Jonathan Leor

Effect of Injectable Alginate Implant on Cardiac Remodeling and Function After Recent and Old Infarcts in Rat

Background— Adverse cardiac remodeling and progression of heart failure after myocardial infarction are associated with excessive and continuous damage to the extracellular matrix. We hypothesized that injection of in situ-forming alginate hydrogel into recent and old infarcts would provide a temporary scaffold and attenuate adverse cardiac remodeling and dysfunction. Methods and Results— We developed a novel absorbable biomaterial composed of calcium-crosslinked alginate solution, which displays low viscosity and, after injection into the infarct, undergoes phase transition into hydrogel. To determine the outcome of the biomaterial after injection, calcium-crosslinked biotin-labeled alginate was injected into the infarct 7 days after anterior myocardial infarction in rat. Serial histology studies showed in situ formation of alginate hydrogel implant, which occupied up to 50% of the scar area. The biomaterial was replaced by connective tissue within 6 weeks. Serial echocardiography studies before and 60 days after injection showed that injection of alginate biomaterial into recent (7 days) infarct increased scar thickness and attenuated left ventricular systolic and diastolic dilatation and dysfunction. These beneficial effects were comparable and sometimes superior to those achieved by neonatal cardiomyocyte transplantation. Moreover, injection of alginate biomaterial into old myocardial infarction (60 days) increased scar thickness and improved systolic and diastolic dysfunction. Conclusions— We show for the first time that injection of in situ-forming, bioabsorbable alginate hydrogel is an effective acellular strategy that prevents adverse cardiac remodeling and dysfunction in recent and old myocardial infarctions in rat.

Population-Based Analysis of the Effect of the Northridge Earthquake on Cardiac Death in Los Angeles County, California

OBJECTIVESnWe sought to determine whether a natural disaster affected total cardiovascular mortality and coronary mortality in an entire population.nnnBACKGROUNDnThe effect of the January 17, 1994 Northridge Earthquake (NEQ) on all deaths and causes of deaths within the entire population of Los Angeles County is unknown. The purposes of our study were to analyze all deaths in this entire population before, during and after the NEQ and to determine whether the NEQ temporally and spatially altered death due to cardiovascular disease.nnnMETHODSnWe analyzed all death certificate data (n = 19,617) from Los Angeles County during January of 1992, 1993 (control periods) and 1994, using International Classification of Diseases, 9th Revision codes for ischemic heart disease (IHD) and atherosclerotic cardiovascular disease (ASCVD), as well as other causes of death.nnnRESULTSnThere was an average of 73 deaths per day due to IHD and ASCVD during January 1 to 16, 1994; this increased to 125 on the day of the NEQ, and then decreased to 57 deaths per day from January 18 to 31 (p < 0.00001, before NEQ vs. day of NEQ; after NEQ vs. day of NEQ; and before NEQ vs. after NEQ). The NEQ was associated with an increase in deaths due to myocardial infarction and trauma but not cardiomyopathy, hypertensive heart disease, valvular heart disease, cerebrovascular disease or noncardiovascular causes. Based on plots of daily deaths due to IHD and ASCVD, the decrease in deaths during the 14 days after the NEQ (-144) overcompensated for the increase on the day of the NEQ (+55). Geographic analysis revealed a redistribution of deaths due to IHD and ASCVD toward the epicenter on the day of the NEQ.nnnCONCLUSIONSnWhen an entire population simultaneously experiences a major environmental stress, there is an increase in death due to coronary artery disease (but not other cardiac causes), followed by a decrease that overcompensates for the excess of death. The overcompensation may represent a residual population that is more resistant to stress or a possible preconditioning effect of the stress, or both. This study supports the concept that cardiovascular events within an entire population can be triggered by a shared stress.

Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors : A cohort study of 11,575 patients with coronary artery disease

OBJECTIVESnThe purpose of this study was to investigate the significance of the possible negative interaction between aspirin and angiotensin-converting enzyme (ACE) inhibitors.nnnBACKGROUNDnSeveral provocative reports have recently suggested that aspirin is unsafe in patients with heart failure and has negative interaction with ACE inhibitors that might attenuate their beneficial effects upon survival.nnnMETHODSnWe analyzed mortality data of 11,575 patients with coronary artery disease screened for the Bezafibrate Infarction Prevention trial. A total of 1,247 patients (11%) were treated with ACE inhibitors. Of them, 618 patients (50%) used aspirin.nnnRESULTSnFive-year mortality was lower among patients on ACE inhibitors and aspirin than patients on ACE inhibitors without aspirin (19% vs. 27%; p < 0.001). After adjusting for confounders, treatment with aspirin and ACE inhibitors remained associated with lower mortality risk than using ACE inhibitors only (relative risk [RR] = 0.71; 95% confidence interval [CI] = 0.56 to 0.91). Subgroup analysis of 464 patients with congestive heart failure treated with ACE inhibitors revealed 221 patients (48%) on aspirin and 243 patients not on aspirin. Although clinical characteristics and therapy were similar, patients taking aspirin experienced lower mortality than patients who did not (24% vs. 34%; p = 0.001). After adjustment, treatment with aspirin was still associated with lower mortality (RR = 0.70; 95% CI = 0.49 to 0.99).nnnCONCLUSIONSnAmong coronary artery disease patients with and without heart failure who are treated with ACE inhibitors, the use of aspirin was associated with lower mortality than treatment without aspirin. Our findings contradict the claim that aspirin attenuates the beneficial effect of ACE inhibitors and supports its use in patients with coronary artery disease treated with ACE inhibitors.

Gene transfer and cell transplant: an experimental approach to repair a ‘broken heart’

Time for primary review 22 days.nnDespite significant progress in prevention and therapy of ischemic heart disease, treating patients with heart failure after myocardial infarction remains a major therapeutic challenge. Adult cardiomyocytes cannot regenerate after injury. Therefore, cardiomyocyte loss due to myocardial infarction is irreversible. Currently, congestive heart failure is the only major cardiovascular disorder that is increasing in incidence and mortality [1]. Thus, there is still a need to develop alternative therapeutic strategies to prevent, arrest or reverse congestive heart failure after myocardial infarction.nnRecent insights into the pathogenesis of myocardial disease and advances in molecular biology have opened up a new era of molecular and cellular therapies that target genes, molecules and peptides. Gene transfer as a therapeutic approach for the treatment of myocardial infarction and congestive heart failure has been suggested as a new treatment strategy for these serious disorders [2, 3]. The introduction, into injured myocardium, of recombinant transgenes that encode growth factors, could stimulate new vessel formation with increased collateral blood flow, accelerate healing and enhance myocardial performance. Today it is even possible to consider genetic manipulation leading to regeneration of myocytes within the infarcted myocardium.nnAn alternative experimental strategy to increase viability and augment ventricular function after myocardial infarction is cell transplantation [4]. Engrafted fetal cells might increase the number of functional myocytes in the infarcted myocardium, could serve as a potential source of growth factors and could be programmed for myocyte-based gene transfer.nnThe purpose of our review is to summarize recent advances in the attempts to develop molecular and cellular strategies for repairing a ‘broken heart’. The biological rationale for these new therapies and the potential limitations of gene therapy and cell transplant in treating myocardial infarction are discussed.nnLeft ventricular remodeling following myocardial infarction refers to the process … nn* Corresponding author. The Heart Institute, Good Samaritan Hospital, 1225 Wilshire Blvd., Los Angeles, CA 90017, USA. Tel.: +1 (213) 977 4050; fax: +1 (213) 977 4107.

Stimulation of 42/44 kDa mitogen-activated protein kinases by arginine vasopressin in rat cardiomyocytes

Vasoconstrictors, such as angiotensin II (Ang II), are involved in the regulatory mechanisms of post myocardial infarction (MI) hypertrophy. Arginine vasopressin (AVP), may be another vasoconstrictor that influences the mechanisms that lead to post MI hypertrophy. In these studies we investigated the possible activation of the 42/44 kDa mitogen-activated protein kinases (MAPKs), also referred as extracellular signal regulated kinases (ERKs), in cultured cardiomyocytes. Treatment of rat cardiomyocytes with AVP, Ang II and phorbol 12-myristate 13-acetate (PMA) increases the activation of ERKs. The activity of the 42/44 kDa MAPKs was tested using the phosphorylation of: (1) EGF receptor peptide (EGFR-P); (2) myelin basic protein (MBP) immobilized in poly acrylamide gels; and (3) T183 and Y185 residues of these proteins. The activity of the MAPKs, induced by AVP or PMA was inhibited by downregulation of protein kinase C (PKC), by the tyrosine kinase inhibitor genistein and by MAPK kinase (MEK) inhibitor, PD98059. In addition, the AVP-induced stimulation of MAPKs was shown to be mediated through a V1 receptor. We suggest that AVP activates the 42/44kDa MAPKs through a signal transduction pathway that involves stimulation of AVP-V1 receptor, tyrosine kinase, PKC and MEK. These results suggest that AVP may be involved in ERKs dependent regulatory functions of cardiomyocytes growth.

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 β-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.

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.

Calcium channel blocker debate: true lies?

Furberg, Psaty, and associates recently added a lot of excitement and color to our professional life. They raised the hypothesis that calcium channel blockers may increase the risk of myocardial infarction in hypertensive patients [1] and mortality in patients with ischemic heart disease [2]. Their provocative reports were published in very prestigious journals and created a panic in the public, attracted a lot of attention from the media, and produced a hot debate among physicians and researchers. The authors have been under fire in the last few months. Their reports have been examined carefully, and the validity of their results and conclusions have been questioned and debated [3-7]. The purpose of our brief editorial is to present our opinion on this debate and to emphasize its potential benefits. In addition, we will suggest what is, in our opinion, the current place of calcium channel blockers in the management of patients with cardiovascular disease. After reviewing the data of Furberg et al. [1], Psaty et al. [2], and the accompanying articles, it seems that the only solid finding was that administration of high doses of short-acting nifedipine may be dangerous in the setting of unstable angina and acute myocardial infarction. This is, however, an old new finding. Furberg et al. [1] re-emphasized the potential pro-ischemic effects of short-acting nifedipine and its ability to activate the sympathetic nervous system and the renin-angiotensin system. These adverse effects, however, can be avoided by concomitant use of beta-blockers [8]. Nevertheless, the results of shortacting nifedipine cannot be applicable to the whole family of calcium channel blockers, particularly the heart rate-lowering calcium channel blockers, verapamil and diltiazem, or the newer longer acting formulations. We may say that Furberg and Pasty suggested but did not prove that calcium channel blockers may be harmful. We do not think that they provided enough evidence that calcium channel blockers, as a class, should not be used in hypertension and ischemic heart disease. A more recent report suggests that long-acting formulations of nifedipine [9] and heart rate-lowering calcium channel blockers [10-12] are effective and safe in various subgroups. On the other hand, Furberg et al. should be complimented because they stimulated our thinking and awareness regarding the indications and contraindications of calcium channel blocker therapy and of all cardiovascular drugs. For patients with left ventricular dysfunction (ejection fraction <40%) following acute myocardial infarction, short-acting calcium channel blockers have been shown to be harmful [13]. Calcium channel blockers, however, are still very popular in treatment of myocardial infarction patients. Data derived from the GUSTO-1 trial indicated that in the United States, calcium channel blockers were used in 31-42% of myocardial infarction patients [14]. Did these patients receive the appropriate formulation (short-acting vs. long-acting, heart rate-lowering vs. short-acting nifedipine) and using the appropriate selection criteria (with and without left ventricular dysfunction)? We are afraid that the answer is no. In the GUST0-1 trial, the overall use of calcium channel blockers among myocardial infarction patients with a left ventricular ejection fraction <40% was 23% [15]. Among patients with a left ventricular ejection fraction <40% and symptoms of congestive heart failure, 17% were taking calcium channel blockers at the time of hospital discharge [15]. The good news is that in the GUSTO-2a trial, those percentages decreased to 19% and 10%, respectively [16]. Still, the number of myocardial infarction patients with left ventricular dysfunction treated with calcium channel blockers is relatively high. Furberg et al. helped us, indirectly, to note that important point. The suggested guidelines for treatment of unstable angina suggest the use of calcium channel blockers for patients whose symptoms are not relieved by adequate doses of nitrates and ~-blockers or in patients unable to tolerate adequate doses of one or both of these agents or in patients with variant angina [17]. Among physicians treating unstable angina, however, calcium channel blockers are still very popular and are more popular among cardiologists (42%) than internists (21%) [18]. Taken together, the

Is It Safe to Administer Thrombolytic Therapy to Myocardial Infarction Patients Soon after Laparoscopic Cholecystectomy

Thrombolytic therapy is usually contraindicated after abdominal surgery because of the risk of bleeding. We report a case of a 73-year-old woman who was admitted because of anterior wall acute myocardial infarction (AMI) two weeks after laparoscopic cholecystectomy. She was treated with streptokinase, aspirin and heparin and subsequently developed a hematoma at the site of the removed gallbladder. Our observation suggests that thrombolytic therapy for anterior AMI, two weeks after laparoscopic cholecystectomy, should be considered as a relative contraindication and an optional treatment in this life-threatening situation.