Citations

Objective: The 2010 AHA Guidelines stress the need for minimally interrupted, high quality CPR. We performed a prospective, before/after trial to determine if real-time audiovisual feedback (RTAVF) along with scenario-based training (SBT) would 1) achieve the 2010 CPR targets and 2) improve survival from OHCA. Methods: Data obtained from EMS care forms and defibrillators (E Series, ZOLL) from 2 EMS agencies (population base-500,000). Phase 1 (P1, before): 18 months of baseline data with the RTAVF mode disabled (9/08-3/10). Interventions: 1) Guideline-based SBT of ~450 EMTs, 2) RTAVF enabled, 3) EMT post-code debriefings. Phase 2 (P2, after): 8 months following implementation of interventions (5/10-12/10). For univariate analyses we used Fisher's exact test (proportions), t-test (means) or Kruskal-Wallis test (medians). To estimate odds ratios for survival to hospital discharge we used multivariable logistic regression and assessed final model diagnostics, fit, and discrimination. Results: The final analysis included 284 adult OHCAs (P1-176, P2-108). Mean age 65.4 years (SD ± 15.3) with 66.6% males. Quality measures improved significantly from P1 to P2: Median (Interquartile range) chest compression (CC) rate-121 CC/min (109-135) to 101 CC/min (100-106), p <0.001; CC depth-1.73 in. (1.42-1.97) to 2.09 in. (1.92-2.3), p <0.001; CC fraction-66.5% (59.3-75.9%) to 84.0% (77.8-88.7%), p <0.001. All-rhythms survival increased significantly (p=0.034) from P1 to P2 (18/176, 10.2% vs. 23/108, 19.4%), an absolute survival increase of 9.2% (95% CI: 0.5%-17.9%). Crude odds ratio for survival for P2 vs. P1 was 2.1 (95% CI: 1.1-4.2) and adjusted odds ratio was 5.8 (95% CI: 1.8-18.9), after controlling for confounders including age, sex, location, witnessed arrest, initial rhythm, and therapeutic hypothermia. Survival for arrests with a shockable rhythm was 27.7% (18/65) for P1 and 53.9% (14/26) for P2 (p=0.028). Conclusion: RTAVF combined with SBT was associated with a significant improvement in the proportion of compressions meeting the 2010 AHA Guidelines. This intervention was associated with a 90% relative increase in overall survival. We believe this is the first report to show an improvement in OHCA survival by achieving the 2010 AHA CPR Guidelines.

Introduction: Cardiac remodeling in heart failure (HF) is associated with conduction abnormalities and dyssynchrony which results in poorly coordinated contractions precipitating metabolic heterogeneity and energetic inefficiency. Cardiac resynchronization therapy (CRT) improves HF symptoms, ventricular function and overall survival. The aim of this study was to determine the changes in metabolomic profiles and substrate utilization after CRT. Methods: 18 patients with advanced HF and 7 healthy controls were included in this study. Blood samples were collected from peripheral vein, femoral artery (FA) and coronary sinus (CS) before and 10-min after CRT. Metabolomic profiling of plasma samples were performed using GC/MS and 1 H NMR spectroscopy. Partial Least Squares Discriminant Analysis (PLS-DA) score plots and regression coefficients were used to examine metabolomic profiles. Results: HF patients have altered plasma metabolomic profile (Fig. A) with distinct panel of metabolites including free fatty acids (FFA), glycerol, 2-hydroxybutyrate, glycine, succinate and uric acid important in group classification compared to controls. Increased release of fumarate and glycerol-3-phosphate from myocardium in HF indicate mitochondrial and substrate shuttle dysfunction. Immediately after CRT, transcardiac metabolomic profile of plasma from CS shifted to a different state with increased myocardial uptake and metabolism of FFA and decreased release of creatinine indicating improved energetic conditions (Fig. B). Conclusion: Metabolomic profiling indicates that CRT improves myocardial substrate metabolism and utilization in patients with advanced HF.

Background. Na + /Ca 2+ exchanger (NCX) is essential in tuning intracellular Ca 2+ and the development of heart failure (HF). We reported that loss of Junctophilin 2 (JPH2) in adult mouse hearts leads to reduced NCX activity in addition to hyperactive RyR2s and more arrhythmogenic Ca 2+ waves. NCX has been found to co-localize with RyR2 recently. However, what is the physiological significance of junctional NCX and whether the reduced junctional NCX activity following JPH2 knockdown contributes to the arrhythmogenesis is still unknown. Hypothesis. Dysfunction of Junctional NCX in response to JPH2 knockdown alters spatial properties of Ca 2+ sparks and contributes to arrhythmogenesis. Methods. Tamoxifen-treated MCM and MCM-shJPH2 (KD) mice were studied. Contractile function was measured by echocardiography. Open probability of single RyR2 was evaluated by lipid bilayer. Ca 2+ spark were assessed with confocal microscopy. NCX activity was measured by exponential fitting of the declining phase of caffeine-induced Ca 2+ transient. Results. JPH2 knockdown increased spark size (MCM: 2.55 ± 0.14; KD: 4.25 ± 0.16, P < 0.001), suggesting an increased occurrence of proarrhythmic macrosparks. Cardiac Contractile function (EF% ) is negatively correlated with Ca 2+ spark size (n = 8, P < 0.05). Increased Open probability of RyR2 (MCM: 0.038 ± 0.018 KD: 0.274 ± 0.142, P < 0.01) is unlikely the reason for the ~70% increase in spark size, since it is not observed in 3 other mouse models with hyperactive RyR2s but normal JPH2 levels (RyR2:S2814D, mdx and FKBP12.6 -/- ). Loss of JPH2 also slows Ca 2+ efflux via NCX by ~50% (MCM: 2.70 ± 0.23 vs. KD: 5.11 ± 0.61 s, P < 0.01) without altering NCX expression level. Spark size and NCX activity are negatively correlated (n = 8 mice, P < 0.05), and partial inhibition (~30%) of NCX with 1 mM Cd 2+ significantly increased spark size by 14.0 ± 2.8% (n = 8, P <0.05) in wt mice. Conclusion. For the first time we showed that reduced NCX activity increases spatial properties of Ca 2+ sparks and thus arrhythmogenesis. Since reduced JPH2 is associated with HF and NCX plays more important role in human than in murine, reduced junctional NCX activity following loss of JPH2 could be a novel mechanism underlying the development of HF and associated ventricular arrhythmias.

Objectives. The use of the left internal mammary artery (IMA) in revascularization of multivessel coronary artery disease has been shown to improve survival following coronary artery bypass graft surgery (CABG), however the incremental survival benefit of multiple arterial grafts is still debated. Methods. We reviewed outcome of 8,622 pt that had isolated primary CABG for multivessel disease from 1993 to 2009.Pt were stratified according to the number of arterial grafts; (1) single IMA plus saphenous vein (SV) IMA/SV group (n=7,435; 83% 3VD) and (2) multiple arterial (MultArt) group (n=1,187; 74% 3VD) Results. Early mortality rate was 0.8% (n=10) in the MultArt group and 2.1% (n=154) in the IMA/SV group (P=0.004). However, the difference was not statistically significant (P=0.996) after adjusting for age, gender, chronic lung disease, renal failure, PVD, MI, EF, and number of diseased vessels. Late survival was significantly greater for the MultArt group compared to IMA/SV group (5-, 10- and 15-year survival rates were 95%, 84% and 71% versus 85%, 61% and 35% p<0.001). MultArt subgroups with the use of bilateral internal mammary artery (BIMA)/SV (n=589) and BIMA only (n=271), had significantly improved 15-years survival (97%, 86%, 76% and 94%, 82%, 75% at 5-, 10- and 15-years, p<0.001), and BIMA/RA (n=147) and LIMA/RA (n=169), had significantly greater 10-years survival (95%, 84% and 93%, 78% at 5- and 10-years, p<0.001) compared to IMA/SV group. In multivariate analysis, use of multiple arterial grafts remained a strong independent predictor of survival (HR=0.78, 95% CI 0.66 - 0.93, p=0.006). Conclusion. Use of the right IMA or radial artery in addition to the left IMA is associated with significantly better overall and late survival compared with single IMA and saphenous vein in patients with two and three-vessel disease undergoing isolated CABG.

BACKGROUND: The immunologic risk associated with preformed donor-specific allo-antibodies (DSA) against human leukocyte antigens (HLA) in heart transplant (HTX) recipients is unclear. The goal of this study was to evaluate potential role of DSA on the progression of cardiac allograft vasculopathy (CAV) in HTX recipients. METHODS: The presence of DSA against HLA was evaluated using solid phase Single Antigen Bead assay (One Lambda, Inc., Canoga Park, CA; Luminex platform) before transplant in 35 HTX recipients. Using alloantibody specification analysis, 11% (4/35) and 20% (7/35) had DSA against donor Class I and II HLA respectively including the one patient who had both (DSA I & II+) . 71% (25/35) of patients had no demonstrable DSA (DSA-). All patients had negative cytotoxicity cross match. Baseline three-dimensional intravascular ultrasound studies (3D IVUS) were performed at 1.0 [0.18, 1.4] year after transplant. Follow up 3D IVUS exams were performed 0.92 [0.85, 1.04] years after the baseline exam. RESULTS: The increase in mean plaque (media and intima) volume (PV) was accelerated in the DSA II+ group as compared to the DSA- group (0.87±1.9 mm (3)/mm vs. 0.16±1.8 mm (3)/mm) but the vessel volume index (follow up vessel volume/ baseline vessel volume) was similar between groups (1.08±0.5 vs. 1.09± 0.4; p=0.9). Plaque index (PI) (PV/vessel volume x 100 [%]) increased significantly in the DSA II+ group (17.9±6.3%) but not in the DSA- group (-13.6±13.2%, P=0.02). None of these values were significant in the DSA I+ only group. Treatment with Sirolimus did not affect PI progression between the DSA II+ and DSA- groups (PI progression: 15.9±8.7% vs. -11.7±7.1%, P=0.03). Age, gender, lipid and uric acid levels, prevalence of diabetes, ischemic time, time between IVUS examinations, the use of steroids, mycophenolate vs. azathioprine or calcineurin inhibitors vs. sirolimus were not different between the groups (P>0.4 for all). CONCLUSIONS: Heart transplant recipients with clearly defined anti-Class II DSA are at risk for accelerated cardiac allograft vasculopathy. Whether interventions to minimize the risk of DSA such as virtual crossmatch, desensitization and complement inhibition will retard CAV remains to be proven.

BACKGROUND: Shear stress-induced dilation (SSD) is an important vascular endothelial function that is impaired in diseases such as diabetes mellitus. Caveolin-1 is the major structural protein required for the formation of endothelial caveolae, where signaling molecules and pathways are assembled. In this study, we hypothesized that SSD of mouse small coronary arteries (MCA) is caveolae-dependent. METHODS: MCA (80-130 μm) freshly isolated from WT and Cav-1 knockout (KO) mice were mounted in a vessel chamber, pressurized at 80 mmHg, pre-contracted to 60-80% baseline diameter with endothelin-1, and subjected to physiological levels of shear stress at 25 dyn/cm 2 using a microinjection pump coupled to a pressure servo controller. SSD was measured by videomicroscopy and expressed as % of maximum diameter measured in the absence of Ca 2+ . Donor (intact WT or KO) and detector (WT with no endothelium) vessels were mounted in separate chambers connected by a micropipette. Diabetes mellitus was produced by streptozotocin (STZ) injection. RESULTS: SSD of MCA is significantly diminished in KO mice. 25 dyn/cm 2 produced 92.9±1.2% SSD in WT but only 42.0±0.7% in KO (n=10 for both, *p<0.05). Removal of endothelium reduced SSD to 22.3±3.3% in WT and to 14.9±1.3% in KO (n=8 for both, * vs. intact vessels but not WT vs. KO). Inhibition of eNOS (L-NAME), PGIS (Indocin), and CYP monooxygenase (SKF525A) reduced endothelial-dependent SSD by 44%, 34%, and 21% respectively in WT (all * vs control) but had no effect in KO, suggesting deficiency in shear stress-induced generation of vasodilators in KO. This is confirmed by the significant reduction in SSD in detector vessels with KO serving as donors (*42.0±0.7%, n=6 vs. 64.3±6.4% n=4, WT donor). With diabetes, MCA from WT and KO lost the ability for SSD (WT 25.9±2.4%, n=6 and KO 24.4±2.3%, n=5), which was similar to the effects of endothelium denudation. CONCLUSION: Integrity of caveolae is critical for endothelium-dependent SSD in MCA. KO endothelium is deficient in shear stress-mediated generation of vasodilators including NO, PGI 2 , and EET. Diabetic MCA have impaired endothelial function with loss of SSD. Caveolae plays a critical role in endothelial signal transduction from shear stress to vasodilator production and release.

Background: Myocardial reperfusion following prolonged ischemia may paradoxically cause additional injury, including edema and microvascular damage. These structural alterations augment tissue echogenicity measurable by integrated backscatter (IB). We sought to characterize alterations of myocardial IB in an ischemic and then reperfused region of the rat heart. Methods: Myocardial IB in 12 adult male Sprague-Dawley rats was studied at baseline, 60 minutes after left anterior descending coronary artery occlusion, and chronologically after coronary reopening. Short-axis scans of the mid left ventricle were acquired at a frequency of 8 MHz. Mean±SD values of IB were measured in the region of interest at baseline, ischemia, and reperfusion, and assessed by a paired t-test. Results: See figure and table. IB did not significantly change between baseline and ischemia. However, within 1 minute of reperfusion, IB significantly increased, as compared to both baseline and ischemia, and continued to increase until 10 minutes after reperfusion, when a plateau was reached. Conclusions: Myocardial reperfusion following acute prolonged ischemia in a rat heart significantly augments tissue echogenicity. A continuing increase of IB within minutes of the reperfusion onset and the subsequent plateau of elevated IB values suggest progression and completion, respectively, of reperfusion injury, detectable by a high-frequency transducer.

The Impact of Ordering Provider Specialty on Appropriateness Classification In prior studies, our laboratory applied the ACCF/ASNC AUC for SPECT MPI to several cohorts of patients in Mayo Clinic Rochester. The purpose of this study was to re-examine our data to test the hypothesis that the specialty of the ordering provider affected the appropriateness. We compared the ordering providers specialty with appropriateness determined in prior studies. The study group consisted of 281 patients who underwent stress SPECT MPI studies in May 2005 and 282 patients in October 2006 (before any quality improvement initiatives were begun at Mayo). Appropriateness categories were assigned by 2 experienced nurses from the CV Research Studies Unit not affiliated with the nuclear laboratory. Patients who were studied for pre-operative evaluation (n = 20) or post myocardial infarction (n = 7) were excluded because they comprised less than 5 percent of the patients. Pre-operative testing in our institution is done primarily by stress echocardiography. The final study group consisted of 526 patients. Excluding the 64 unclassified patients, AUE categories were appropriate (75 %), uncertain (13 %), inappropriate (12%). Results by ordering provider are shown in the figure, where CV = Cardiovascular MDs, ED = Emergency Department MDs, IM = General and Internal Medicine MDs, RN = Registered Nurses, and SP = other Specialty MDs. There was no significant association (p = 0.19); Chi-square analysis between appropriateness and specialty groups. In a clinical practice where pre-operative testing using SPECT is infrequent, the rate of inappropriate studies was similar for all ordering providers. Quality improvement efforts in similar practices will likely require a broad focus on all ordering physicians/nurses.

Introduction: IL2 soluble receptor (IL2Rs) and neopterin (NPT) are peripheral markers of T cell and monocyte activation investigated extensively in auto-immune disorders. We assessed these biomarkers in subjects with non ischemic cardiomyopathy of recent onset (ROCM) from the IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) registry. We compared the degree of cellular activation in peripartum cardiomyopathy (PPCM) with that evident in non-peripartum women and men with ROCM. Methods: 130 subjects were investigated: 96 subjects with ROCM including 37 women with PPCM (group 3), 27 non-peripartum women (group 2) and 32 men (group 1), and 34 controls without cardiac disease (CTL). All subjects with ROCM had serum obtained at entry and an assessment of LVEF by transthoracic echocardiography. LVEF was reassessed 6 months after enrollment. Results: The ROCM cohort (n=96, 64F/32M, mean age 30±6) had a mean LVEF at baseline of 0.24±0.08 which increased to 0.43±0.13 at 6 months. For controls (mean age 45±6, 24F/10M) the mean LVEF was 0.58±0.10. Both IL2Rs and NPT were markedly elevated in ROCM subjects compared to controls (IL2Rs: ROCM=1411±671, CTL=970±329 pg/ml, p<0.001; NPT: ROCM=9.2±5.6, CTL=6.2±3.1 nmol/l, p=0.003). Increased NYHA class was associated with higher serum levels for both NPT (p=0.013) and IL2Rs (p=0.009). No differences were evident in subjects with PPCM versus men and women with ROCM for either IL2Rs (group 1/2/3 =1524±504/1531±904/1225±566 pg/ml, p=0.10) or NPT (group 1/2/3=9.4±6.5 /9.3±5.8 /8.9±4.7 nmol/l, p=0.92). IL2Rs levels were lower in black subjects: blacks (n=25) IL2Rs=1123±496; whites (n=71) 1513±698, p=0.012. Levels of IL2Rs and NPT did not predict the degree of recovery at 6 months, although there was a nonsignificant trend towards more recovery with lower IL2Rs levels. Conclusions: Marked elevation of IL2Rs and NPT, biomarkers of cellular immune activation, are evident in subjects with ROMC. The degree of activation in subjects with PPCM appears similar to that seen in men and non-peripartum women with ROCM, suggesting similar inflammatory pathogenesis for these syndromes of acute heart failure. The relationship of cellular activation to myocardial injury and recovery in ROCM should be further investigated.

Background: Pulmonary hypertension is common in HFpEF and is associated with increased mortality. Pulmonary hypertension can lead to right ventricular systolic dysfunction. However, the magnitude and prognostic significance of RV dysfunction in the HFpEF population are unclear. Hypothesis: RV systolic dysfunction is common in HFpEF and is associated with increased mortality. Methods: RV size and systolic function were assessed qualitatively (as normal or abnormal) and pulmonary artery systolic pressure (PASP) was estimated using echocardiography in 548 consecutive HFpEF subjects (Framingham criteria and EF ≥50%) from a prospective population based study (Olmsted County, Minnesota). Control group was a retrospectively identified random sample of age and sex matched hypertensive (N=360) and normotensive subjects (N=168) from Olmsted County. HFpEF group was followed for up to 5 years (median follow up 4.4 years). Results: See table and figure. RV enlargement and systolic dysfunction were more prevalent in HFpEF compared with age and sex matched hypertensive and normotensive controls. In HFpEF subjects with PASP above the median, RV systolic dysfunction was associated with poor survival compared with normal RV function. RV systolic dysfunction was a significant predictor of mortality even after adjustment for age and PASP in a Cox regression model (Hazard Ratio=1.4, p=0.02). Conclusions: In the community, RV systolic dysfunction is common in HFpEF and is associated with higher mortality. Although quantitative assessment of RV function is difficult owing to its complex geometry, qualitative assessment is feasible on the majority of subjects and provides significant prognostic information.