requires ≥3 days to form. Thus, patients with acute atrial fibrillation (i.e., <3 days) frequently undergo cardioversion without anticoagulation prophylaxis. Methods. Three hundred seventeen patients (250 men, 67 women; mean [±SD] age 64 ± 12 years) with acute (n = 143) or chronic (n = 174) atrial fibrillation were studied by two-dimensional transesophageal echocardiography. Results. Left atrial appendage thrombus was present in 20 patients (14%) with acute and 47 patients (27%, p < 0.01) with chronic atrial fibrillation. In patients with a recent embolic event, the frequency of left atrial appendage thrombus did not differ between those with acute (5 [21%] of 24) and those with chronic (12 [23%] of 52, p = NS) atrial fibrillation. Patients with acute versus chronic atrial fibrillation, respectively, did not differ (p = NS) in mean age (64 ± 13 vs. 65 ± 11 years), frequency of concentric left ventricular hypertrophy (32% vs. 26%), hypertension (32% vs. 41%), coronary artery disease (35% vs. 39%), congestive heart failure (43% vs. 48%), mitral stenosis (4% vs. 7%) or mitral valve replacement (1.4% vs. 6%). The minimally detectable difference in proportions between patients with acute and chronic atrial fibrillation based on a power of 0.80 and base proportion of 0.20 was 14%. Conclusions. Left atrial thrombus does occur in patients with acute atrial fibrillation <3 days in duration. The frequency of left atrial thrombus in patients with recent emboli is comparable between those with acute and chronic atrial fibrillation. These data suggest that patients with acute atrial fibrillation for <3 days require anticoagulation prophylaxis or evaluation by transesophageal echocardiography before cardioversion and should not be assumed to be free of left atrial thrombus.

Administration of Cardiac Stem Cells in Patients with Ischemic Cardiomyopathy (the SCIPIO Trial): Surgical Aspects and Interim Analysis of Myocardial Function and Viability by Magnetic Resonance

Background— SCIPIO is a first-in-human, phase 1, randomized, open-label trial of autologous c-kit+ cardiac stem cells (CSCs) in patients with heart failure of ischemic etiology undergoing coronary artery bypass grafting (CABG). In the present study, we report the surgical aspects and interim cardiac magnetic resonance (CMR) results. Methods and Results— A total of 33 patients (20 CSC-treated and 13 control subjects) met final eligibility criteria and were enrolled in SCIPIO. CSCs were isolated from the right atrial appendage harvested and processed during surgery. Harvesting did not affect cardiopulmonary bypass, cross-clamp, or surgical times. In CSC-treated patients, CMR showed a marked increase in both LVEF (from 27.5±1.6% to 35.1±2.4% [P=0.004, n=8] and 41.2±4.5% [P=0.013, n=5] at 4 and 12 months after CSC infusion, respectively) and regional EF in the CSC-infused territory. Infarct size (late gadolinium enhancement) decreased after CSC infusion (by manual delineation: −6.9±1.5 g [−22.7%] at 4 months [P=0.002, n=9] and −9.8±3.5 g [−30.2%] at 12 months [P=0.039, n=6]). LV nonviable mass decreased even more (−11.9±2.5 g [−49.7%] at 4 months [P=0.001] and −14.7±3.9 g [−58.6%] at 12 months [P=0.013]), whereas LV viable mass increased (+11.6±5.1 g at 4 months after CSC infusion [P=0.055] and +31.5±11.0 g at 12 months [P=0.035]). Conclusions— Isolation of CSCs from cardiac tissue obtained in the operating room is feasible and does not alter practices during CABG surgery. CMR shows that CSC infusion produces a striking improvement in both global and regional LV function, a reduction in infarct size, and an increase in viable tissue that persist at least 1 year and are consistent with cardiac regeneration. Clinical Trial Registration— This study is registered with clinicaltrials.gov, trial number NCT00474461.

Preconditioning of Human Myocardium With Adenosine During Coronary Angioplasty

BACKGROUND It is unknown whether adenosine can precondition human myocardium against ischemia in vivo. METHODS AND RESULTS Thirty patients were randomized to receive a 10-minute intracoronary infusion of adenosine (2 mg/min) or normal saline; 10 minutes later, they underwent percutaneous transluminal coronary angioplasty (PTCA; three 2-minute balloon inflations 5 minutes apart). In control patients, the ST-segment shift on the intracoronary ECG was significantly greater during the first inflation than during the second and third inflations, consistent with ischemic preconditioning. In contrast, in adenosine-treated patients, there were no differences in ST-segment shift during the three inflations. The ST-segment shift was significantly smaller in the adenosine-treated group compared with the control group during all three inflations. The reduction in ST-segment shift afforded by adenosine during the first inflation (-72% versus first inflation in control subjects) was greater than that afforded by ischemic preconditioning in control subjects (-52% during the third versus first inflation). Measurements of chest pain score paralleled those of ST-segment shift. Adenosine had no effect on baseline regional wall motion as determined by quantitative two-dimensional echocardiography. Thus, intracoronary infusion of adenosine before PTCA rendered the myocardium remarkably resistant to subsequent ischemia. Judging from the intracoronary ECG, the protection provided by adenosine was even superior to that provided in control subjects by the ischemia associated with the first two balloon inflations. Infusion of adenosine had no major adverse effects in patients undergoing PTCA of the left anterior descending or circumflex arteries. CONCLUSIONS Adenosine preconditions human myocardium against ischemia in vivo. Pretreatment with adenosine is remarkably effective (even more effective than ischemic preconditioning) and could be used prophylactically to attenuate ischemia in selected patients undergoing PTCA of the left anterior descending coronary artery. Whether adenosine can be safely infused into the right or the circumflex coronary artery in the presence of a temporary pacemaker remains to be established.

Delayed Preconditioning-Mimetic Action of Nitroglycerin in Patients Undergoing Coronary Angioplasty

Background—Experimental studies suggest that the cardioprotective effects of the late phase of ischemic preconditioning (PC) can be mimicked pharmacologically. However, to date, no drug has been tested with respect to its ability to elicit a late PC effect in humans. As a consequence, clinical exploitation of the powerful anti-stunning and anti-infarct actions of late PC has been elusive thus far. Methods and Results—A total of 66 patients were randomized to receive a 4-hour intravenous infusion of nitroglycerin (NTG) or normal saline; on the following day, they underwent percutaneous transluminal coronary angioplasty (three 2-minute balloon inflations 5 minutes apart). Measurements of ST-segment shifts (intracoronary and surface ECGs), regional wall motion (quantitative 2D echocardiography), and chest pain score indicated that the infusion of NTG 24 hours before angioplasty rendered the myocardium relatively resistant to ischemia and that the degree of this cardioprotective effect was comparable to that afforded by the ischemia associated with the first balloon inflation in control subjects (early phase of ischemic PC). Collateral flow (estimated from a pressure-derived index) did not differ between control and NTG-pretreated patients, indicating that the enhanced tolerance to ischemia in NTG-pretreated patients cannot be accounted for by baseline differences in collateral function. Conclusions—NTG protects human myocardium against ischemia 24 hours after its administration. To the best of our knowledge, this is the first report that a late PC effect can be recruited pharmacologically in humans. The results suggest that prophylactic administration of nitrates could be a novel approach to the protection of the ischemic myocardium in patients.

Prolongation of isovolumetric relaxation time as assessed by Doppler echocardiography predicts doxorubicin-induced systolic dysfunction in humans☆

A reasonably sensitive and specific noninvasive test for doxorubicin cardiotoxicity is needed. In addition, few data exist on the short- and long-term effects of doxorubicin on diastolic filling. To determine if pulsed Doppler indexes of diastolic filling could predict doxorubicin-induced systolic dysfunction, 26 patients (mean age 48 +/- 12 years) were prospectively studied before receiving chemotherapy (control) and 3 weeks after obtaining cumulative doses of doxorubicin. In nine patients developing doxorubicin-induced systolic dysfunction (that is, a decrease in ejection fraction by greater than or equal to 10 ejection fraction units to less than 55%), the isovolumetric relaxation time was prolonged (from 66 +/- 18 to 84 +/- 24 ms, p less than 0.05) after a cumulative doxorubicin dose of 100 to 120 mg/m2. This prolongation preceded a significant decrease in ejection fraction. Other Doppler indexes of filling were impaired after doxorubicin therapy but occurred simultaneously with the decrease in ejection fraction. A greater than 37% increase in isovolumetric relaxation time was 78% (7 of 9) sensitive and 88% (15 of 17) specific for predicting the ultimate development of doxorubicin-induced systolic dysfunction. In 15 patients studied 1 h after the first treatment, doxorubicin enhanced Doppler indexes of filling and shortened isovolumetric relaxation time. In 22 patients, indexes of filling remained impaired and isovolumetric relaxation time was prolonged 3 months after the last doxorubicin dose. In conclusion, doxorubicin-induced systolic dysfunction is reliably predicted by prolongation of Doppler-derived isovolumetric relaxation time. Early after administration, doxorubicin enhances filling and isovolumetric relaxation time. The adverse effects of doxorubicin on both variables persist at least 3 months after cessation of treatment.

Bradykinin-induced preconditioning in patients undergoing coronary angioplasty

OBJECTIVES The purpose of this study was to determine whether administration of bradykinin reproduces the cardioprotective effects of ischemic preconditioning (PC) in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND Experimental studies suggest that activation of the bradykinin B2 receptor is an important trigger of ischemic PC. However, it is unknown whether bradykinin can precondition human myocardium against ischemia in vivo. Multicenter clinical trials have demonstrated an anti-ischemic effect of angiotensin-converting enzyme inhibitors, which has been postulated to result from potentiation of bradykinin; however, direct evidence for an anti-ischemic action of bradykinin in patients is lacking. METHODS Thirty patients were randomized to receive a 10-min intracoronary infusion of bradykinin (2.5 microg/min) or normal saline. Ten minutes later they underwent PTCA (three 2-min balloon inflations 5 min apart). RESULTS In control patients, the ST-segment shift on the intracoronary and surface electrocardiogram was significantly greater during the first inflation than during the second and third inflations, consistent with ischemic PC. In bradykinin-treated patients, the ST-segment shift during the first inflation was significantly smaller than in the control group, and there were no appreciable differences in ST-segment shift during the three inflations. Measurements of chest pain score and regional wall motion during inflation (quantitative two-dimensional echocardiography) paralleled those of ST-segment shift. Infusion of bradykinin had no hemodynamic effects and no significant adverse effects. Thus, intracoronary infusion of bradykinin before PTCA rendered the myocardium relatively resistant to subsequent ischemia, and the degree of this cardioprotective effect was comparable to that afforded by the ischemia associated with the first balloon inflation in control subjects. In a separate cohort of seven patients given the same dose of bradykinin, coronary hyperemia resolved completely within 10 min after the end of the infusion, indicating that bradykinin-induced vasodilation cannot account for the protective effects observed during the first balloon inflation. CONCLUSIONS Bradykinin preconditions human myocardium against ischemia in vivo in the absence of systemic hemodynamic changes. Pretreatment with bradykinin appears to be just as effective as ischemic PC and could be used prophylactically to attenuate ischemia in selected patients undergoing PTCA.

Transesophageal echocardiographic guidance of cardioversion in patients with atrial fibrillation

The role of TEE in the guidance of cardioversion of atrial fibrillation was studied. Thirty-seven (18%) of 206 patients had left atrial thrombus. Cardioversion was attempted in 153 patients receiving no (n = 107) or < 7 days (n = 46) of anticoagulation prophylaxis, in 27 patients after > or = 3 weeks of anticoagulation, and was cancelled in 26 patients, primarily on the basis of TEE findings. Left atrial thrombus was observed in 37 (18%) of 206 patients. No embolic complications occurred over a 4-week follow-up period. In 7 (41%) of 17 patients new left atrial appendage spontaneous echocardiographic contrast developed immediately after electric cardioversion. In this group, significant decreases occurred in the left atrial appendage maximal emptying shear rate (11.1 +/- 11.1 sec-1 vs 5.0 +/- 5.1 sec-1; p < 0.05), maximal filling shear rate (6.7 +/- 5.9 sec-1 vs 3.7 +/- 3.5 sec-1; p < 0.05), and peak emptying velocity (0.38 +/- 0.29 cm/sec vs 0.19 +/- 0.14 cm/sec; p < 0.05). In one patient a left atrial appendage thrombus formed after electric cardioversion. Left atrial thrombus resolved in 1 (5%) of 21 patients and became immobile in 0 (0%) of 16 patients after 3 to 5 weeks of anticoagulation but resolved (n = 9) or became immobile (n = 6) in 15 (71%) of 21 patients after > 5 weeks of anticoagulation. TEE-guided cardioversion was safely done without or with < 7 days of anticoagulation prophylaxis in selected patients, but the potential for left atrial thrombus to form after electric cardioversion makes anticoagulation advisable in all patients. The conventional recommendation of 3 to 4 weeks of anticoagulation prophylaxis before cardioversion is usually inadequate for left atrial thrombus to resolve or to become immobile.

The influence of obesity on left ventricular filling and systolic function

Little information on the possible influence of obesity on diastolic function is available. Thus we studied 24 asymptomatic obese volunteers (greater than 120% ideal body weight; mean 153 +/- 30%), aged 34 +/- 11 years. Each obese subject was matched for age, height, and sex, with a healthy normal-weight control subject. Isovolumic relaxation time (IVRT) and diastolic filling indexes were determined by pulsed Doppler echocardiography. The IVRT was significantly prolonged in the obese group (84 +/- 17 msec) as compared with the control group (57 +/- 13 msec; p less than 0.0002). Multiple regression analysis showed that percentage of ideal body weight was the most important predictor of peak early filling velocity (r = 0.59, p less than 0.005) and mean deceleration rate of early filling (r = 0.61, p less than 0.005) in the obese group. However, age as compared with percentage of ideal body weight was a more important determinant of the relative distribution of early and atrial filling, such as peak early-to-atrial filling velocity ratio (r = -0.75, p less than 0.0001). Ejection fraction, heart rate, and blood pressure did not differ between the obese and control groups. In conclusion, obesity is associated with preclinical abnormalities of IVRT, which may reflect impaired relaxation. The IVRT may be useful in the early detection of left ventricular dysfunction in obesity. Last, studies comparing Doppler indexes of diastolic filling among groups must control for potential differences in percentage of ideal body weight.

Effects of anesthesia on echocardiographic assessment of left ventricular structure and function in rats

Echocardiography is an essential diagnostic tool for accurate noninvasive assessment of cardiac structure and function in vivo. However, the use of anesthetic agents during echocardiographic studies is associated with alterations in cardiac anatomical and functional parameters. We sought to systematically compare the effects of three commonly used anesthetic agents on echocardiographic measurements of left ventricular (LV) systolic and diastolic function, LV dimensions, and LV mass in rats. Adult male Fischer 344 rats underwent echocardiographic studies under pentobarbital (PB, 25 mg/kg i.p.) (group I, n = 25), inhaled isoflurane (ISF, 1.5%) (group II, n = 25),or ketamine/xylazine (K/X, 37 mg/kg ketamine and 7 mg/kg xylazine i.p.) (group III, n = 25) anesthesia in a cross-over design. Echocardiography was also performed in an additional group of unanesthetized conscious rats (group IV, n = 5). Postmortem studies were performed to validate echocardiographic assessment of LV dimension and mass. Rats in group I exhibited significantly higher LV ejection fraction, fractional shortening, fractional area change, velocity of circumferential fiber shortening corrected for heart rate, and heart rate as compared with groups II and III. LV end-diastolic volume, end-diastolic diameter, and cross-sectional area in diastole were significantly smaller in group I compared with groups II and III. Cardiac output was significantly lower in group III compared with groups I and II. Postmortem LV mass measurements correlated well with echocardiographic estimation of LV mass for all anesthetic agents, and the correlation was best with PB anesthesia. Limited echocardiographic data obtained in conscious rats were similar to those obtained under PB anesthesia.We conclude that compared with ISF and K/X anesthesia, PB anesthesia at a lower dose yields echocardiographic LV structural and functional data similar to those obtained in conscious rats. In addition, PB anesthesia also facilitates more accurate estimation of LV mass.