Obstructive sleep apnea alters microRNA levels: Effects of continuous positive airway pressure.

Background: Obstructive sleep apnea (OSA) has been linked to cytokine-mediated chronic inflammatory states. Continuous positive airway pressure (CPAP) is an established therapy for OSA, but its effects on inflammation remain unclear. A recent study from our group identified soluble cytokine receptors altered in OSA patients and modified by CPAP adherence. However, the upstream regulatory pathways responsible for these shifts in proinflammatory cascades with OSA and CPAP therapy remained unknown. Accordingly, this study mapped OSA and CPAP-modulated soluble cytokine receptors to specific microRNAs and then tested the hypothesis that OSA and CPAP adherence shift cytokine-related microRNA expression profiles. Study Design: Plasma samples were collected from patients with OSA (n=50) at baseline and approximately 90 days after CPAP initiation and compared to referent control subjects (n=10). Patients with OSA were further divided into cohorts defined by adherence vs nonadherence to CPAP therapy. The microRNAs that mapped to soluble cytokine receptors of interest were subjected to quantitative polymerase chain reaction. Results: At baseline, increased hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-5p, hsa-miR-195-5p, hsa-miR-424-5p, hsa-miR-223-3p, and hsa-miR-223-5p were observed in patients with OSA compared to controls (p<0.05). In CPAP adherent patients (n=22), hsa-miR233-3p and hsa-miR233-5p decreased at follow-up (p<0.05) whereas there was no change in miR levels from baseline in non-adherent CPAP patients (n=28). The miRs hsa-miR233-3p and hsa-miR233-5p mapped to both proinflammatory and innate immunity activation; the inflammasome. Conclusion: A specific set of microRNAs, including hsa-miR233-3p and hsa-miR233-5p, may serve as a marker of inflammatory responses in patients with OSA, and be used to assess attenuation of inflammasome activation by CPAP.

Same day discharge following non-elective PCI for non-ST elevation acute coronary syndromes.

BACKGROUND AND AIM: Timing of discharge after percutaneous coronary intervention (PCI) is a crucial aspect of procedural safety and patient turnover. We examined predictors and outcomes of same-day discharge (SDD) after non-elective PCI for non-ST elevation acute coronary syndromes (NSTE-ACS) in comparison with next-day discharge (NDD). METHODS: Baseline demographic, clinical, and procedural data were collected as were in-hospital outcomes and post-PCI length of stay (LOS) for all patients undergoing non-elective PCI for NSTE-ACS between 2011 and 2014 at a central tertiary care center. Thirty day and 1-year mortality and bleeding as well as 30-day readmission rates were determined from social security record and medical chart review. Logistic regression was performed to identify predictors of SDD, and propensity-matched analysis was done to examine the differences in outcomes between NDD and SDD. RESULTS: Out of 2,529 patients who underwent non-elective PCI for NSTE-ACS from 2011 to 2014, 1,385 met the inclusion criteria (mean age = 63 years; 26% women) and were discharged either the same day of (N = 300) or the day after (N = 1,085) PCI. Thirty-day and one-year mortality and major bleeding rates were similar between the 2 groups. Logistic regression identified male sex, radial access, negative troponin biomarker status, and procedure start time as predictors of SDD. In propensity-matched analyses, there was no difference in 30-day mortality and readmission between SDD and NDD groups. CONCLUSIONS: SDD after non-elective PCI for NSTE-ACS may be a reasonable alternative to NDD for selected low-risk patients with comparable mortality, bleeding, and readmission rates.

Implementation of an accelerated discharge process following percutaneous coronary intervention for patients with non-ST elevation acute coronary syndromes.

AIMS: Historically, patients with non-ST elevation acute coronary syndrome (NSTE-ACS) are monitored as inpatients following successful percutaneous coronary intervention (PCI), but accumulating evidence demonstrates that accelerated discharge is safe, reduces cost, and enhances patient satisfaction. This quality improvement project examined the impact of implementing a post-PCI streamlined discharge process for NSTE-ACS patients on length of stay (LOS), major adverse cardiovascular events, and provider utilization at a university-affiliated hospital system. METHODS AND RESULTS: Clinical characteristics, the timing of admission, PCI, and discharge data were collected prospectively from patients presenting to the catheterization laboratory for intervention for NSTE-ACS during 90-day historical control and implementation periods. The knowledge to action implementation model was employed to establish a peer-coaching based educational tool for educating interventional cardiologists and inpatient clinicians regarding patients with low-risk characteristics suitable for same-day discharge (SDD) following PCI. Patient characteristics were similar between the historical and implementation periods. Although total hospital LOS did not decrease (51 ± 24 vs. 41 ± 18 h; P = 0.14), the discharge process reduced LOS after PCI among low-risk patients (22 ± 6 vs. 17 ± 8 h; P = 0.003). Complication and readmission rates were unchanged by SDD. Provider utilization of the discharge process increased four-fold during the implementation period (8% vs. 32%; P = 0.02). CONCLUSIONS: Implementation of an accelerated discharge process following PCI for low-risk NSTE-ACS patients reduced post-PCI LOS without increasing readmissions or complications. Increased utilization of the process throughout the implementation period may be attributed to peer coaching.

PROVIDE-HF primary results: Patient-Reported Outcomes inVestigation following Initiation of Drug therapy with Entresto (sacubitril/valsartan) in heart failure.

BACKGROUND: In PARADIGM-HF, sacubitril/valsartan improved quality of life (QOL) versus enalapril in heart failure with reduced ejection fraction (HFrEF), yet limited data are available regarding QOL changes after sacubitril/valsartan initiation in routine practice. METHODS: PROVIDE-HF was a prospective study within a national research network (Patient-Centered Outcomes Research Network) of HFrEF outpatients recently initiated on sacubitril/valsartan versus controls with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change. The primary end point was mean Kansas City Cardiomyopathy Questionnaire (KCCQ) change through 12 weeks. Other end points included responder analyses: ≥5-point and ≥20-point KCCQ increase. Adjusted QOL change was estimated after propensity score weighting. RESULTS: Overall, 270 patients had both baseline and 12-week KCCQ data (151 sacubitril/valsartan; 119 control). The groups had similar demographics and HF details: median EF 28% and N-terminal pro-brain natriuretic peptide 1083 pg/mL. Sacubitril/valsartan patients had larger improvements in KCCQ (mean difference +4.76; P = .027) and were more likely to have a ≥5-point and ≥20-point response (all P < .05). Adjusted comparisons demonstrated similar numerical improvements in the change in KCCQ (+4.55; 95% CI -0.89 to 9.99; P = .101) and likelihood of ≥5-point increase (odds ratio 1.55; 95% CI: 0.84-2.86; P = .16); ≥20-point increase remained statistically significant (odds ratio 3.79; 95% CI 1.47-9.73; P = .006). CONCLUSIONS: In this prospective HFrEF study of sacubitril/valsartan initiation compared with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change, the between-group difference in the primary end point, mean KCCQ change at 12 weeks was not statistically significant following adjustment, but sacubitril/valsartan initiation was associated with early improvements in QOL and a higher likelihood of ≥20-point improvement in KCCQ at 12 weeks. These data add additional real-world evidence related to patient-reported outcomes following the initiation of sacubitril/valsartan in routine clinical practice.

Trends, Predictors, and Outcomes Associated With 30-Day Hospital Readmissions After Percutaneous Coronary Intervention in a High-Volume Center Predominantly Using Radial Vascular Access.

BACKGROUND AND AIM: Patients undergoing percutaneous coronary intervention (PCI) are at high-risk for hospital readmission. We examined the rate, factors associated with, and outcomes of 30-day readmissions for patients who underwent a PCI. METHODS: We reviewed medical records of all patients who underwent PCI between 2011 and 2014 at a central New England radial first, tertiary care center. Data was collected on occurrence and cause of readmission as well as patients' bleeding events and survival at one year. Logistic regression was used to examine factors associated with 30-day readmission as well as its association with bleeding and all-cause mortality. RESULTS: A total of 3858 patients were studied (mean age = 62.8 years with 26.1% women), among whom 348 (9.5%) patients were readmitted within 30-days. Cardiac causes of readmission represented 62% of all readmissions. In the multi-variable adjusted regression model, factors that were significantly associated with 30-day readmission included female gender, prior coronary bypass surgery, acute coronary syndrome, anemia, length of stay, and delay in initial presentation. Patients who were readmitted had more than twice the risk of bleeding and mortality at one year as compared to those who were not readmitted within 30 days. CONCLUSIONS: In conclusion, our results suggest that early hospital readmission after undergoing PCI is common and has not changed in recent years. Efforts should be made to identify and closely monitor patients who are at risk for readmission after PCI.

The Effects of Regular Exercise on Circulating Cardiovascular-related MicroRNAs.

The purpose of the present study was to examine the effects of regular exercise on the abundance of targeted circulating microRNAs (miRNAs). The present analysis examined 20 previously sedentary adults from the HERITAGE Family Study who completed 20 weeks of endurance exercise training. The expression of 53 miRNAs related to cardiovascular disease were measured in serum collected at baseline and post-training by performing RT-qPCR on the Human Cardiovascular Disease miRNA array (Qiagen, Germany). The effect of regular exercise on circulating miRNAs was assessed using paired t-tests of baseline and post-training expression levels. A false discovery rate threshold of 5% was used to determine significance. Regular exercise resulted in significantly decreased mean serum expression of nine miRNAs (miR-486-5p, let-7b-5p, miR-29c-3p, let-7e-5p, miR-93-5p, miR-7-5p, miR-25-3p, miR-92a-3p, and miR-29b-3p; fold change range: 0.64-83, p = 0.0002-0.01) and increased mean expression of five miRNAs (miR-142-3p, miR-221-3p, miR-126-3p, miR-146a-5p, and miR-27b-3p; fold change range: 1.41-3.60, p = 0.001-0.006). Enrichment analysis found that these 14 miRNAs target genes related to over 345 different biological pathways. These results provide further evidence of the effects of regular exercise on the circulating miRNA profile.

Operator and institutional experience reduces room-to-balloon times for transradial primary percutaneous coronary intervention.

BACKGROUND: Transradial (TR) access for primary percutaneous coronary intervention (PCI) is becoming accepted as the preferred approach but has not gained widespread adoption due to technical challenges that may limit procedural success and delay time to revascularization, particularly among patients treated by inexperienced operators. We report our experience over the first 2 years of our TR primary PCI program and determined the impact of TR access on clinical and procedural outcomes. METHODS: Clinical characteristics and procedural outcomes were collected prospectively from 488 patients presenting with ST-segment elevation myocardial infarction and compared according to whether patients underwent primary PCI via the TR or transfemoral (TF) approach. RESULTS: Hospital mortality was very low in both groups (1.1% [TR] vs 2.6% [TF]; P=.23). Access-site intended procedural success for primary PCI was equivalent (98.4% for TR vs 98.6% for TF; P=.85). Catheterization room-to-balloon (RTB) times were significantly lower among patients undergoing TR primary PCI as compared with those in the TF group (20:33 ± 06:41 [TR] vs 25:11 ± 08:22 [TF]; P<.001). TR patients treated by operators who had performed >50 TR PCIs had lower RTB times (20:03 ± 06:12 vs 24:26 ± 10:01; P<.06) and lower doses of radiation exposure (1812 ± 1007 mGy vs 2827 ± 954 mGy; P<.01) than patients treated by less experienced operators. Dual-purpose guide catheter usage was also associated with lower RTB times (18:38 ± 5:42 vs 25:15 ± 8:20; P<.001) and radiation exposure (1824 ± 6205 mGy vs 2407 ± 1389 mGy; P<.01). CONCLUSIONS: TR primary PCI may be performed rapidly and successfully despite only modest operator and institutional experience.

Outcomes from patients with multi-vessel disease following primary PCI: staged PCI imparts very low mortality.

BACKGROUND: CABG and PCI are effective means for revascularization of patients with multi-vessel coronary artery disease, but previous studies have not focused on treatment of patients that first undergo primary PCI. METHODS: Among patients enrolled in the global registry of acute coronary events (GRACE), clinical outcomes for patients presenting with STEMI treated with primary PCI were compared according to whether residual stenoses were treated medically, surgically, or with staged PCI. Clinical characteristics and data pertaining to major adverse cardiac events during hospitalization and 6 months after discharge were collected. RESULTS: Of the 1,705 patients included, 1,345 (79%) patients were treated medically, 303 (18%) underwent staged PCI, and 57 (3.3%) underwent CABG following primary PCI. Hospital mortality was lowest among patients treated with staged PCI (Medical = 5.7%; PCI = 0.7%; CABG = 3.5%; P < 0.001 [PCI vs. Medical]), a finding that persisted after risk adjustment (Odds Ratio PCI vs. Medical 5 0.16, [0.04-0.68]; P 5 0.01). Six month postdischarge mortality likewise was lowest in the staged PCI group (Medical = 3.1%; PCI = 0.8%; CABG = 4.0%; P = 0.04 [PCI vs. Medical]). Patients revascularized surgically were rehospitalized less frequently (Medical = 20%; PCI = 19%; CABG = 6.3%; P < 0.05) and underwent fewer unscheduled procedures (Medical 5 9.8%; PCI = 10.0%; CABG = 0.0%; P < 0.02). CONCLUSIONS: The results of this multinational registry demonstrate that hospital mortality in patients who undergo staged percutaneous revascularization of multivessel coronary disease following primary PCI is very low. Patients undergoing CABG following primary PCI are hospitalized less frequently and undergo fewer unplanned catheter-based procedures.

Impact of independent data adjudication on hospital-specific estimates of risk-adjusted mortality following percutaneous coronary interventions in massachusetts.

BACKGROUND: As part of state-mandated public reporting of outcomes after percutaneous coronary interventions (PCIs) in Massachusetts, procedural and clinical data were prospectively collected. Variables associated with higher mortality were audited to ensure accuracy of coding. We examined the impact of adjudication on identifying hospitals with possible deficiencies in the quality of PCI care. METHODS AND RESULTS: From October 2005 to September 2006, 15 721 admissions for PCI occurred in 21 hospitals. Of the 864 high-risk variables from 822 patients audited by committee, 201 were changed, with reassignment to lower acuities in 97 (30%) of the 321 shock cases, 24 (43%) of the 56 salvage cases, and 73 (15%) of the 478 emergent cases. Logistic regression models were used to predict patient-specific in-hospital mortality. Of 241 (1.5%) patients who died after PCI, 30 (12.4%) had a lower predicted mortality with adjudicated than with unadjudicated data. Model accuracy was excellent with either adjudicated or unadjudicated data. Hospital-specific risk-standardized mortality rates were estimated using both adjudicated and unadjudicated data through hierarchical logistic regression. Although adjudication reduced between-hospital variation by one third, risk-standardized mortality rates were similar using unadjudicated and adjudicated data. None of the hospitals were identified as statistical outliers. However, cross-validated posterior-predicted P values calculated with adjudicated data increased the number of borderline hospital outliers compared with unadjudicated data. CONCLUSIONS: Independent adjudication of site-reported high-risk features may increase the ability to identify hospitals with higher risk-adjusted mortality after PCI despite having little impact on the accuracy of risk prediction for the entire population.

Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells: safety of a high dose, "off-the-shelf", cellular cardiomyoplasty strategy.

BACKGROUND: Efficacy of cellular cardiomyoplasty seems to occur in a dose-related manner. However, the safety of multiple transendomyocardial transplantation procedures to administer high cell dosages has not been previously reported. The aims of this study were to assess the short- and intermediate-term results of a repeated cell administration strategy and evaluate the safety of an "off-the-shelf" allogeneic mesenchymal stem cell (MSC) source. METHODS: Porcine bone marrow-derived MSCs were culture-expanded through three cycles in vitro before transplantation. Yorkshire swine weighing 30-40 kg were allocated to receive the total dose during 1 injection procedure or divided over 2 procedures separated by 14 days, as follows: (i) 400x10(6) allogeneic MSC (n=5), (ii) 800x10(6) allogeneic MSC divided in 2 doses (n=5), (iii) cryopreservant vehicle containing 10% DMSO, 5% porcine serum and 85% PlasmaLyte A, 14 days apart (n=2), or (iv) sterile saline 14 days apart (n=2). During each procedure, twenty 0.5 ml aliquots of the assigned injectant were administered using the Stiletto Endocardial Direct Injection Catheter System, targeting at the left ventricular anterior, septal and lateral walls under fluoroscopy. Vital signs and electrocardiograms were recorded during the procedure and at 24 h. The animals were examined daily and cardiac enzymes were measured immediately post-procedure, and on days 1, 15 and 90. Necropsy and histopathology were performed at day 90. RESULTS: Mean transendocardial injection procedure time was 40+/-10 min. All ventricular target areas were accessed by the Stiletto system. Ventricular ectopic beats and/or non-sustained ventricular tachycardia associated with catheter contact or endomyocardial injections were observed in all cases. However, no sustained ventricular arrhythmia, anaphylaxis, or significant cardiac enzyme release was seen. One mortality resulted from air embolism during the procedure. All other swine survived from the time of recovery until planned sacrifice at day 90 and had normal physical examination findings. The 3-month histopathology showed no evidence of rejection, calcification, teratoma or myocardial infarction. CONCLUSION: Repeated endomyocardial transplantation of high dose, bone marrow-derived allogeneic cells appeared safe in a large animal, human surrogate model. Such cellular cardiomyoplasty strategy warrants further investigation.

The proteasome inhibitor lactacystin attenuates growth and migration of vascular smooth muscle cells and limits the response to arterial injury.

BACKGROUND: There is emerging evidence that the ubiquitin-proteasome system plays a role in vascular proliferative disorders such as restenosis after percutaneous coronary interventions. The present study examined the effect of proteasome inhibition on cultured vascular smooth muscle cell (VSMC) growth and migration, as well as on vascular lesion formation, following balloon arterial injury in the rat. METHODS: The effect of the proteasome inhibitor clasto-lactacystin beta-lactone (lactacystin) on cultured VSMC proliferation was assessed using cell proliferation assays and immunohistochemical assessment of S-phase entry. To test the effect of proteasome inhibition on lesion formation and to confirm the role of p21(Cip1/Waf1) (p21) in this effect in vivo, carotid injury was performed on anesthetized male Sprague-Dawley rats, followed by local treatment with either lactacystin or vehicle. RESULTS: Treatment of VSMCs with the proteasome inhibitor lactacystin resulted in a 60% and 80% decrease in cell number versus controls at day 3 and day 5 after treatment, respectively. This effect was accompanied by an 86% decrease in S-phase entry and an increased level of the cyclin-dependent kinase inhibitor p21. Additionally, lactacystin significantly inhibited VSMC migration in a modified Boyden chamber assay. Lactacystin resulted in a 59% reduction of neointimal formation at 14 days following balloon injury. This effect was associated with an early increase in p21 protein in the arterial wall. CONCLUSIONS: Inhibition of the ubiquitin-proteasome system resulted in the attenuation of VSMC growth both in cultured cells and in an animal model of vascular injury, possibly via a mechanism involving upregulation of the p21 cyclin-dependent kinase inhibitor. These data provide support for a role of the proteasome in the vascular response to injury, and suggest an important role for p21 and attenuation of cellular migration in the mechanism of this effect.

High left ventricular mass index does not limit the utility of fractional flow reserve for the physiologic assessment of lesion severity.

OBJECTIVES: To demonstrate that fractional flow reserve (FFR) of vessels in patients with high left ventricular mass index (LVMI) should be similar to that of matched vessels in patients with normal LVMI. BACKGROUND: FFR is a physiologic index of coronary lesion severity. It is not known whether FFR remains useful in the setting of increased LVMI, when microvascular abnormalities may be present. METHODS: LVMI was calculated in 84 patients using contrast left ventriculography after validation with cardiac magnetic resonance imaging. Cardiac risk factors, LV ejection fraction (LVEF), minimal lumen diameter (MLD), percent diameter stenosis (%DS), lesion length and FFR were compared in 22 patients with high LVMI to 62 patients with normal LVMI and angiographically-matched vessels. RESULTS: LVMI was 126 +/- 21 g/m2 in the high LVMI group and 84 +/- 21 g/m2 in the normal LVMI group. There were no differences in age, LVEF, diabetes, hypertension or dyslipidemia between groups. Angiographic lesion characteristics were well matched in patients with high versus normal LVMI (MLD 1.3 +/- 0.6 mm vs. 1.3 +/- 0.6 mm, %DS 61 +/- 13% vs. 62 +/- 13%, and lesion length 14.2 +/- 7.0 mm vs. 14.3 +/- 7.0 mm; p = NS for all). Importantly, no difference in FFR was observed (0.79 +/- 0.12 vs. 0.78 +/- 0.16; p = NS) between the groups, and LVMI did not correlate with FFR in a multivariate analysis. CONCLUSIONS: FFR of coronary lesions in patients with high LVMI is no different than FFR of angiographically-matched lesions in patients with normal LVMI, suggesting that high LV mass should not limit the utility of FFR as an index of coronary lesion severity.

Fractional flow reserve of infarct-related arteries identifies reversible defects on noninvasive myocardial perfusion imaging early after myocardial infarction.

OBJECTIVES: We hypothesized that fractional flow reserve (FFR) of an infarct-related artery (IRA) early after myocardial infarction (MI) identifies inducible ischemia on noninvasive imaging. BACKGROUND: Early after MI, IRAs frequently have angiographically indeterminant lesions. Whether FFR can detect reversible perfusion defects early after MI when dynamic microvascular abnormalities are present is not known. METHODS: Rest and dipyridamole (DP)-stress 99mTc sestamibi single-photon emission computed tomography (SPECT) were performed in 48 patients 3.7 +/- 1.3 days after MI, with 23 patients undergoing concurrent myocardial contrast echocardiography (MCE). Angiography, FFR, and percutaneous coronary intervention (PCI) of the IRA (as necessary) were subsequently performed. Follow-up SPECT was performed 11 weeks after PCI to identify true reversibility on baseline SPECT. RESULTS: The sensitivity, specificity, positive and negative predictive value, and concordance of FFR < or =0.75 for detecting reversibility on SPECT were 88%, 50%, 68%, 89%, and 71% (chi-square <0.001), respectively; which improved to 88%, 93%, 88%, 93%, and 91% (chi-square <0.001), respectively, for the detection of true reversibility. The corresponding values of FFR < or =0.75 for detecting reversibility on DP-MCE were 90%, 100%, 100%, 75%, and 93% (chi-square <0.001), respectively, and on either SPECT or MCE were 88%, 93%, 91%, 91%, and 91% (chi-square <0.001), respectively. The optimal FFR value for discriminating inducible ischemia on noninvasive imaging was 0.78. CONCLUSIONS: Fractional flow reserve of the IRA accurately identifies reversibility on noninvasive imaging early after MI. These findings support the utility of FFR early after MI.

Alpha4beta1 integrin (VLA-4) blockade attenuates both early and late leukocyte recruitment and neointimal growth following carotid injury in apolipoprotein E (-/-) mice.

BACKGROUND: The alpha(4)beta(1) integrin (VLA-4) supports rolling and firm adhesion of leukocytes to inflamed tissues via ligation of VCAM-1 or fibronectin expressed on the activated endothelium. We tested the hypothesis that VLA-4 mediates leukocyte recruitment and neointimal growth after arterial injury in the atherosclerosis-prone apolipoprotein E (ApoE)-deficient mouse. METHODS: ApoE (-/-) mice fed a Western diet underwent air desiccation injury, and the expression patterns of VLA-4 and VCAM-1 were determined by immunohistochemistry (IHC). To determine the effect of targeted VLA-4 blockade on leukocyte recruitment and neointimal growth, ApoE (-/-) mice received an intraperitoneal injection of a VLA-4 neutralizing monoclonal antibody (PS/2) at the time of injury alone or over a prolonged administration course. Additional mice received an isotype control antibody. RESULTS: IHC demonstrated a marked increase in VLA-4 expression 7 days following injury. Prolonged administration of PS/2 resulted in a 72% reduction (p < 0.02) in neointimal growth 28 days following injury. IHC revealed a marked 95% reduction in neutrophil recruitment at 7 days and a 48% reduction in macrophage recruitment 28 days following injury with prolonged PS/2 administration. CONCLUSIONS: Prolonged VLA-4 blockade reduces leukocyte recruitment and neointimal growth following air desiccation injury in ApoE (-/-) mice. These findings demonstrate an important role for VLA-4 in the response to arterial injury.

Intron retention generates a novel Id3 isoform that inhibits vascular lesion formation.

The expression of intron-containing messages has been shown to occur in a variety of diseases including lactic acidosis, Cowden Syndrome, and several cancers. However, it is unknown whether these intron-containing messages result in protein production in vivo. Indeed, intron-containing RNAs are typically retained in the nucleus, targeted for degradation, or are repressed translationally. Here, we show that during vascular lesion formation in rats, an alternative isoform of the helix-loop-helix transcription factor Id3 (Id3a) generated by intron retention is abundantly expressed. We demonstrate that Id3 is expressed early in lesion formation when the proliferative index of the neointima is highest and that Id3 promotes smooth muscle cell (SMC) proliferation and S-phase entry and inhibits transcription of the cell-cycle inhibitor p21(Cip1). Using an Id3a-specific antibody developed by our laboratory, we show that Id3a protein is induced during vascular lesion formation and that Id3a expression peaks late when the proliferative index is low or declining and extensive apoptosis is observed. Furthermore, Id3a fails to promote SMC growth and S-phase entry or to inhibit p21(Cip1) promoter transactivation. In contrast, Id3a stimulates SMC apoptosis and inhibits endogenous Id3 production. Adenoviral delivery of Id3a inhibited lesion formation in balloon-injured rat carotid arteries in vivo. These data describe a novel feedback loop whereby intron retention generates an Id3 isoform that acts to limit SMC growth during vascular lesion formation, providing the first evidence that regulated intron retention can modulate a pathologic process in vivo.

Effect of acute myocardial infarction on the utility of fractional flow reserve for the physiologic assessment of the severity of coronary artery narrowing.

Fractional flow reserve (FFR) has been shown to be a useful physiologic index of coronary lesion severity in myocardial beds of patients without prior infarction and in those with remote infarction. Acute myocardial infarction (AMI) causes myocardial necrosis and microvascular stunning, embolization, and damage. Whether FFR remains a useful index of epicardial flow in the setting of recent myocardial infarction is not established. Cardiac risk factors, serum troponin I, angiographic minimal lumen diameter (MLD), percent diameter stenosis (DS), lesion length, vessel reference diameter, hyperemic central aortic pressure, hyperemic pressure distal to stenosis, and FFR were compared in 43 vessels subtending recent AMI beds to 25 control vessels, matched by lesion length and MLD, in patients without AMI. There were no differences in DS, MLD, lesion length, or reference diameter between AMI and non-AMI groups. Patients with AMI had mean troponin I levels of 91.8 +/- 162 ng/ml. Left ventricular ejection fraction was significantly lower in patients with than without AMI (55 +/- 9% vs 62 +/- 8%, p <0.05). There were no significant differences in hyperemic central aortic pressure (92 +/- 13 vs 99 +/- 15 mm Hg, p = NS), hyperemic pressure distal to the stenosis (62 +/- 17 vs 66 +/- 19 mm Hg, p = NS), or FFR (0.67 +/- 17 vs 0.68 +/- 17, p = NS) between recent AMI and non-AMI control patients. There was a significant correlation between DS and FFR for both patients with (p <0.001) and without (p = 0.003) infarctions. Thus, FFR and the relation between FFR and DS of lesions subtending AMI was not significantly different from FFR of angiographically matched lesions in patients without AMI.

Rosiglitazone reduces the accelerated neointima formation after arterial injury in a mouse injury model of type 2 diabetes.

BACKGROUND: Hyperglycemia (HG) and hyperinsulinemia (HI) may be factors enhancing the atherosclerotic complications of diabetes. We hypothesized that specific feeding of C57BL/6 apolipoprotein (apo) E-/- mice would alter their metabolic profiles and result in different degrees of neointima (NI) formation. We additionally hypothesized that an insulin-sensitizing agent (rosiglitazone) would prevent the development of type 2 diabetes and reduce neointima formation after carotid wire injury measured at 28 days. METHODS AND RESULTS: Fasting glucose and insulin levels were elevated in the Western diet (WD) group, with a trend toward higher insulin levels and euglycemia in the fructose diet (FD)--fed mice. NI formation was exaggerated in the WD group compared with the FD or chow control groups. In the WD mice given rosiglitazone, glucose and insulin levels remained normal and NI formation was significantly reduced, as was NI macrophage content. CONCLUSIONS: These findings demonstrate that apoE-/- mice fed a WD develop type 2 diabetes with an exaggerated NI response to injury. FD mice maintain euglycemia but develop insulin resistance, with an intermediate degree of NI growth compared with chow diet controls. Rosiglitazone prevents the development of hyperglycemia and hyperinsulinemia and normalizes the insulin release profile in the apoE-/-, WD-fed mouse and significantly reduces NI formation by 65% after carotid wire injury while reducing macrophage infiltration. These data support the hypothesis that type 2 diabetes in the setting of elevated cholesterol accelerates the response to vascular injury and suggest that agents that improve insulin sensitivity may have therapeutic value in reducing restenosis in type 2 diabetes.

Single injection of P-selectin or P-selectin glycoprotein ligand-1 monoclonal antibody blocks neointima formation after arterial injury in apolipoprotein E-deficient mice.

BACKGROUND: Emerging data suggest that P-selectin, by controlling adhesion of white blood cells, may be important in limiting the response to vascular injury. METHODS AND RESULTS: We tested the hypothesis that transient inhibition of P-selectin with either anti-P-selectin monoclonal antibody (mAb) or anti-P-selectin glycoprotein ligand-1 (PSGL-1) mAb would reduce neointima formation in the setting of carotid denudation injury in atherosclerosis-prone apolipoprotein E-/- mice. Neointima formation at 28 days was reduced significantly, by 50% or 80%, by a single injection on the day of injury of 100 or 200 microg P-selectin mAb RB 40.34 and by 55% by a single injection of 100 microg PSGL-1 mAb 4RA10 (P< or =0.005). In addition, there was a significant reduction in neointimal macrophage content. CONCLUSIONS: These findings demonstrate that transient P-selectin or PSGL-1 blockade at the time of arterial injury significantly limits plaque macrophage content and neointima formation in a dose-dependent manner after carotid denudation injury in apolipoprotein E-/- mice.