Human umbilical cord blood cells: a new alternative for myocardial repair?

Cell therapy for myocardial disease is a rapidly progressive field. However, present strategies of cell transplantation into the infarcted myocardium have limitations from practical points of view. One of the biggest challenges is to achieve a sufficient number of suitable cells. Umbilical cord blood (UCB), an unlimited source of stem/progenitor cells that could be used for transplantation into the injured heart, is readily available. The aim of our review is to describe the potential and prospect of UCB as a new supplier of cells for myocardial repair. The use of UCB stem cells might be of importance to elderly and sick people in whom the availability of autologous stem cells is limited.

[Out-of-hospital resuscitation in Israel 2000].

The aim of the study was to evaluate the impact of pre-hospital cardio-pulmonary resuscitation, performed by mobile intensive cardiac care units of Magen David Adom (MDA) teams in the framework of a national survey conducted in the period February and March 2000. During the survey, MDA performed 539 resuscitations, 485 of which were performed by mobile intensive care units of MDA, and they constitute the study population of the present analysis. The average age of the patients was 70.5 years, and 68% were men. The mean response time of the mobile intensive care units was 10.3 minutes. In 14% of the cases, a bystander initiated basic cardiac life support before the arrival of the MDA team. Upon arrival of the resuscitation team, 242 patients (50%) had asystole, 19% ventricular tachycardia (VT)/ventricular fibrillation (VF), 13% pulseless electrical activity (PEA), and 18% had other severe arrhythmias. One hundred and ninety-nine patients (41%) were transferred alive to the hospital after successful resuscitation. Hospital summaries were obtained for 148 of these patients. The cause of cardiac arrest was cardiac in 64% of the cases and 48% of the patients who reached the hospital had a previous history of heart disease. Fifty-three patients (11%) were discharged alive from the hospital. Patients discharged alive were younger, more promptly resuscitated, 78% had a cardiac cause of death and 38% of them were in ventricular tachycardia/fibrillation when first seen by the resuscitation team. The rate of successful resuscitation to discharge in the sub-group with VT/VF was 21%, and only 4% for patients in asystole, which is in line with other studies. However, the rate of initiation of resuscitation by bystanders is low in Israel. These data may help the medical staff and the health policy providers in Israel.

Interventional magnetic resonance imaging for guiding gene and cell transfer in the heart.

BACKGROUND: Interventional magnetic resonance imaging (iMRI) has the potential for guiding interventional cardiac procedures in real time. OBJECTIVES: To test the feasibility of iMRI guided gene and cell transfer to the heart and to monitor myocardial remodelling after myocardial infarction in a rat model. METHODS: The MRI contrast agent GdDTPA, together with either Evans blue dye, or a recombinant adenovirus encoding the LacZ gene, or primary fibroblasts tagged by BrdU, were injected into the myocardium of rats under iMRI guidance. Rats were killed seven days after the injection and the hearts sectioned to identify the blue dye, LacZ expression, or fibroblast presence, respectively. In a parallel study, left ventricular area was measured before and after myocardial infarction and in sham operated rats by T1 weighted MRI and by echocardiography. RESULTS: Location of GdDTPA enhancement observed with iMRI at the time of injection was correlated with Evans blue stain, beta-gal expression, and the primary fibroblast location in histological studies. iMRI and echocardiography measured a comparable increase in left ventricular area at seven and 30 days after myocardial infarction. A good correlation was found between the iMRI and echocardiographic assessment of left ventricular area (r = 0.70; p < 0.0001) and change in left ventricular area with time (r = 0.75; p < 0.0001). CONCLUSIONS: The results show the feasibility and efficiency of iMRI guided intramyocardial injections, and the ability to monitor heart remodelling using iMRI. Genes, proteins, or cells for tissue engineering could be injected accurately into the myocardial scar under iMRI guidance.

Improved prognosis of patients presenting with clinical markers of spontaneous reperfusion during acute myocardial infarction.

OBJECTIVE: To describe the clinical features, management, and prognosis of patients presenting with clinical markers of spontaneous reperfusion (SR) during acute myocardial infarction (AMI). DESIGN: Cohort study. SETTING: National registry of 26 coronary care units. PATIENTS: 2382 consecutive patients with AMI. MAIN OUTCOME MEASURES: Patient characteristics, management, and mortality. RESULTS: The incidence of SR was 4% of patients (n = 98) compared with thrombolytic treatment (n = 1163, 49%), primary angioplasty (n = 102, 4%), and non-reperfusion (n = 1019, 43%). SR patients were more likely to develop less or no myocardial damage as indicated by a higher percentage of non-Q wave AMI (58% v 32%, 47%, and 44%, respectively, p < 0.0001), aborted AMI (25% v 9%, 8%, and 12%, p < 0.001), and lower peak creatine kinase (503 v 1384, 1519, and 751 IU, p < 0.0001). SR patients, however, were more likely to develop recurrent ischaemic events (35% v 17%, 12%, and 16%, respectively; p < 0.001) and subsequently were more likely to be referred to coronary angiography (67%), angioplasty (41%), or bypass surgery (16%, p < 0.001). Mortality at 30 days (1% v 8%, 7%, and 13%, respectively, p < 0.0001) and one year (6% v 11%, 12%, and 19%, p < 0.0001) was significantly lower for SR patients than for the other subgroups. By multivariate analysis, SR remained a strong determinant of 30 day survival (odds ratio (OR) 0.16, 95% confidence interval (CI) 0.01 to 0.74). At one year, the association between SR and survival decreased (OR 0.49, 95% CI 0.18 to 1.13). CONCLUSIONS: Clinical markers of SR are associated with greater myocardial salvage and favourable prognosis. The vulnerability of SR patients to recurrent ischaemic events suggests that they need close surveillance and may benefit from early intervention.

Effect on survival of acute myocardial infarction in Killip classes II or III patients undergoing invasive coronary procedures.

The purpose of the present study was to determine whether patients with acute myocardial infarction (AMI) in Killip class II or III are likely to benefit from catheterization and coronary revascularization performed within 30 days of AMI. The study population was drawn from 2 national surveys performed during 1996 and 1998 in 26 coronary care units operating in Israel. Our analysis included 3,113 patients with AMI who were divided into 2 groups according to their admission Killip class: 2,484 patients (80%) in Killip class I, of whom 1,408 (57%) underwent cardiac catheterization and 1,076 were treated noninvasively; and 629 patients in Killip class II or III, of whom 314 (50%) underwent cardiac catheterization and 315 were managed conservatively. Patients in Killip class II or III who were treated invasively had lower mortality rates than their counterparts who were treated noninvasively at 30 days: 7.6% versus 15.6%, respectively (adjusted odds ratio [OR] 0.52, 95% confidence interval [CI] 0.28 to 0.92), and thereafter from 30 days to 6 months, 4.3% versus 13.6%, respectively (OR 0.34, 95% CI 0.16 to 0.68). In Killip class I patients, an invasive versus noninvasive management was not associated with a better outcome at 30 days: 1.6% versus 3.2%, respectively (OR 0.58, 95% CI 0.32 to 1.05), but with similar mortality rates at 30 days to 6 months, 1.9% versus 2.0%, respectively (OR 1.46, 95% CI 0.79 to 2.74). Thus, the present study suggests that patients with AMI in Killip class II or III on admission may benefit from cardiac catheterization and revascularization performed within 30 days from admission, whereas patients with AMI in Killip class I are less likely to benefit from this approach.

Aspirin and percutaneous coronary angioplasty are associated with a decline in mortality from cardiogenic shock. Results from a national Israeli survey, 1992--1998.

BACKGROUND AND METHODS: Despite the significant progress in the care and outcome of patients with acute myocardial infarction (AMI), the impact of evolving therapies on the incidence and outcome of patients with cardiogenic shock complicating AMI has been questioned. We analyzed trends in the incidence, care and outcome of cardiogenic shock from four national surveys conducted during 1992--1998. RESULTS: Of the 5,351 AMI patients admitted to all coronary care units in Israel, 254 (4.7%) developed cardiogenic shock. The incidence of cardiogenic shock decreased over time (5.8, 5.1, 4.3 and 4.4% for the years 1992, 1994, 1996 and 1998, respectively, p = 0.08). Concomitantly, there was an increase in utilization of coronary angiography, urgent angioplasty and intra-aortic balloon counterpulsation. In addition, there was an increase in hospital use of aspirin, nitrates, ACE inhibitors and beta-blockers. Patients with shock were more likely to die within 7 days compared with AMI patients not having shock (65 vs. 4%; p < 0.001). During the study period, the mortality of patients with shock decreased: at 7 days (72% in 1992 to 60% in 1998; p = 0.09), at 30 days (87 to 70%, respectively; p = 0.01) and at 6 months (89 to 77%, respectively; p = 0.02). Both aspirin and angioplasty were independently associated with improved outcome after adjustment for baseline characteristics and study period. CONCLUSIONS: Although the mortality rate of cardiogenic shock complicating AMI remains high, the increased utilization of aspirin and angioplasty is associated with improved outcome.

Influence of embryonic cardiomyocyte transplantation on the progression of heart failure in a rat model of extensive myocardial infarction.

Cell transplantation has been proposed as a future therapy for various myocardial diseases. It is unknown, however, whether the encouraging results obtained in animal models of ischemia and reperfusion, cryoinjury or cardiomyopathy can be reproduced in the setting of permanent coronary artery occlusion and extensive myocardial infarction (MI). Embryonic cardiac cells were isolated and cultured for 3 days to confirm viability, morphology and to label cells with BrdU or the reporter gene LacZ. Seven days after extensive MI, rats were randomized to cell (1.5x10(6)) transplantation (n=11) or culture medium injection (n=16) into the myocardial scar. Echocardiography study was performed before and 53+/-3 days after implantation to assess left ventricular (LV) remodeling and function. During follow-up, there was no mortality among cell-treated rats v 4 of 16 control rats (P=0.12). X-gal staining, BrdU and alpha -SMA immunohistochemistry identified the engrafted cells 1 week, 4 weeks and 8 weeks after transplantation, respectively. Antibodies against alpha -SMA, connexin-43, fast and slow myosin heavy chain revealed grafts in various stages of differentiation in 10 of 11 cell-treated hearts. Many of them, however, kept their embryonic phenotype and were isolated from the host myocardium by scar tissue. Serial echocardiography studies revealed that cell transplantation prevented scar thinning, LV dilatation and dysfunction while control animals developed scar thinning, significant LV dilatation accompanied by progressive deterioration in LV contractility. Transplantation of embryonic cardiomyocytes after extensive MI in a rat model attenuate LV dilatation, infarct thinning, and myocardial dysfunction. Still, many grafts remain isolated and do not differentiate into an adult phenotype, even when studied 2 months after grafting.

Management and outcome of cardiogenic shock complicating acute myocardial infarction in hospitals with and without on-site catheterisation facilities.

OBJECTIVE: To determine whether the availability of on-site catheterisation and revascularisation facilities influenced hospital management and outcome of patients with acute myocardial infarction complicated by cardiogenic shock. METHODS: Patients with acute myocardial infarction were enrolled prospectively in four nationwide surveys during 1992, 1994, 1996, and 1998. The characteristics, management, and outcome of patients with cardiogenic shock were compared between hospitals with on-site catheterisation facilities (group 1; 18 hospitals) and without such facilities (group 2; 8 hospitals). RESULTS: Of 5351 patients with acute myocardial infarction, 254 (4.7%) developed cardiogenic shock. Group 1 patients (n = 186 of 3854; 4.6%) were younger (mean (SD) age, 69.6 (12) v 73.7 (10) years, p = 0.006) and had a lower proportion of women (36% v 52%, p = 0.03) than group 2 (n = 68 of 1243; 5.2%). There was no difference in other characteristics including the use of thrombolysis. Group 1 patients more often underwent coronary angiography (26% v 4%, p < 0.001), angioplasty (21% v 4%, p = 0.002), and intra-aortic balloon counterpulsation (28% v 4%, p < 0.001). Seven day mortality was lower among group 1 than among group 2 patients (61% v 77%, p = 0.02), even after age and sex adjustment (odds ratio (OR) 0.54; 95% confidence interval (CI) 0.28 to 1.02). This outcome benefit persisted at 30 days (74% v 88%, p = 0.01; OR 0.45, 95% CI 0.18 to 0.98), and at 6 months (80% v 90%, p = 0.06; OR 0.57, 95% CI 0.22 to 1.33). CONCLUSIONS: The greater use of invasive and interventional procedures in hospitals with catheterisation facilities is associated with improved survival of patients with acute myocardial infarction complicated by cardiogenic shock. Immediate availability of invasive care facilities will improve the outcome of cardiogenic shock in the community setting.

Myocardial regeneration: present and future trends.

Cardiomyocytes are terminally differentiated and are unable to proliferate in response to injury. Genetic modulation, cell transplantation and tissue engineering promise a revolutionary approach for myocardial regeneration and tissue repair after myocardial injury. Current data derived from animal models suggest that it may be possible to treat heart failure by inserting genetic materials or myogenic cells into injured myocardium. Success with animal models has raised the hope for new treatment after heart attacks and could prove an alternative to transplantation, particularly in elderly patients for whom there is often a lack of donor hearts. This exciting research, however, still faces significant difficulties before it can develop into a clinical therapeutic tool and many challenges need to be overcome before cell transplantation, gene therapy and tissue engineering can be considered efficient, therapeutic strategies for myocardial regeneration.

Cytotoxic T lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro.

The damage of myocardial infarction (MI) is often progressive. A possible mechanism for subsequent myocardial damage and heart failure after MI is immune response against cardiac self-antigens. The purpose of our study was to test the hypothesis that cytotoxic T lymphocytes are activated following acute MI and may have a role in producing further myocardial damage. Rats were allocated into three experimental groups: acute MI, Sham MI and non-operated control. One, two and three weeks after surgery, lymphocytes were obtained from rat spleens and incubated with neonatal cardiac myocytes. Lymphocyte proliferation was assessed by a thymidine incorporation assay and calculated as proliferation index (PI). Myocyte destruction was measured by a crystal-violet staining assay and expressed as percentage of cell destruction. Proliferation index was significantly higher among lymphocytes obtained from MI animals (44. 3+/-5.8 and 44.9+/-5.1, at 2 and 3 weeks after MI, respectively) than sham MI (29.3+/-5.3, 27.1+/-4.7) (P<0.05) or control animals (17.1+/-2.5, 16.2+/-2.8) (P=0.03). Cytotoxic activity of the MI lymphocytes against the cultured cardiomyocytes was significantly higher 2 and 3 weeks after MI, (36.4+/-7.3%, 69.3+/-4.9%) compared to sham MI (17.9+/-3.14%, 36.6+/-5.3%) (P<0.001) and control animals respectively (13.3+/-5.4%, 17.4+/-6.1%) (P<0.001). The cytotoxic activity against healthy cardiomyocytes was myocyte-specific, induced by CD8 lymphocytes and major-histocompatibility complex (MHC) restricted. Cytotoxic T lymphocytes (CD8) are activated following MI and can recognize and kill normal cardiomyocytes in vitro. The newly described pathophysiological insights may provide novel oportunities to prevent death of non-ischemic cardiomyocytes and heart failure following myocardial infarction.

Sex differences in management and outcome after acute myocardial infarction in the 1990s: A prospective observational community-based study. Israeli Thrombolytic Survey Group.

BACKGROUND: Previous studies have suggested that women with acute myocardial infarction (AMI) are less aggressively managed than are men. The aim of this study was to assess sex differences in medical and invasive coronary procedures (angiography, PTCA, and CABG) in AMI patients admitted to cardiac care units (CCUs) in Israel in the mid 1990s and their association with early and 1-year prognosis. METHODS AND RESULTS: We studied 2867 consecutive AMI patients (2125 men, 74%) hospitalized in all 25 CCUs in Israel from 3 prospective nationwide surveys conducted in 1992, 1994, and 1996. Women were, on average, older than men (69 versus 61 years, P:<0.0001) and had a higher prevalence of hypertension, diabetes, Killip class >/=II on admission, and in-hospital complications. Women received aspirin and beta-blockers less often than did men, but these differences were not significant after age adjustment. The unadjusted rates of thrombolysis, angiography, and PTCA/CABG use were lower in women than in men but not after covariate adjustment: 42% versus 48% (adjusted odds ratio [OR] 0.92, 95% CI 0.77 to 1.11), 23% versus 31% (OR 0.88, 95% CI 0.70 to 1.09), and 15% versus 19% (OR 0.93, 95% CI 0.72 to 1.19), respectively. The 30-day mortality was higher in women than in men (17.6% versus 9.6%, respectively; OR 1.39, 95% CI 1.06 to 1.82), but the 30-day to 1-year mortality rate was not (9.1% versus 5.6%, respectively; hazard ratio 1.18, 95% CI 0.84 to 1.66). CONCLUSIONS: This prospective nationwide observational community-based study of consecutive AMI patients hospitalized in the CCUs in the mid 1990s indicates that women fare significantly worse than do men at 30 days but not thereafter at 1-year. The difference in 30-day outcome was not influenced by the use of different therapeutic modalities, including thrombolysis and invasive coronary procedures, but was rather due to the older age and greater comorbidity of women; these findings seem also to explain the less frequent use of invasive procedures in women.

Incidence and clinical significance of bacteremia and sepsis among cardiac patients treated with intra-aortic balloon counterpulsation pump.

In this prospective study, a significant incidence of fever (47%), true bacteremia (15%), and sepsis (12%), were found in 60 cardiac patients treated with an intra-aortic balloon counterpulsation pump. The benefit of antibiotic prophylaxis in this setting should therefore be evaluated.

Bioengineered cardiac grafts: A new approach to repair the infarcted myocardium?

BACKGROUND: The myocardium is unable to regenerate because cardiomyocytes cannot replicate after injury. The heart is therefore an attractive target for tissue engineering to replace infarcted myocardium and enhance cardiac function. We tested the feasibility of bioengineering cardiac tissue within novel 3-dimensional (3D) scaffolds. METHODS AND RESULTS: We isolated and grew fetal cardiac cells within 3D porous alginate scaffolds. The cell constructs were cultured for 4 days to evaluate viability and morphology before implantation. Light microscopy revealed that within 2 to 3 days in culture, the dissociated cardiac cells form distinctive, multicellular contracting aggregates within the scaffold pores. Seven days after myocardial infarction, rats were randomized to biograft implantation (n=6) or sham-operation (n=6) into the myocardial scar. Echocardiography study was performed before and 65+/-5 days after implantation to assess left ventricular (LV) remodeling and function. Hearts were harvested 9 weeks after implantation. Visual examination of the biograft revealed intensive neovascularization from the neighboring coronary network. Histological examination revealed the presence of myofibers embedded in collagen fibers and a large number of blood vessels. The specimens showed almost complete disappearance of the scaffold and good integration into the host. Although control animals developed significant LV dilatation accompanied by progressive deterioration in LV contractility, in the biograft-treated rats, attenuation of LV dilatation and no change in LV contractility were observed. CONCLUSIONS: Alginate scaffolds provide a conducive environment to facilitate the 3D culturing of cardiac cells. After implantation into the infarcted myocardium, the biografts stimulated intense neovascularization and attenuated LV dilatation and failure in experimental rats compared with controls. This strategy can be used for regeneration and healing of the infarcted myocardium.

[Thrombolytic therapy or primary coronary angioplasty in acute myocardial infarction? Israel Thrombolytic Survey Group].

There has been continuous debate over the superiority of primary percutaneous, transluminal, coronary angioplasty (PTCA) over thrombolysis for acute myocardial infarction (AMI). It was questioned whether this advantage of primary PTCA reported in selected populations by experienced centers can be replicated in our clinical practice. We compared demographic and clinical variables, therapies and outcome in AMI treated with primary PTCA vs thrombolytic therapy. Clinical and demographic variables of 1,678 unselected AMI patients (admitted January/February and May/July 1996) were analyzed in 16 cardiac care units with on-site catheterization facilities and ability to perform PTCA. Of these 803 (48%) were treated by thrombolysis and 99 (6%) by primary PTCA. The prevalence of adverse prognostic variables, such as anterior wall MI, heart failure on admission or during hospital stay, pulmonary edema, and ventricular tachycardia or fibrillation, was higher in the PTCA group. The 7-day, 30-day and 1-year mortality rates were similar in the 2 groups: 4%, 7.2% and 12.8%, respectively, in the PTCA group and 5%, 7.2% and 11.1% in the thrombolysis group. There was a trend toward lower mortality in subgroups of high-risk patients: those with heart failure on admission (Killip class > 1), the elderly (> 65 years), and those with previous MI treated with PTCA. After adjusting for confounders, treatment with primary PTCA was not found to be associated with lower mortality. Only a small proportion of AMI patients in Israel were treated with primary PTCA in 1996. The frequency of adverse prognostic factors among them was higher but their short and long term outcomes were similar to those of high risk patients treated with thrombolysis.

Cardiogenic shock: single center experience with and without on-site catheterization facilities.

BACKGROUND: The beneficial effect of on-site catheterization facilities on the survival of all patients with myocardial infarction complicated by cardiogenic shock has been questioned. Our objective was to evaluate the impact of the availability of on-site catheterization facilities on the outcome of unselected patients with cardiogenic shock. METHODS AND RESULTS: We studied the hospital records of 70 consecutive patients with cardiogenic shock admitted to our intensive coronary care unit during 1990-1996, and compared two groups of patients: those admitted before (n = 34) and after (n = 36) the opening of our catheterization laboratory. Patients admitted when the catheterization laboratory was available were of similar age, but included fewer males and fewer patients with prior myocardial infarction. Following the activation of the catheterization laboratory, utilization rates of coronary angiography, percutaneous transluminal coronary angioplasty and intra-aortic balloon pump increased, compared with the previous period. However, there was no improvement in in-hospital (88 vs. 83%; p = 0.7) and 30-day mortality (91 vs. 86%; p = 0.7) before versus after the activation of our catheterization laboratory. Twelve patients selected to cardiac catheterization (9 underwent percutaneous transluminal coronary angioplasty) experienced lower in-hospital and 30-day mortality compared with patients who were not selected (58 vs. 96, and 67 vs. 96%, respectively; p < 0.02). CONCLUSIONS: Following the activation of the catheterization laboratory, the mortality of the entire population of cardiogenic shock patients remained relatively unchanged. Still, a small subgroup of these patients selected for urgent cardiac catheterization had a lower mortality compared with patients who were not selected.