Cardiovascular Factors Associated with Septic Shock Mortality Risks.

CONTEXT: The presence of at least one underlying chronic health condition, such as long-term care facility residence, malnutrition, immunosuppression, or prosthetic device use, are well known factors increasing infection risks and progression to severe sepsis. Furthermore, some degree of cardiovascular dysfunction occurs in the majority of septic patients and this prognostic significance has become increasingly recognized. Since septic shock carries the highest mortality risk on the sepsis spectrum, it is important to evaluate the cardiovascular risk impact on mortality in this subset of patients. METHODS: The retrospective parent study contributing these electronic health record data was IRB approved and conducted across four hospital intensive care units within the authors' Michigan healthcare system. Patients with cardiopulmonary arrest or transfers from an outside facility were excluded. The authors evaluated the presence of modifiable and non-modifiable cardiovascular risk factors in septic shock patients upon admission to an emergency department. RESULTS: The authors' final analytic sample included n = 109 adults who were discharged alive compared to those who died during hospitalization. Those patients who died were more often male with an underlying history of hypertension, congestive heart failure, coronary artery disease, or peripheral arterial diseases, were taking pre-admission beta-blocker medications, and had higher APACHE II scores at admission compared to the patients who survived to discharge. Significantly higher mortality risks were found in sample patients with increased troponin levels on admission and atrial fibrillation. CONCLUSIONS: Appropriate triage and prompt treatment of these patient groups with tailored therapy to stabilize and improve cardiac dysfunction in the emergency department could potentially lead to improved survival outcomes. Clinicians need more studies to determine therapeutic targets most impacting underlying pathophysiologic mechanisms such as elevated troponin and atrial fibrillation that greatly increase mortality risks.

Rapid epinephrine administration improves early outcomes in out-of-hospital cardiac arrest.

INTRODUCTION: Early administration of epinephrine (Epi) improves outcomes in animal models of cardiac arrest, but there is limited time-dependent clinical data regarding its benefit. OBJECTIVE: Our objective was to assess whether timing of Epi administration was associated with improved outcomes after out of hospital cardiac arrest (OHCA). METHODS: We performed a retrospective analysis of a cardiac arrest database from a suburban EMS system from November 2005 to April 2011. Data was abstracted from EMS run sheets, including drug treatment, route and timing of drug administration, and other Utstein variables. Our primary outcome was return of spontaneous circulation (ROSC). Secondary outcomes measured were survival to hospital admission and discharge. For analysis, data were dichotomized according to timing of Epi administration: early Epi group (defined as 911 call to Epi administration of ≤10 min) and late Epi group (>10 min). Further, exploratory analyses were conducted looking at subgroups sorted by initial rhythm and whether the arrest was witnessed. Wilcoxon rank sum tests, chi-square tests, 95% confidence intervals, and multi-variable regression were used for statistical analysis. RESULTS: We reviewed 809 patients from study communities: 123 patients were excluded, leaving a sample size of 686 for study analysis. The mean time from 911-Epi was 14.3±5.5 min, with 155 (22.6%) receiving early Epi. Key arrest and treatment characteristics were similar between groups. Patients who received early Epi were more likely to have ROSC (32.9% vs. 23.4%, OR 1.59 (1.07, 2.38)), however, no significant increase in survival to admission or discharge was observed. Patients with an initial rhythm of PEA had an increased rate of ROSC (48.6% vs. 21.5%, OR 3.45 (1.56, 7.62)) but not survival to discharge (5.9% vs. 2.6%), OR 2.35 (0.38, 14.7) with early Epi. In a multivariable analysis of bystander witnessed arrests, early Epi was associated with a higher rate of ROSC (OR 3.20 (1.75, 5.88) but not survival to discharge (OR 1.48 (0.50, 4.36)). No improvement in ROSC or secondary outcomes was noted in patients with other arrest rhythms or un-witnessed arrest with Early Epi. CONCLUSIONS: Within the limitations of our study, this data suggests improved rates of ROSC with early Epi administration during OHCA resuscitation, but this study lacks adequate sample size to demonstrate impact on survival to discharge. Large prospective trials are needed to further delineate the benefit of early Epi administration in OHCA.

Nonviral gene delivery to mesenchymal stem cells using cationic liposomes for gene and cell therapy.

Mesenchymal stem cells (MSCs) hold a great promise for application in several therapies due to their unique biological characteristics. In order to harness their full potential in cell-or gene-based therapies it might be advantageous to enhance some of their features through gene delivery strategies. Accordingly, we are interested in developing an efficient and safe methodology to genetically engineer human bone marrow MSC (BM MSC), enhancing their therapeutic efficacy in Regenerative Medicine. The plasmid DNA delivery was optimized using a cationic liposome-based reagent. Transfection efficiencies ranged from approximately 2% to approximately 35%, resulting from using a Lipid/DNA ratio of 1.25 with a transgene expression of 7 days. Importantly, the number of plasmid copies in different cell passages was quantified for the first time and approximately 20,000 plasmid copies/cell were obtained independently of cell passage. As transfected MSC have shown high viabilities (>90%) and recoveries (>52%) while maintaining their multipotency, this might be an advantageous transfection strategy when the goal is to express a therapeutic gene in a safe and transient way.

Dual antiplatelet therapy for more than 12 months after percutaneous coronary intervention: insights from the Guthrie PCI Registry.

OBJECTIVE: To assess the impact of dual antiplatelet (DAP) therapy of >12 months on long-term death and myocardial infarction (MI) after percutaneous coronary intervention (PCI). DESIGN, SETTING AND PATIENTS: Prospective, single-centre, observational study of 1859 consecutive patients who underwent successful PCI of a native coronary artery and survived event-free for at least 12 months. MAIN OUTCOME MEASURES: Combined end point of death or non-fatal MI determined by survival analysis and propensity-adjusted multivariable Cox regression. Similar analyses were performed in the two stent subsets: bare metal stents (n = 835), drug-eluting stents (n = 1024); and three high-risk subsets: diabetic patients (n = 486), patients presenting with MI (n = 713), and those with ACC/AHA type C lesions (n = 717). RESULTS: Baseline characteristics were as follows: mean (SD) age 64 (12) years, male 69%, diabetic 26%, presentation with MI 38%, mean (SD) ejection fraction 49 (12)%, mean (SD) vessel diameter 3.1 (0.5) mm. Duration of DAP was 27 (11) months in "DAP >12 months" and 4.1 (4.1) months in "DAP < or =12 months" (p<0.001). At a median follow-up of 3.4 years after PCI, "DAP >12 months" vs "DAP < or =12 months" had similar incidence of death or MI (9.4% vs 10.3%, log-rank p = 0.83). After multivariable adjustment, DAP therapy >12 months was not associated with lower incidence of death or MI than DAP therapy < or =12 months (adjusted HR = 1.01; 95% CI 0.74 to 1.37, p = 0.95). Analysis of each of the five predefined subsets showed similar results. CONCLUSIONS: In patients who undergo successful native coronary PCI and survive event-free for at least 12 months, continuation of dual antiplatelet therapy beyond 12 months does not confer long-term protection from death or MI.

Importance of time to reperfusion on outcomes with primary coronary angioplasty for acute myocardial infarction (results from the Stent Primary Angioplasty in Myocardial Infarction Trial).

The mortality benefit of thrombolytic therapy for acute myocardial infarction (AMI) is strongly dependent on time to treatment. Recent observations suggest that time to treatment may be less important with primary percutaneous transluminal coronary angioplasty (PTCA). Patients with AMI of <12 hours duration, without cardiogenic shock, who were treated with primary PTCA from the Stent PAMI Trial (n = 1,232) were evaluated to assess the effect of time to reperfusion on outcomes. Thrombolysis In Myocardial Infarction grade 3 flow was achieved in a high proportion of patients regardless of time to treatment. Improvement in ejection fraction from baseline to 6 months was substantial with reperfusion at <2 hours but was modest and relatively independent of time to reperfusion after 2 hours (<2 hours, 12.3% vs > or =2 hours, 4.2%, p = 0.004). There were no differences in 1- or 6-month mortality by time to reperfusion (6-month mortality: <2 hours [5.5%], 2 to <4 hours [4.6%], 4 to <6 hours [4.5%], >6 hours [4.2%], p = 0.97). There were also no differences in other clinical outcomes by time to reperfusion, except that reinfarction and infarct artery reocclusion at 6 months were more frequent with later reperfusion. The lack of correlation between time to treatment and mortality in patients without cardiogenic shock suggests that the survival benefit of primary PTCA may be related principally to factors other than myocardial salvage. These data may also have implications regarding the triage of patients with AMI for primary PTCA.

Chlamydia pneumoniae exposure and inflammatory markers in acute coronary syndrome (CIMACS).

Previous studies have shown higher levels of Chlamydia pneumoniae (C. pneumoniae, CP) antibody titers (CPIgG), C-reactive protein (CRP), and fibrinogen in patients with coronary artery disease. The role of these infectious and inflammatory markers in precipitating acute coronary syndrome (ACS) is unclear. We conducted a cross-sectional study on patients (n = 830, mean age 63 +/- 15 years, 57% male) admitted to the chest pain center of our institution. The differences in the CPIgG, CRP, and fibrinogen levels in patients who were diagnosed with ACS versus those who were not (non-ACS) were evaluated. CPIgG titers tended to be higher in the ACS group than in the non-ACS group. However, when different titers were used to define seropositivity, the difference achieved statistical significance only at the titer of > or =1:1,024 (35% vs 26%, p = 0.004). CRP (median 0.48 vs 0.33 mg/dl, p <0.0001), fibrinogen (median 317 vs 293 mg/dl, p <0.0001), and leukocyte count (median 7.7 vs 6.9 10(9)/L, p <0.0001) were higher in the ACS group. On multivariate analysis, CPIgG > or =1:1,024 (odds ratio [OR] 1.62), diabetes (OR 1.91), hypertension (OR 1.46), prior myocardial infarction (OR 1.78), smoking (OR 1.70), Caucasian race (OR 1.7), high-density lipoprotein (OR 0.98), and elevated troponin-T (OR 12.44) were the only factors independently associated with ACS. Thus, we found a strong association between high level seropositivity to CP and ACS. This may indicate recent re-infection or an exaggerated immune response to CP as an etiologic factor for ACS. This study also suggests that therapeutic interventions may need to be specifically targeted to these patients.

Predictive value of the Killip classification in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction.

The predictive value of Killip classification of acute myocardial infarction (AMI) in patients undergoing percutaneous coronary intervention (PCI) is not well established. We performed a pooled analysis of 2,654 patients with AMI enrolled in 3 primary angioplasty trials. Of these, 2,305 patients were class I, 302 were class II, and 47 were class III (class IV patients were excluded). Univariate and multivariate analyses were performed to determine if Killip class at admission was a predictor of in-hospital and 6-month mortality. Higher Killip classification was associated with greater in-hospital (2.4%, 7%, and 19% for class I, II, and III, respectively) and 6-month mortality (4%, 10%, and 28% for class I, II, and III, respectively). Higher Killip class was associated with increased age (p <0.001), history of diabetes (p <0.02), lower systolic blood pressure and higher heart rate at presentation (p <0.0001 for both), more 3-vessel disease (p <0.001), lower left ventricular ejection fraction (p <0.0001), and higher peak creatine phosphokinase (p <0.0001). With each increasing Killip class, there was an increased need for an intra-aortic balloon counterpulsation (p <0.001) and greater incidence of renal failure (p <0.001), major arrhythmia (p <0.001), and major bleeding (p <0.001). After controlling for potential confounding variables, Killip classification remained a multivariate predictor of mortality at both time end points. Killip classification at hospital admission remains a simple and useful independent predictor of in-hospital and 6-month mortality in patients with AMI who are undergoing primary PCI.

One-year follow-up after primary coronary intervention for acute myocardial infarction in diabetic patients. A substudy of the STENT PAMI trial.

OBJECTIVE: This analysis was undertaken to determine the composite incidence of cumulative adverse events (death, reinfarction, disabling stroke, and target vessel revascularization) at the end of the first year after acute myocardial infarction, in diabetic patients who underwent coronary stenting or primary coronary balloon angioplasty. METHODS: From the STENT PAMI trial, we analyzed the 6-month angiographic and 1-year clinical outcomes of 135 diabetic (112, noninsulin dependent) patients who underwent the randomization process of the trial and compared them with 758 nondiabetic patients. RESULTS: Coronary stenting did not significantly reduce the primary composite clinical end point when compared with PTCA (20 vs. 30%, p=0.2). A significant benefit from stenting was observed in patients with noninsulin dependent diabetes, with a trend toward a lesser need for new revascularization procedures (10 vs. 21%, p<.001), with a significant reduction in the primary composite clinical end point at 1 year (12 vs. 28%, p=. 04). At 6 months, the restenosis rate were significantly reduced only in nondiabetic patients (18 vs. 33%, p<. 001). Diabetic patients had the same restenosis rate (38%) either with stenting or balloon PTCA. CONCLUSIONS: Coronary Stenting in diabetics noninsulin dependent offered a significant reduction in the composite incidence of major clinical adverse events compared with balloon PTCA.

Role of cardiac surgery in the hospital phase management of patients treated with primary angioplasty for acute myocardial infarction.

Although cardiac surgery is performed in approximately 10% of acute myocardial infarction (AMI) patients undergoing a primary percutaneous transluminal coronary angioplasty (PTCA) reperfusion strategy before discharge, the indications for and timing of operative revascularization, and the short- and long-term outcomes after surgery have not been characterized. In the prospective, controlled Primary Angioplasty in Myocardial Infarction-2 trial, cardiac catheterization was performed in 1,100 patients within 12 hours of onset of AMI at 34 centers, followed by primary PTCA when appropriate. Cardiac surgery was performed before hospital discharge in 120 patients (10.9%), electively in 42.6%, and on an urgent or emergent basis in 57.4%. Surgery was performed in 6.1% of 982 patients after primary PTCA (although emergently for failed PTCA in only 4 cases [0.4%]), and in 53 of 118 patients (44.9%) not undergoing primary PTCA. Patients requiring surgery were older, and more frequently had diabetes and 3-vessel disease than those managed nonoperatively. Internal mammary artery grafts were placed in only 31% of patients. In-hospital mortality was 6.4% in patients undergoing urgent/emergent surgery, 2.0% after elective surgery, and 2.6% in patients not undergoing surgery (p = NS). After multivariate correction for baseline risk factors, early and late survival free of reinfarction were similar in patients undergoing versus not undergoing in-hospital cardiac surgery. Thus, the appropriate use of coronary artery bypass graft surgery in the peri-infarction period is an integral component of the primary PTCA approach, and is frequently used to optimize the prognosis of a high-risk AMI cohort with unfavorable baseline features. The implications for the performance of primary PTCA in AMI at centers without on-site surgical facilities are discussed.

Angiographic and clinical characteristics associated with increased in-hospital mortality in elderly patients with acute myocardial infarction undergoing percutaneous intervention (a pooled analysis of the primary angioplasty in myocardial infarction trials).

Advanced age is associated with increased mortality in acute myocardial infarction (AMI) but the mechanism remains unclear. We performed a pooled analysis of 3,032 patients from the Primary Angioplasty in Myocardial Infarction (PAMI)-2, Stent-PAMI, and PAMI-No Surgery On Site trials to determine which clinical, hemodynamic, and angiographic characteristics in the elderly were associated with in-hospital death. There were 452 patients aged >/=75 years and 2,580 patients aged <75 years. Older patients had a lower number of risk factors for coronary artery disease but more comorbidities. Acute catheterization demonstrated more 3-vessel disease, higher left ventricular (LV) end-diastolic pressure, lower LV ejection fraction, and higher initial rates of Thrombolysis In Myocardial Infarction (TIMI) trial 2 or 3 flow. Elderly patients were equally likely to undergo percutaneous intervention but had a lower procedural success rate and lower rates of final TIMI 3 flow, and older patients were more likely to have post-AMI complications. In-hospital mortality was 10.2% and 1.8%, respectively (p = 0.001). Cardiac and noncardiac mortality was higher in elderly patients, and no significant differences in causes of death were identified. Multivariate analysis revealed that the strongest predictors of death were age >/=75 years, lower LV ejection fraction, lower final TIMI flow, higher Killip class, need for an intra-aortic balloon pump (IABP), and post-AMI stroke/transient ischemic attack, or significant arrhythmia. Despite avoiding thrombolysis, elderly patients remain at increased risk of bleeding, stroke, and other post-AMI complications, and death. Cardiac risk factor analysis and acute catheterization offer prognostic information but do not completely explain the mechanism of increased in-hospital mortality in the elderly.

Clinical and angiographic outcomes in patients with previous coronary artery bypass graft surgery treated with primary balloon angioplasty for acute myocardial infarction. Second Primary Angioplasty in Myocardial Infarction Trial (PAMI-2) Investigators.

OBJECTIVES: We sought to characterize the presenting characteristics of patients with previous coronary artery bypass graft surgery (CABG) and acute myocardial infarction (AMI) and to determine the angiographic success rate and clinical outcomes of a primary percutaneous transluminal coronary angioplasty (PTCA) strategy. BACKGROUND: Patients who have had previous CABG and AMI comprise a high risk group with decreased reperfusion success and increased mortality after thrombolytic therapy. Little is known about the efficacy of primary PTCA in AMI. METHODS: Early cardiac catheterization was performed in 1,100 patients within 12 h of onset of AMI at 34 centers in the prospective, controlled Second Primary Angioplasty in Myocardial Infarction trial (PAMI-2), followed by primary PTCA when appropriate. Data were collected by independent study monitors, end points were adjudicated and films were read at an independent core laboratory. RESULTS: Of 1,100 patients with AMI, 58 (5.3%) had undergone previous CABG. The infarct-related vessel in these patients was a bypass graft in 32 patients (55%) and a native coronary artery in 26 patients. Compared with patients without previous CABG, patients with previous CABG were older and more frequently had a previous myocardial infarction and triple-vessel disease. Coronary angioplasty was less likely to be performed when the infarct-related vessel was a bypass graft rather than a native coronary artery (71.9% vs. 89.8%, p = 0.001); Thrombolysis in Myocardial Infarction trial (TIMI) flow grade 3 was less frequently achieved (70.2% vs. 94.3%, p < 0.0001); and in-hospital mortality was increased (9.4% vs. 2.6%, p = 0.02). As a result, mortality at six months was 14.3% versus 4.1% in patients with versus without previous CABG (p = 0.001). By multivariate analysis, independent determinants of late mortality in the entire study group were advanced age, triple-vessel disease, Killip class and post-PTCA TIMI flow grade <3. CONCLUSIONS: Reperfusion success of a primary PTCA strategy in patients with previous CABG, although favorable with respect to historic control studies, is reduced as compared with that in patients without previous CABG. New approaches are required to treat patients with previous CABG and AMI, especially when the infarct-related vessel is a diseased saphenous vein graft.

A comparative analysis of primary stenting and optimal balloon coronary angioplasty in acute myocardial infarction. Six month results from the STENT PAMI trial.

OBJECTIVE: To compare the outcome of balloon PTCA with final coronary stenosis diameter (SD) < or =30 %, with elective coronary stenting. METHODS: We performed a comparative analysis of the 6 month outcomes in patients treated with primary stenting and those who obtained an optimal balloon PTCA result treated during the first 12 hours of AMI onset included in the STENT PAMI randomized trial. RESULTS: The results were analysed into 3 groups: primary stenting (441 patients, SD=22+/-6 %), optimal PTCA (245 patients), and non-optimal PTCA (182 patients, SD= 37+/-5 %). At the end of the 6 months primary stent group presented with the lowest restenosis(23 vs. 31 vs. 45 %, p=0.001, respectively). Ischemia-driven target vessel revascularization rate (TVR) (7 vs. 15.5 vs. 19 %, p=0.001, respectively). CONCLUSION: At the 6 month follow-up, primary stenting offered the lowest restenosis and ischemia-driven TVR rates. Compared to optimal balloon PTCA. Non-optimal primary balloon PTCA pts (SD=31-50 %), had the worst late angiographic outcomes and should be treated more actively with coronary stent implantation.