Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy.

BACKGROUND: Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. METHODS: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. RESULTS: Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. CONCLUSION: Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.

Angiogram based fractional flow reserve in patients with dual/triple vessel coronary artery disease.

OBJECTIVE: To assess the performance of angiography derived Fractional Flow Reserve (FFRangio) in multivessel disease (MVD) patients undergoing angiography. BACKGROUND: FFR is the reference standard for physiologic assessment of coronary stenosis and guidance of revascularization, especially in patients with MVD, yet it remains grossly underutilized. The non-wire based FFRangio performs well in non-MVD patients, but its accuracy in MVD is unknown. METHODS: A prospective clinical study was conducted at Gifu Heart Centre, Japan. Patients underwent physiologic assessment of all relevant coronary lesions using wire-based FFR (wbFFR) and FFRangio. Primary outcome was diagnostic performance (sensitivity, specificity, accuracy) for FFRangio with wbFFR as reference. Other outcomes were the correlation between wbFFR/FFRangio, time required for wbFFR/FFRangio measurements, and the effect of wbFFR/FFRangio on the reclassification of coronary disease severity. RESULTS: Fifty patients (118 lesions in total) were included. Mean age was 72 ±â€¯9 years, 72% were male, 36% had triple vessel disease and the average SYNTAX score was 13. The mean measurement of wbFFR and FFRangio were 0.83 ±â€¯0.12 and 0.81 ±â€¯0.11, respectively. Accuracy, sensitivity and specificity for FFRangio were 92.3% (95% CI 79.1-98.4%), 92.4% (95% CI 84.3-97.2%) and 92.4% (95% CI 87.4-97.3%), respectively. Pearson's r between wbFFR and FFRangio was 0.83. FFRangio measurement was faster than wbFFR (9.6 ±â€¯3.4 vs. 15.0 ±â€¯8.9 min, p < 0.001). CONCLUSIONS: In patients with MVD, FFRangio shows good correlation and excellent diagnostic performance compared to wbFFR, and measuring FFRangio is faster than wbFFR. These results highlight the potential clinical benefits of utilizing FFRangio among patients with MVD.

Comparison of sirolimus eluting stent with bioresorbable polymer to everolimus eluting stent with permanent polymer in bifurcation lesions: Results from CENTURY II trial.

OBJECTIVE: To demonstrate the safety and efficacy of a new sirolimus eluting stent with bioresorbable polymer, Ultimaster, (BP-SES) compared with everolimus-eluting, permanent polymer, Xience stent (PP-EES) in bifurcation lesions with respect to the freedom from Target Lesion Failure at 1-year. METHODS: Within 1,119 patients enrolled in the CENTURY II randomized controlled multicenter trial, 194 patients were treated for bifurcation lesions and randomized to either BP-SES (n = 95) or PP-EES (n = 99). The primary endpoint was freedom from target lesion failure (TLF) composite endpoint [cardiac death, MI not clearly attributable to a non-target vessel, and clinically driven target lesion revascularization (TLR)] at 1-year. RESULTS: Baseline patient demographic, angiographic, and stenting characteristics were similar in both study arms. A single stent technique with provisional or "cross over" stenting were the most widely used in both arms (93.2% BP-SES vs. 92.4% PP-EES). Freedom from TLF at 1-year was 94.7% for BP-SES and 91.9% for PP-EES (P for noninferiority 0.031). The rate of clinically driven target lesion revascularization (TLR) at 1-year was 3.2% for BP-SES and 3.0% for PP-EES (P = 0.95). There were no significant differences detected in any of the individual clinical endpoints or other secondary clinical endpoints between the study arms at 1-year follow up. CONCLUSIONS: The new bioresorbable polymer sirolimus-eluting stent showed safety and efficacy profiles similar to durable polymer everolimus-eluting in the treatment of patients with bifurcation lesions at 1-year follow up. © 2015 Wiley Periodicals, Inc.

The role of FDG-PET/CT imaging in early detection of extra-cardiac complications of infective endocarditis.

The exact incidence of extra-cardiac complications (ECC) in patients with infective endocarditis (IE) is unknown but presumed to be high. These patients, although mostly asymptomatic, may require a more aggressive therapeutic approach. (18)fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is used for the diagnosis of infections, but its role in the early diagnosis of IE complications is still unclear. This study aimed to evaluate the role of FDG-PET/CT in the early diagnosis of ECC in IE and its implications for medical management. We prospectively studied 40 consecutive patients with a confirmed diagnosis of IE (according to the modified Duke criteria) who underwent a whole body FDG-PET/CT study within 14 days from diagnosis. The FDG-PET/CT demonstrated ECC in 17 (42.5%) patients, while 8 (38.1%) of them were asymptomatic. The most frequent embolic sites were musculoskeletal and splenic. Owing to the FDG-PET/CT findings, treatment planning was modified in 14 (35%) patients. This included antibiotic treatment prolongation (27.5%), referral to surgical procedures (15%) and, most substantially, prevention of unnecessary device extraction (17.7%). According to our experiences, FDG-PET/CT imaging was useful in the detection of embolic and metastatic infections in IE. This clinical information had a significant diagnostic and therapeutic impact in managing IE disease.

Effect of High Dose Statin Pretreatment on Endothelial Progenitor Cells After Percutaneous Coronary Intervention (HIPOCRATES Study).

BACKGROUND: Pretreatment with high-dose statins given before percutaneous coronary intervention (PCI) has been shown to have beneficial effects, in particular by reducing peri-procedural myocardial infarction. The mechanism of these lipid-independent beneficial statin effects is unclear. Circulating endothelial progenitor cells (EPCs) have an important role in the process of vascular repair, by promoting re-endothelization following injury. We hypothesized that statins can limit the extent of endothelial injury induced by PCI and promote re-endothelization by a positive effect on EPCs. We, therefore, aimed to examine the effect of high-dose statins given prior to PCI on EPCs profile. METHODS: Included were patients, either statin naïve or treated chronically with low-dose statins, with stable or unstable angina who underwent PCI. Patients were randomized to receive either high-dose atorvastatin (80 mg the day before PCI and 40 mg 2-4 h before PCI) or low- dose statin. EPCs profile was examined before PCI and 24 h after it. Circulating EPCs levels were assessed by flow cytometry as the proportion of peripheral mononuclear cells co-expressing VEGFR-2+ CD133+ and VEGFR-2+ CD34+. The capacity of the cells to form colony forming units (CFUs) was quantified after 7 days of culture. RESULTS: Twenty three patients (mean age 61.4 ± 7.4 years, 87.0% men) were included in the study, of which 12 received high-dose atorvastatin prior to PCI. The mean number of EPC-CFUs before PCI was higher in patients treated with high-dose atorvastatin vs. low-dose statins (165.8 ± 58.8 vs. 111.7 ± 38.2 CFUs/plate, respectively, p < 0.001). However, 24 h after the PCI, the number of EPC-CFUs was similar (188.0 ± 85.3 vs. 192.9 ± 66.5 CFUs/plate in patients treated with high-dose atorvastatin vs. low- dose statins, respectively, p = 0.15). There were no statistical significant differences in FACS analyses between the 2 groups. CONCLUSIONS: The current study showed higher EPC- CFUs levels in patients treated with high-dose atorvastatin before PCI and a lower increment in EPC-CFUs after PCI. These findings could account for the beneficial effects of statins given prior to PCI, yet further investigation is required.

Mesh-covered embolic protection stent implantation in ST-segment-elevation myocardial infarction: final 1-year clinical and angiographic results from the MGUARD for acute ST elevation reperfusion trial

The MGuard, a bare metal stent covered with a polymer mesh, was designed to reduce distal embolization during percutaneous coronary intervention in ST-segment-elevation myocardial infarction. In the MGUARD for Acute ST Elevation Reperfusion trial, the primary end point of complete ST-segment resolution was significantly improved with the MGuard compared with control. We evaluated 1-year clinical and angiographic results.METHODS AND RESULTS:Patients with ST-segment-elevation myocardial infarction ≤12 hours undergoing primary percutaneous coronary intervention of a single de novo native lesion were randomized to the MGuard versus any commercially available metallic stent (39.8% drug-eluting). Clinical follow-up was performed through 1 year, and angiography at 13 months was planned in 50 MGuard patients. There was no difference in major adverse cardiac events (1.8% versus 2.3%; P=0.75) at 30 days between the groups. Major adverse cardiac events at 1 year were higher with the MGuard, driven by greater ischemia-driven target lesion revascularization (8.6% versus 0.9%; P=0.0003). Conversely, mortality tended to be lower with the MGuard at 30 days (0% versus 1.9%; P=0.04) and at 1 year (1.0% versus 3.3%; P=0.09). Late lumen loss at 13 months in the MGuard was 0.99±0.80 mm, and binary restenosis was 31.6%.CONCLUSIONS:In patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, a trend toward reduced 1-year mortality was present in patients treated with the MGuard stent. Target lesion revascularization and major adverse cardiac events rates during follow-up were higher in the MGuard group than in the control stent group, and angiographic late loss of the MGuard was consistent with that expected from bare metal stents.

Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)-dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB's regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation.

Physical influences on right ventricular infarction and cardiogenic shock in acute myocardial infarction.

AIM: To determine if complicated acute myocardial infarction (AMI) is related to specific cosmophysical activities. METHODS: The study group included 1170 patients who had undergone primary percutaneous coronary intervention (PCI) for AMI in 2000-2006. Geomagnetic and cosmic ray (neutron) activity (GMA, CRA) on the day of PCI were derived from international observatories. The findings were compared among patients with right ventricular infarction (RVI), cardiogenic shock, and uncomplicated AMI. RESULTS: Relative to the whole study period, the mean CRA was higher on days on which PCI was performed for RVI (n=123, 10.5%) (p = .0003) and cardiogenic shock (n=102, 8.72%) (p = .018). When the same artery was involved (LAD, RCA, CRX), CRA was significantly higher for complicated than for uncomplicated AMI (RVI group: p = .006, p = .00027, p = .014, c ardiogenic shock: p = .009, p = .029, p = .089, respectively). At the highest levels of GMA, more RVI cases were seen than cases of cardiogenic shock (p = .06). CONCLUSION: RVI and cardiogenic shock were associated with higher CRA than uncomplicated AMI. RVI occurred more often on days of high GMA than cardiogenic shock. Higher CRA may induce more myocardial damage in patients predisposed to AMI.

Body mass index and risk of all-cause and cardiovascular mortality in hospitalized elderly patients with diabetes mellitus.

AIMS: Obesity is linked to increased morbidity and mortality risk in both the general population and in patients with diabetes mellitus; however, recent reports suggest that, in hospitalized elderly individuals, the association between body mass index (BMI) and mortality may be inverse. The present study sought to investigate the association between BMI and survival in hospitalized elderly individuals with diabetes mellitus. METHODS: The medical records of 470 patients (226 males, mean age of 81.5 +/- 7.0 years) admitted to an acute geriatric ward between 1999 and 2000 were reviewed. Of the 140 patients with diabetes mellitus, 122 had more than 6 months of follow-up and were included in this analysis. Patients were followed up until 31 August 2004. Mortality data were extracted from death certificates. RESULTS: During a mean follow-up of 3.7 +/- 1.6 years, 69 (56.6%) subjects died, 31 (25.4%) from cardiovascular causes. Those who died from any cause had lower baseline BMI than those who survived (24.0 +/- 4.0 vs. 27.1 +/- 4.3 kg/m(2); P < 0.0001). Similarly, those who died of cardiovascular causes had lower baseline BMI than those who did not (23.7 +/- 3.6 vs. 25.9 +/- 4.5, P = 0.01). BMI was inversely associated with all-cause [relative risk (RR) 0.89, 95% confidence interval (CI) 0.83-0.96, P = 0.002] and cardiovascular death (RR 0.83, 95% CI 0.74-0.93, P = 0.002) even after controlling for age, sex, smoking, dyslipidaemia and reason for hospital admission. CONCLUSIONS: In very elderly subjects with diabetes mellitus, increased BMI was associated with reduced mortality risk.

Clinical results of drug eluting stents compared to bare metal stents for patients with ST elevation acute myocardial infarction.

OBJECTIVE: To investigate the clinical outcomes in patients with ST segment elevation acute myocardial infarction (STEMI) treated with drug eluting stents (DES) versus a matched control group of patients with STEMI treated with bare metal stents (BMS). METHODS: This registry included 122 patients with STEMI undergoing primary coronary angioplasty with DES implantation at our institution. The control group consisted of 506 patients implanted with BMS, who were matched for age, infarct location, and diabetic status. The incidences of major adverse cardiac events (MACE) including target vessel/lesion revascularization (TVR/TLR) and stent thrombosis were assessed up to 12 months. RESULTS: Twelve months follow up showed a non-significant trend towards reduced deaths (3.3% versus 7.1%, P=0.1), significantly reduced recurrent MI (0.0% versus 6.1%, P=0.02), TVR (5.7% versus 15.2%, P=0.006) and TLR (2.5% versus 14.0%, P=0.004) events in the DES group as compared to BMS group. The composite incidences of MACE at 12 months follow-up was lower in the DES group (11.5%) as compared to the BMS group (21.3%, P=0.01). CONCLUSION: According to our experiences, the use of DES in STEMI is safe and effective as compared to BMS. DES was effective in reducing the incidence of restenosis outcomes and overall adverse cardiac events up to 12 months.

Cardiac surgery in patients on chronic hemodialysis: short and long-term survival.

OBJECTIVE: Open-heart surgery carries a high risk for hemodialysis patients. This study focuses on the short and long-term outcomes of hemodialysis patients undergoing heart surgery. DESIGN: The study was carried out as a retrospective analysis in the Department of Cardiothoracic Surgery in a large university-affiliated hospital. PATIENTS: 115 hemodialysis patients underwent cardiac surgery in our department between 1 July 1996 and 31 July 2006. 67.5 % (77 patients) underwent isolated coronary artery bypass grafting (CABG), 13.2 % (15 patients) underwent isolated aortic valve replacement (AVR) and 20.2 % (23 patients) underwent mitral valve surgery or combined valve and coronary artery bypass grafting or multiple valve surgery. METHODS: The relationship between several variables (age, sex, hypertension, diabetes, and previous myocardial infarction, type of disease, preoperative ejection fraction, and congestive heart failure) and operative (30 days) mortality and late survival was analyzed. RESULTS: The overall 30-day mortality was 18.3 % (21 patients). It was 13 % (10/77 patients) for the isolated CABG group and 13.3 % (2/15) for the isolated AVR group. Patients undergoing combined valve and coronary surgery or multiple valve surgery had a higher perioperative mortality of 39.1 % (9/23) compared to the isolated CABG and isolated AVR patients. Perioperative death was also higher in patients with moderate and severe LV dysfunction, and in patients with diabetes. The duration of dialysis periods was not related to perioperative death. Mean follow-up was 26.4 +/- 29.7 months (0.1 to 104 months). Actuarial survival at 1 year and 5 years was 76 % and 55 % for isolated CABG, 59 % and 21 % for isolated AVR, and 44 % and 33 % for all other cases, respectively (log rank P = 0.001). CONCLUSION: Patients on dialysis have a high risk of perioperative mortality and poor long-term survival rates. Mortality is higher and survival is worse after combined CABG and valve-related procedures or multiple valve surgery than after isolated CABG and AVR.

Clinical outcomes of compromised side branch (stent jail) after coronary stenting with the NIR stent.

Acute side-branch (SB) compromise or occlusion stent jail after native coronary stenting is a matter of concern. Attempts at maintaining SB patency can be a technical challenge. The purpose of this study was to determine the clinical impact of SB compromise or occlusion in patients undergoing stenting of parent vessel lesions. We evaluated in-hospital and long-term clinical outcomes (death, Q-wave myocardial infarction, and repeat revascularization rates at 6 months) in 318 consecutive patients undergoing NIR stent implantation across an SB. Based on independent angiographic analysis, 218 (68.6%) patients had no poststent SB compromise, 85 (26.7%) patients had narrowed SB (> 70% narrowing, without total occlusion), and 15 (4.7%) patients had an occluded SB after stent implantation. The baseline patient and lesion characteristics were similar between the groups. Procedural success was 100%. Patients with SB occlusion had a higher stents/lesion ratio (P < 0.006). Side-branch occlusion was associated with higher in-hospital ischemic complications (Q-wave myocardial infarction, 7%; non-Q-wave myocardial infarction, 20%; P < 0.05) compared to patients with SB compromise or normal SB. At 6-month follow-up, there was a trend for more myocardial infarctions in the group with SB occlusion during the index procedure (Q-wave myocardial infarction, 7% vs. 1% in the narrowed and 0% in normal SB; P = 0.09). However, late target lesion revascularization and mortality were similar in the three groups (P = 0.91). SB occlusion after parent vessel stenting is associated with more frequent in-hospital Q-wave and non-Q-wave myocardial infarctions. However, with the NIR stent, side-branch compromise or occlusion does not influence late (6 month) major adverse events, including death, myocardial infarction, or need for repeat revascularization.

Could plasmid-mediated gene transfer into the myocardium be augmented by left ventricular guided laser myocardial injury?

Early studies have indicated no correlation between the amount of mechanical injury and the level of myocardial gene expression following direct plasmid vector injection. Recently, however, evidence suggests that combined laser myocardial injury and plasmid-based gene delivery exert synergistic effects on gene expression and activity. The purpose of the study was to determine whether laser-induced myocardial injury followed by transendocardial gene transfer increases gene expression compared to gene transfer alone. We assessed the ability of a plasmid vector to express its transgene after injection into porcine ischemic myocardium with and without preceding laser myocardial injury. Thirteen animals had transendocardial injections of the luciferase reporter gene in a plamid vector using a catheter-based injection system. Injections (0.5 mg per animal, 50 microg per injection site) were divided into 10 sites in the ischemic territory. Eight animals underwent transendocardial laser injury of the ischemic region (2 Joule per pulse x 10 sites) prior to gene delivery. In five animals, gene injection sites were dispersed between laser channels, and in three animals laser and gene delivery were applied in close proximity (< 5 mm) or at the same location. Luciferase activity was measured at 3 and 7 days. Luciferase expression in ischemic zones was markedly elevated at day 3 and 7, and similar whether animals were pretreated using laser injury followed by gene transfer compared to gene transfer alone. Neither same-spot injection nor dispersed gene delivery were associated with augmented gene expression compared to gene transfer alone. Using the above-described catheter-based approach to combine localized laser injury and injection of naked DNA into ischemic myocardium, laser injury did not augment gene expression above levels present with gene transfer alone.

Paclitaxel-coated Gianturco-Roubin II (GR II) stents reduce neointimal hyperplasia in a porcine coronary in-stent restenosis model.

BACKGROUND: Drug-coated stents may treat both mechanisms of restenosis, namely, geometric remodeling and neointimal hyperplasia. Paclitaxel, an antimicrotubule agent, has been shown to inhibit smooth muscle cell proliferation and migration, and may be an excellent candidate for local elution from a stent platform. METHODS: To study the antirestenosis effects of drug-coated stents, we impregnated paclitaxel (175-200 microg/stent with programmed elution over 6 months) on Gianturco-Roubin II (GR II) stents. These stents and control stents without drugs were implanted in porcine coronary arteries (stent/artery approx. 1.1) and evaluated 4 weeks later. RESULTS: The vessel size and the stent-to-artery ratio were similar between the groups. However, at 4 weeks, the paclitaxel group had significantly reduced in-stent restenosis compared with the controls (51 +/- 27 versus 27 +/- 27% diameter stenosis, P < 0.05 and 669 +/- 357 versus 403 +/- 197 microm neointimal thickness, P < 0.05). This study further confirmed the biocompatibility of the polymer, with no foreign body reaction in any of the groups. CONCLUSIONS: This study shows that the paclitaxel-coated stents significantly reduced in-stent restenosis without eliciting inflammation.

Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: a device-specific analysis of 7147 patients.

BACKGROUND: The relative prognostic importance of ECG myocardial infarction (MI) after intervention compared with varying degrees of enzymatic elevation has not been characterized, and the device-specific implications of periprocedural MI are also unknown. METHODS AND RESULTS: Serial creatine phosphokinase (CPK)-MB levels were determined after elective percutaneous intervention of 12 098 lesions in 7147 consecutive patients at a tertiary referral center. Procedural, in-hospital, and follow-up data were collected by independent research nurses, and clinical and ECG events were adjudicated by a separate committee. Stents were implanted in 50.6% of lesions, atheroablation was performed in 54.8%, and PTCA alone was performed in 9.8%. The peak periprocedural CPK-MB level was >3x the upper limit of normal (ULN) in 17.9% of patients, and Q-wave MI developed in 0.6%. By multivariate analysis, the periprocedural development of new Q waves was the most powerful independent determinant of death (2-year mortality rate, 38.3%; hazard ratio, 9.9; P<0.0001). Non-Q-wave MI with CPK-MB >8x ULN was also a strong predictor of death (2-year mortality rate, 16.3%; hazard ratio, 2.2; P<0.0001); survival was unaffected by lesser degrees of CPK-MB elevation. Though CPK-MB elevation was more common after atheroablation and stenting than PTCA, the rates of Q-wave MI and survival were device-independent. CONCLUSIONS: Myonecrosis after percutaneous intervention is common in a high-risk referral population dominated by atheroablation and stent use. Large periprocedural infarctions (signified by new Q waves and CPK-MB >8xULN) are powerful determinants of death, whereas lesser degrees of CPK-MB release and specific device use do not adversely affect survival.

Prognostic value of cardiac troponin I re-elevation following percutaneous coronary intervention in high-risk patients with acute coronary syndromes.

Troponin I is a predictive marker of short- and intermediate-term adverse cardiac events in patients with acute coronary syndromes (ACS). These high-risk patients may benefit from early percutaneous coronary intervention. However, whether additional myocardial injury, defined as postprocedural troponin I elevation, may be associated with adverse short- and intermediate-term outcomes has not been fully explored. Accordingly, we studied 132 consecutive patients with non-ST-elevation ACS (62% with non-Q-wave myocardial infarction) and elevated troponin I levels at admission (>0.15 ng/ml) who underwent percutaneous coronary intervention > or =48 hours after admission. Troponin I levels were routinely measured at 6 and 18 to 24 hours after intervention and patients were stratified according to the presence or absence of troponin I re-elevation, defined as postprocedural troponin I levels >1 times the admission levels. In-hospital and cumulative 6-month clinical outcomes were compared between groups. Patients with troponin I re-elevation (n = 51) were older (68 +/- 13 vs 64 +/- 12 years, p = 0.05) and had experienced prior myocardial infarction more frequently (92.5 vs 82.1, p = 0.09), but otherwise had similar baseline clinical characteristics. Patients with troponin I re-elevation had significantly higher in-hospital mortality (9.8% vs 0%, p = 0.016) and a higher 6-month cumulative death rate (24% vs 3.7%, p = 0.001). There was a trend for an increased 6-month myocardial infarction rate in patients with troponin I re-elevation (13.7% vs 3.7%, p = 0.11) and target vessel revascularization was similar between groups (16.7% vs 17.4%, p = 0.92). By multivariate analysis, troponin I re-elevation (odds ratio [OR] 6.2, p = 0.011) and diabetes mellitus (OR 5.7, p = 0.014) were the strongest independent predictors for increased 6-month cumulative mortality, whereas creatine kinase MB-fraction re-elevation had no prognostic value. We conclude that troponin I re-elevation after percutaneous coronary intervention in high-risk patients with ACS is associated with a substantial increase in mortality and reduced event-free survival at 6-month follow-up.

Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia.

OBJECTIVES: We tested the hypothesis that intramyocardial injection of autologous bone marrow (ABM) promotes collateral development in ischemic porcine myocardium. We also defined, in vitro, whether bone marrow (BM) cells secrete vascular endothelial growth factor (VEGF) and macrophage chemoattractant protein-1 (MCP-1). BACKGROUND: The natural processes leading to collateral development are extremely complex, requiring multiple growth factors interacting in concert and in sequence. Because optimal angiogenesis may, therefore, require multiple angiogenic factors, we thought that injection of BM, which contains cells that secrete numerous angiogenic factors, might provide optimal therapeutic angiogenesis. METHODS: Bone marrow was cultured four weeks in vitro. Conditioned medium was assayed for VEGF and MCP-1 and was added to cultured pig aortic endothelial cells (PAEC) to assess proliferation. Four weeks after left circumflex ameroid implantation, freshly aspirated ABM (n = 7) or heparinized saline (n = 7) was injected transendocardially into the ischemic zone (0.2 ml/injection at 12 sites). Echocardiography to assess myocardial thickening and microspheres to assess perfusion were performed at rest and during stress. RESULTS: Vascular endothelial growth factor and MCP-1 concentrations increased in a time-related manner. The conditioned medium enhanced, in a dose-related manner, PAEC proliferation. Collateral flow (ischemic/normal zone X 100) improved in ABM-treated pigs (ABM: 98 +/- 14 vs. 83 +/- 12 at rest, p = 0.001; 89 +/- 18 vs. 78 +/- 12 during adenosine, p = 0.025; controls: 92 +/- 10 vs. 89 +/- 9 at rest, p = 0.49; 78 +/- 11 vs. 77 +/- 5 during adenosine, p = 0.75). Similarly, contractility increased in ABM-treated pigs (ABM: 83 +/- 21 vs. 60 +/- 32 at rest, p = 0.04; 91 +/- 44 vs. 36 +/- 43 during pacing, p = 0.056; controls: 69 +/- 48 vs. 64 +/- 46 at rest, p = 0.74; 65 +/- 56 vs. 37 +/- 56 during pacing, p = 0.23). CONCLUSIONS: Bone marrow cells secrete angiogenic factors that induce endothelial cell proliferation and, when injected transendocardially, augment collateral perfusion and myocardial function in ischemic myocardium.

Low-power helium: neon laser irradiation enhances production of vascular endothelial growth factor and promotes growth of endothelial cells in vitro.

BACKGROUND AND OBJECTIVE: Numerous reports suggest that low-power laser irradiation (LPLI) is capable of affecting cellular processes in the absence of significant thermal effect. The objective of the present study was to determine the effect of LPLI on secretion of vascular endothelial growth factor (VEGF) and proliferation of human endothelial cells (EC) in vitro. STUDY DESIGN/MATERIALS AND METHODS: Cell cultures were irradiated with single different doses of LPLI (Laser irradiance from 0.10 to 6.3 J/cm(2)) by using a He:Ne continuous wave laser (632 nm). VEGF secretion by smooth muscle cells (SMC) and fibroblasts was quantified by sandwich enzyme immunoassay technique. The endothelial cell proliferation was measured by Alamar Blue assay. VEGF and transforming growth factor beta (TGF-beta) expression by cardiomyocytes was studied by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: We observed that (1) LPLI of vascular and cardiac cells results in a statistically significant increase of VEGF secretion in culture (1.6-fold for SMC and fibroblasts and 7-fold for cardiomyocytes) and is dose dependent (maximal effect was observed with LPLI irradiance of 0.5 J/cm(2) for SMC, 2.1 J/cm(2) for fibroblasts and 1.05 J/cm(2) for cardiomyocytes). (2) Significant stimulation of endothelial cell growth was obtained with LPLI-treated conditioned medium of SMC (maximal increase was observed with LPLI conditioned medium with irradiance of 1.05 J/cm(2) for SMC and 2.1 J/cm(2) for fibroblasts. CONCLUSIONS: Our studies demonstrate that low-power laser irradiation increases production of VEGF by SMC, fibroblasts, and cardiac myocytes and stimulates EC growth in culture. These data may have significant importance leading to the establishment of new methods for endoluminal postangioplasty vascular repair and myocardial photoangiogenesis.