Arman T. Askari

Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

BACKGROUND Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. METHODS We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. FINDINGS Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). INTERPRETATION These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction

Stem cell transplantation at the time of acute myocardial infarction (AMI) improves cardiac function. Whether the improved cardiac function results from regeneration of cardiac myocytes, modulation of remodeling, or preservation of injured tissue through paracrine mechanisms is actively debated. Because no specific stem cell population has been shown to be optimal, we investigated whether the benefit of stem cell transplantation could be attributed to a trophic effect on injured myocardium. Mesenchymal stem cells secrete SDF‐1 and the interaction of SDF‐1 with its receptor, CXCR4, increases survival of progenitor cells. Therefore, we compared the effects of MSC and MSC engineered to overexpress SDF‐1 on cardiac function after AMI. Tail vein infusion of syngeneic MSC and MSC:SDF‐1 1 day after AMI in the Lewis rat led to improved cardiac function by echocardiography by 70.7% and 238.8%, respectively, compared with saline controls 5 wk later. The beneficial effects of MSC and MSC:SDF‐1 transplantation were mediated primarily through preservation, not regeneration of cardiac myocytes within the infarct zone. The direct effect of SDF‐1 on cardiac myocytes was due to the observation that’ between 24 and 48 h after AMI, SDF‐1‐expressing MSC increased cardiac myocyte surviva, vascular density (18.2±4.0 vs. 7.6±2.3 vessels/mm2, P<0.01; SDF‐1:MSC vs. MSC), and cardiac myosin‐positive area (MSC: 49.5%;mSC:SDF‐1: 162.1%) within the infarct zone. There was no evidence of cardiac regeneration by the infused MSC or endogenous cardiac stem cells based on lack of evidence for cardiac myocytes being derived from replicating cells. These results indicate that stem cell transplantation may have significant beneficial effects on injured organ function independent of tissue regeneration and identify SDF‐1:CXCR4 binding as a novel target for myocardial preservation.—Zhang, M., Mal, N., Kiedrowski, M., Chacko, M., Askari, A. T., Popovic, Z. B., Koc, O. N., Penn, M. S. SDF‐1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB J. 21, 3197–3207 (2007)

Myeloperoxidase and Plasminogen Activator Inhibitor 1 Play a Central Role in Ventricular Remodeling after Myocardial Infarction

Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO), which accumulates in the infarct zone, is released from neutrophils and monocytes leading to the formation of reactive chlorinating species capable of oxidizing proteins and altering biological function. We studied acute myocardial infarction (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO−/−). MPO−/− demonstrated decreased leukocyte infiltration, significant reduction in LV dilation, and marked preservation of LV function. The mechanism appears to be due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1) in the MPO−/−, leading to decreased tissue plasmin activity. MPO and PAI-1 are shown to have a critical role in the LV response immediately after MI, as demonstrated by markedly delayed myocardial rupture in the MPO−/− and accelerated rupture in the PAI-1−/−. These data offer a mechanistic link between inflammation and LV remodeling by demonstrating a heretofore unrecognized role for MPO and PAI-1 in orchestrating the myocardial response to AMI.

Association of Hospital Primary Angioplasty Volume in ST-Segment Elevation Myocardial Infarction With Quality and Outcomes

CONTEXT Earlier studies indicate an inverse relationship between hospital volume and mortality after primary angioplasty for patients presenting with ST-segment elevation myocardial infarction (STEMI). However, contemporary data are lacking. OBJECTIVE To assess the relationship between hospital primary angioplasty volume and outcomes and quality of care measures in patients presenting with STEMI. DESIGN, SETTING, AND PATIENTS An observational analysis of data on 29,513 patients presenting with STEMI and undergoing primary angioplasty in the American Heart Associations Get With the Guidelines registry. Patients were treated between July 5, 2001, and December 31, 2007, at 166 angioplasty-capable hospitals across the United States. Hospitals were divided into tertiles (<36 procedures per year, 36-70 procedures per year, and >70 procedures per year) based on their annual primary angioplasty volume. MAIN OUTCOME MEASURES Door-to-balloon (DTB) times, length of hospital stay, adherence with evidence-based quality of care measures, and in-hospital mortality. RESULTS Compared with low- and medium-volume centers, high-volume centers had better median DTB times (98 vs 90 vs 88 minutes, respectively; P for trend < .001). High-volume centers were more likely than low-volume centers to follow evidence-based guidelines at discharge. Length of stay was similar between the 3 groups (P for trend = .13). There was no significant difference in the crude mortality between the tertiles of volume (incidence rate, 3.9% vs 3.2% vs 3.0% for low-, medium-, and high-volume centers, respectively; P = .26 and P = .99 for low- and medium- vs high-volume hospitals, respectively). Sequential multivariable modeling using generalized estimating equations revealed no significant association between hospital primary angioplasty volume and in-hospital mortality (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 0.78-1.91; P = .38 and adjusted OR, 1.14; 95% CI, 0.78-1.66; P = .49 for low- and medium- vs high-volume hospitals, respectively). CONCLUSION In a contemporary registry of patients with STEMI, higher-volume primary angioplasty centers vs lower-volume centers were associated with shorter DTB times and more use of evidence-based therapies, but not with adjusted in-hospital mortality or length of hospital stay.

Characterization of Post-Operative Risk Associated With Prior Drug-Eluting Stent Use

OBJECTIVES The aim of this study was to assess risk of inpatient surgery at any time after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). BACKGROUND Risk of adverse events, including stent thrombosis (ST), in patients undergoing surgical procedures with prior DES remains poorly defined. METHODS Outcomes of consecutive patients having inpatient surgical procedures after PCI with DES, placed from April 28, 2003 until December 31, 2006 at a tertiary-care medical center, were studied. Primary and secondary end points were 30-day post-operative risk of the Academic Research Consortium (ARC) definite and modified probable definitions of ST and combined 30-day post-operative risk of death, nonfatal myocardial infarction (MI), or ST, respectively. Multivariable logistic regression analyses were used to determine independent risk factors. RESULTS Six hundred six inpatient surgeries on 481 patients with a mean time from PCI to surgery of 1.07 +/- 0.89 years were evaluated. The primary and secondary end points occurred after 11 (2.0%) and 56 (9%) surgeries, respectively. Risk of the combined end point and ST decreased significantly in the first 1 to 6 months after PCI (p < 0.0001 and p < 0.014, respectively); however, risk persisted when time between PCI and surgery was >12 months. Independent correlates of the combined end point include emergency surgery, antecedent MI, the pre-operative use of intravenous heparin, and atherosclerotic lesion length treated with DES. Oral antiplatelet status at time of surgery was not a correlate of events. CONCLUSIONS Risk of 30-day post-operative adverse events, including ST, remains significantly higher when surgery is performed soon after PCI, while intermediate-term risk extending at least 2 to 3 years remains important.

Long-term benefit of statin therapy initiated during hospitalization for an acute coronary syndrome: a systematic review of randomized trials.

ObjectiveThis study sought to determine if the initiation of statin (HMG-CoA reductase inhibitor) therapy during acute coronary syndromes reduces long-term mortality and other adverse cardiac outcomes.BackgroundInitiation of statin therapy during acute coronary syndromes has not been shown to reduce mortality, myocardial infarction or stroke within 4 months of follow-up.MethodsClinical trials that randomized patients with acute coronary syndromes to early statin therapy compared with less intensive lipid reduction (placebo/lower-dose statin/usual care), and reported long-term outcomes were included for analysis.ResultsIn all, there were seven studies (L-CAD, PTT, FLORIDA, Colivicchi et al., PROVE-IT, ESTABLISH, and A-to-Z) with 9553 patients who started statin therapy within 12 days of hospital presentation. The incidence of all-cause mortality was 3.4% in the statin group versus 4.6% in the less intensive lipid reduction group over a weighted mean follow-up of 22.9 months (relative risk [RR] 0.74; 95% CI 0.61, 0.90; p = 0.003). The number of patients needed to treat to prevent one death was 84 patients. Similarly, the incidence of cardiovascular mortality in the statin versus the less intensive lipid reduction group was 2.4% versus 3.3% (RR 0.74; 95% CI 0.58, 0.93; p = 0.010), unstable angina 4.1% versus 5.0% (RR 0.81; 95% CI 0.68, 0.98; p = 0.027), revascularization 11.2% versus 12.9% (RR 0.86; 95% CI 0.78, 0.96; p = 0.006), stroke 1.1% versus 1.2% (RR 0.90; 95% CI 0.62, 1.30; p = 0.56), and myocardial infarction 6.6% versus 7.0% (RR 0.94; 95% CI 0.81, 1.09; p = 0.41).ConclusionsThe benefit of early initiation of statin therapy during acute coronary syndromes slowly accrues over time so that a survival advantage is seen around 24 months. Relatively few patients need to be treated to prevent one death over this time period. Furthermore, this approach significantly reduces unstable angina and the need for revascularization.

The association between early ventricular arrhythmias, renin-angiotensin-aldosterone system antagonism, and mortality in patients with ST-segment-elevation myocardial infarction: Insights from global use of strategies to open coronary arteries (GUSTO) V

BACKGROUND The long-term prognostic significance of early (<48 hours) ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) in patients with an acute myocardial infarction remains controversial. Emerging data suggest that some of the benefit of renin-angiotensin-aldosterone system (RAAS) antagonism may be derived from a reduction in the incidence of these arrhythmias in the setting of acute myocardial infarction. METHODS We assessed the relationship between early VF/VT (defined as within 48 hours after admission) and mortality in 16,588 patients from global use of strategies to open coronary arteries (GUSTO) V trial. Furthermore, we examined the relationship between baseline use of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), early VF/VT, and mortality. RESULTS Early VF or VT occurred in 732 (4.4%) patients. Compared to patients without VF/VT, those experiencing early VF or VT had a significant increase in 30-day mortality (22% vs 5%, P < .001). Baseline use of an ACEI/ARB was associated with a decreased incidence of early VF/VT (odds ratio 0.65, 0.47-0.89, P = .008). A lower 30-day mortality was seen in patients with early VF/VT on baseline ACEI/ARB compared with patients with early VF/VT not receiving an ACEI/ARB at baseline (17.7% vs 24.2%, respectively, P = .04). The association between baseline RAAS antagonism and mortality persisted after adjustment for multiple confounders. CONCLUSIONS In patients presenting with acute myocardial infarction, early VF/VT identifies those at increased risk for 30-day mortality. Baseline use of RAAS antagonists is associated with a reduced incidence of malignant arrhythmias. Identifying how this association impacts short-term mortality in this patient population requires further prospective evaluation.

Eptifibatide-induced thrombocytopenia and thrombosis

Glycoprotein (GP) IIb/IIIa inhibitors have been shown to reduce morbidity and mortality in patients with acute coronary syndromes undergoing percutaneous coronary interventions (PCI). With their widespread use, there is a growing body of literature describing adverse outcomes, including severe thrombocytopenia. Here we report a case of a 75-year-old man who presented with an ST-elevation myocardial infarction, underwent primary PCI and stenting, and subsequently developed profound thrombocytopenia and thrombosis after eptifibatide administration. This report adds to the literature regarding eptifibatide-induced thrombocytopenia and also raises the possibility of a new syndrome of eptifibatide-induced thrombosis. A case is made to examine available databases for thrombosis after administration of eptifibatide and other GPIIb/IIIa inhibitors.

Antithrombotic drug therapy in cardiovascular disease

Antithrombotic drug therapy in cardiovascular disease , Antithrombotic drug therapy in cardiovascular disease , کتابخانه دیجیتالی دانشگاه علوم پزشکی و خدمات درمانی شهید بهشتی

Management Strategies in Antithrombotic Therapy

Management strategies in antithrombotic therapy / , Management strategies in antithrombotic therapy / , کتابخانه دیجیتال جندی شاپور اهواز