Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover. METHODS: Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables. RESULTS: Sixty-two patients were included (mean age: 57.5 ± 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P2Y12 assay (Spearman's correlation coefficient: 0.55 for P2Y12 reaction units, -0.49 for percent inhibition) and MEA (Spearman's: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P2Y12 assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI. CONCLUSIONS: The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment.

Retroperitoneal bleeding after cardiac catheterization: a 7-year descriptive single-center experience.

BACKGROUND: Retroperitoneal bleeding (RPB) is an unusual but potentially fatal vascular complication occurring after cardiac catheterization (CC). Contemporary data of RPB in the era of dual antiplatelet therapy and vascular closure devices are lacking. METHODS: We retrospectively examined all RPB cases that occurred after CC in the Rabin Medical Center between the years 2005 and 2011. RESULTS: Of 26,487 patients who underwent CC, a total of 48 patients (mean age 60.9 ± 13.8 years, 52.1% female) with RPB were identified (0.18%). The indication for CC was acute coronary syndrome (43.7%), myocardial infarction (35.4%), stable angina pectoris (8.3%), hemodynamic studies for valvular heart disease (10.4%) and others (2.1%). Coronary intervention was performed in 34 patients (70.9%) and a vascular closure device (VCD) was used in 16 patients (33.3%). Seventy-seven percent of patients were treated with clopidogrel, 20.8% with glycoprotein IIb-IIIa inhibitors and 85.4% with anticoagulation during CC. Median time to diagnosis of bleeding was 9.0 h, while the median time to bleeding differed between patients with and without a VCD (12 vs. 5 h, respectively). The clinical presentation of RPB was hemorrhagic shock in 39.6% of patients and 50.0% required at least one blood transfusion. Patients were managed either with conservative treatment (79.2%), angiography stenting (14.6%) or vascular surgery (6.2%). A total of 3 patients died during hospitalization, of which RPB was the etiology in 2 (4.2%). CONCLUSIONS: RPB which is a rare complication of CC is associated with younger age and female gender, as compared to patients without RPB. Onset of bleeding can be delayed in patients with VCDs. With careful and early diagnosis, most patients with RPB after CC can be managed conservatively.

Feasibility of myocardial perfusion imaging with half the radiation dose in obese patients using ordered-subset expectation maximization with resolution recovery software.

BACKGROUND: We previously described the feasibility of myocardial perfusion imaging (MPI) with nearly half the radiation dose using ordered-subset expectation maximization with resolution recovery (OSEM-RR) processing. This study sought to determine if the findings can be expanded to obese patients. METHODS: Fifty obese patients (>100 kg) referred for MPI underwent stress-rest or rest-stress studies with a half dose of Tc-99m sestamibi in a 1-day protocol using OSEM-RR processing. Image quality and clinical results were compared with matched patients (by age, sex, weight, presence/probability of coronary artery disease) evaluated with standard "full-dose" Tc-99m sestamibi, mostly in a 2-day protocol. Dose activities were adjusted individually by weight. RESULTS: Mean Tc-99m activity was 33.4 ± 13.9 mCi in the half-dose group and 60 ± 10 mCi in the full-dose group (P < .0001). Respective mean effective doses per study were 10 ± 4 and 18 ± 3 mSv (P < .0001). Overall image quality was good-to-excellent in 94% of the half-dose group and 80% of the full-dose group (P < .045). There was no between-group difference in rate or size of ischemia or infarction, except for stress left ventricular ejection fraction. CONCLUSIONS: MPI with half the radiation dose is feasible in obese patients. Image quality is better than for full-dose MPI, and the procedure can be performed in 1 day.

[Transcatheter aortic-valve implantation].

Aortic valve stenosis is associated with severe morbidity and death within several years of symptom onset, and its accepted treatment is surgical aortic valve replacement. However, many affected patients are not referred for surgery because of old age and significant comorbidities. In recent years, an alternative treatment approach has been developed, transcatheter aortic-valve implantation. In this review we would like to describe this treatment modality and to present several cases performed in our center.

Feasibility of myocardial perfusion imaging with half the radiation dose using ordered-subset expectation maximization with resolution recovery software.

OBJECTIVE: This study sought to assess the feasibility of performing myocardial perfusion imaging (MPI) with half the technetium activity using ordered-subset expectation maximization with resolution recovery (OSEM-RR), an iterative reconstruction software developed to improve count statistics and acquisition time. METHODS: Two hundred eighteen patients referred for MPI were randomly allocated to undergo stress-rest or rest-stress protocols with standard full-dose (FD) injections of technetium (Tc)-99m sestamibi or half-dose (HD) injections and OSEM-RR processing. Dose activities were adjusted individually by weight. The groups were compared for image quality and clinical results. RESULTS: The groups were similar for mean patient age, weight, and body mass index, sex distribution, pre-test probability of CAD and CAD prevalence. Mean Tc-99m activities for the low-dose and high-dose stages were as follows: FD group: 429 ± 85 MBq and 1132 ± 200 MBq; HD group: 263 ± 129 MBq and 629 ± 85 MBq (P < .0001 for both). Mean effective dose per study was 13.6 ± 1.4 mSv in the FD group and 7.7 ± 1.0 mSv in the HD group (P < .001). Over all image quality was good-to-excellent in 98% and 95% of the groups, respectively. However, when we analyzed the low-dose stage separately, image quality was slightly worse in the HD than the FD, though still within the good-to excellent range. CONCLUSIONS: MPI with nearly half the radiation dose is feasible with good image quality.

A comparative analysis of major clinical outcomes with drug-eluting stents versus bare metal stents in male versus female patients.

AIMS: To conduct a risk-adjusted gender-based analysis of clinical outcomes following drug-eluting stent (DES) versus bare metal stent (BMS) implantation in patients with coronary artery disease. METHODS AND RESULTS: We compared risk-adjusted total mortality rate, myocardial infarction, and event-free survival (defined as freedom from death, myocardial infarction and/or repeat revascularisation) in a consecutive cohort of 7,662 patients undergoing percutaneous coronary intervention at our institution, including 1,835 (25.4%) women. Follow-up was six months to 6.2 years (mean: 3.5 years; median: 3.6 years). The women were older than men and more likely to suffer from diabetes, hypertension or congestive heart failure. Smokers were more often men, and men were more likely to have had prior coronary bypass surgery compared to women. A DES was used in 39.9% of males and 39.5% of females. Both genders derived a significant long-term clinical benefit from DES compared to BMS; advantages were observed for mortality (men: HR=0.78, 95% CI: 0.64-0.96, p=0.016; women: HR=0.62, 95% CI: 0.45-0.85, p=0.003) and major adverse cardiac events (men: HR=0.73, 95% CI: 0.63-0.84, p<0.001; women: HR=0.76, 95% CI: 0.52-0.84, p=0.001). Among BMS-treated patients, women had worse cumulative clinical outcomes than men. DES eliminated the gender differences in cardiac prognosis. CONCLUSIONS: Our analysis indicated a profound prognostic advantage for DES versus BMS among both genders, though female patients appeared to derive the greatest benefit.

Endothelial cell surface vimentin binding peptide induces angiogenesis under hypoxic/ischemic conditions.

We have previously identified several angiogenic peptides that bind cell surface proteins by screening a phage display peptide library on human umbilical endothelial cells exposed to hypoxic conditions. In this study we describe one of the selected peptides, SP. We found by protein precipitation of endothelial cell lysates that the 12 amino acid SP peptide binds cell surface vimentin. Surprisingly, vimentin was detected on the cell surface of about 30% of intact endothelial cells under both normoxic and hypoxic conditions, as was demonstrated by fluorocytometric analysis on viable cells. The assessment of SP in the induction of angiogenesis was established by a significant increase in endothelial cell proliferation and tube formation under hypoxic conditions and not under normoxic conditions. Cell proliferation and tube length increased two-fold in endothelial cells in the presence of 10 ng/ml SP peptide when compared to controls. The specificity of SP binding to vimentin was demonstrated by SP inhibition of anti-vimentin binding and by the inhibition of tube formation in cells transfected with siRNA against vimentin. Local intramuscular administrations of the peptide SP to ischemic hind limbs using the mouse hind limb ischemia model, demonstrated that SP inoculated at 1 and 10 µg, improved blood perfusion compared to inoculations with an irrelevant peptide or PBS. The recovery of blood perfusion correlated with the increase in the number of detectable capillaries in the ischemic limb. The development of novel peptides for the induction of pro-angiogenic activity may pave the way for new therapeutic strategies in the treatment of cardiovascular ischemic diseases.

Circulating endothelial progenitor cells in patients with dysfunctional versus normally functioning congenitally bicuspid aortic valves.

Patients with bicuspid aortic valve (BAV) may gradually develop significant valve dysfunction, whereas others remain free of dysfunction. Factors that determine the prognosis of BAV remain unclear. Because endothelial progenitor cells (EPCs) have a role in the repair of endothelial surfaces after injury, we hypothesized that EPCs may also be involved in preventing BAV degeneration. Accordingly, we compared EPC level and function in patients with BAV with versus without valve dysfunction. The study group included 22 patients with BAV and significant valve dysfunction (at least moderate aortic regurgitation and/or at least moderate aortic stenosis). The control group included 28 patients with BAV without valve dysfunction. All patients had 1 blood sample taken. Proportion of peripheral mononuclear cells expressing vascular endothelial growth factor receptor 2, CD133 and CD34 was evaluated by flow cytometry. EPC colony-forming units (CFUs) were grown from peripheral mononuclear cells, characterized, and counted after 7 days of culture. The 2 groups had similar clinical characteristics except for higher prevalence of hypertension in the dysfunctional valve group. Number of EPC CFUs was smaller in the dysfunctional valve group (32 CFUs/plate, 15 to 42.5, vs 48 CFUs/plate, 30 to 62.5, respectively, p = 0.01), and the migratory capacity of the cells in this group was decreased. In addition, the proportion of cells coexpressing vascular endothelial growth factor receptor 2, CD133, and CD34 tended to be smaller in the dysfunctional valve group. In conclusion, patients with BAV and significant valve dysfunction appear to have circulating EPCs with impaired functional properties. These findings require validation by further studies.

Treatment of aspirin-resistant patients with omega-3 fatty acids versus aspirin dose escalation.

OBJECTIVES: The aim of this study was to evaluate whether addition of omega-3 fatty acids or increase in aspirin dose improves response to low-dose aspirin among patients who are aspirin resistant. BACKGROUND: Low response to aspirin has been associated with adverse cardiovascular events. However, there is no established therapeutic approach to overcome aspirin resistance. Omega-3 fatty acids decrease the availability of platelet arachidonic acid (AA) and indirectly thromboxane A2 formation. METHODS: Patients (n = 485) with stable coronary artery disease taking low-dose aspirin (75 to 162 mg) for at least 1 week were screened for aspirin response with the VerifyNow Aspirin assay (Accumetrics, San Diego, California). Further testing was performed by platelet aggregation. Aspirin resistance was defined by > or =2 of 3 criteria: VerifyNow score > or =550, 0.5-mg/ml AA-induced aggregation > or =20%, and 10-micromol/l adenosine diphosphate (ADP)-induced aggregation > or =70%. Thirty patients (6.2%) were found to be aspirin resistant and randomized to receive either low-dose aspirin + omega-3 fatty acids (4 capsules daily) or aspirin 325 mg daily. After 30 days of treatment patients were re-tested. RESULTS: Both groups (n = 15 each) had similar clinical characteristics. After treatment significant reductions in AA- and ADP-induced aggregation and the VerifyNow score were observed in both groups. Plasma levels of thromboxane B2 were also reduced in both groups (56.8% reduction in the omega-3 fatty acids group, and 39.6% decrease in the aspirin group). Twelve patients (80%) who received omega-3 fatty acids and 11 patients (73%) who received aspirin 325 mg were no longer aspirin resistant after treatment. CONCLUSIONS: Treatment of aspirin-resistant patients by adding omega-3 fatty acids or increasing the aspirin dose seems to improve response to aspirin and effectively reduces platelet reactivity.

Activation of GRP78 on endothelial cell membranes by an ADAM15-derived peptide induces angiogenesis.

Impaired angiogenesis is one of the features of ischemic diseases. We have previously identified, by screening a phage display peptide library, a peptide that induces angiogenesis in endothelial cells under hypoxic conditions by binding the cell's membrane heat shock protein GRP78. Protein data base search identified 4 amino acids (HWRR) of that synthetic peptide present on the ADAM15 metalloprotease domain, a protein considered to be involved in neovascularization. Three peptides were synthesized according to the ADAM15 sequence placing HWRR at different positions. Peptide ADoPep1 exhibited significant angiogenic properties under hypoxic conditions as determined by cell proliferation, migration and tube formation. In a mouse hind limb ischemia model, a single injection of the peptide restored blood perfusion. The identified peptide was found to activate GRP78 on endothelial cell membrane and siRNA directed against the GRP78 mRNA interfered with induction of angiogenesis by the peptide. The peptide binding induced a decrease in heat shock protein GRP78 that is overexpressed under hypoxic conditions. The mechanism of peptide-induced angiogenic activity involves inhibition of apoptosis as well as increased Akt phosphorylation and ERK 1/2 activation. The peptide did not induce VEGF receptor-2 protein synthesis and phosphorylation, suggesting a VEGF-independent mechanism of angiogenesis.

Hematocrit level as a marker of outcome in ST-segment elevation myocardial infarction.

Anemia is a well-known predictor of a poor outcome in patients with ST-segment elevation myocardial infarction (STEMI). In contrast, data relating erythrocytosis to clinical outcomes in patients with STEMI are limited. Because erythrocytosis predisposes to a prothrombotic state, we hypothesized it would be associated with an increased risk of thrombotic complications in patients with STEMI undergoing primary percutaneous coronary intervention. We studied 1,042 consecutive patients with STEMI who underwent primary percutaneous coronary intervention and were a part of our primary percutaneous coronary intervention registry from 2001 to 2007. Patients with cardiogenic shock and late arrival were excluded. Patients were allocated into 3 groups according to their baseline hematocrit: anemia (<36% for women and <39% for men), normal, erythrocytosis (>46% for women and >47% for men). The clinical outcomes were assessed at 1, 6, and 12 months. The patients with anemia had the greatest clinical risk profile. Patients with erythrocytosis had a lower risk profile than the other 2 groups, except for greater rates of smoking. The mortality rates were greatest among the patients with anemia, followed by the patients with erythrocytosis, who in turn had greater short-term mortality than patients with normal hematocrit. Multivariate analysis, which included patients with erythrocytosis and those with normal hematocrit (excluding the patients with anemia), revealed that erythrocytosis was associated with an odds ratio of 4.3 (95% confidence interval 1.4 to 13, p = 0.01) for 1-month mortality. In conclusion, although not as strong a predictor of mortality as anemia, erythrocytosis might be associated with increased short-term mortality compared to a normal hematocrit. The measurement of hematocrit can be used as a useful prognostic marker in patients with STEMI.

Myocardial perfusion profile in a young population with and without known coronary artery disease: comparison by gender.

BACKGROUND: More and more young people are being referred for evaluation or screening for coronary artery disease (CAD). However, the value of myocardial perfusion imaging (MPI) in this population is unclear, especially in the absence of symptoms. METHODS: The study sample included 1765 consecutive patients less than 51 years old who were referred to a major medical center for stress/rest MPI study. Clinical and MPI variables were compared between patients with and without known CAD, by gender. RESULTS: There were 1346 (76%) men and 419 (24%) women of mean age 44 +/- 6 years; 461 (26%) had known CAD. Stress-induced ischemia was detected in 321 patients (18.2%) and significant ischemia in 131 (7.4%); there was no difference in the rate or severity of ischemia by presence of symptoms. Among those without known CAD, the rate of stress-induced ischemia by MPI was significantly lower in women than men. On logistic regression analysis, the independent predictors of ischemia in men were high cholesterol, diabetes, angina during stress testing, ST depression, and smoking (P<.0001); and in women, the independent predictors were diabetes and high cholesterol. CONCLUSION: Known CAD and stress-induced ischemia are significantly more prevalent in young men than in young women, irrespective of risk factors. The independent predictors of ischemia differ between men and women.

Individualized immune monitoring of cardiac transplant recipients by noninvasive longitudinal cellular immunity tests.

BACKGROUND: Common immunosuppression strategies after heart transplantation (HTx) are based on accepted target drug levels, disregarding that drug levels do not correlate with the individual patient's pharmacokinetics or with the actual immunosuppressive drug effect on the patient. The Immuknow assay is used for immune monitoring and management of organ transplant recipients. This study evaluated the Immuknow assay for longitudinal immune monitoring of HTx patients throughout various clinical settings. METHODS: The functional immune response as measured by the Immuknow assay was determined in 327 samples collected from 50 HTx patients at the Rabin Medical Center and was analyzed together with common clinical parameters. RESULTS: The median Immuknow levels measured throughout the infection episodes and the episodes of biopsy-proven acute rejection were 129 and 619 ng ATP/mL, respectively. These values were significantly dissimilar to the median Immuknow level measured during clinical quiescence, which was 351 ng ATP/mL (P<0.05). Calcineurin inhibitors drug-level measurements did not provide a reliable depiction of the patients' immune function, because the median deviation from the recommended drug trough levels range was significantly higher than the median deviation of Immuknow levels from their expected immune response zones. Longitudinal monitoring of Immuknow levels through serial testing proved to be a reliable method for individual patient immune management. CONCLUSIONS: The Immuknow assay reliably reflects the cellular immune function of HTx patients, thereby supporting the immune monitoring and management of these patients. Serial longitudinal Immuknow monitoring allows immune management of therapy according to the individual patient's immune status.

The effect of cardiac angiography timing, contrast media dose, and preoperative renal function on acute renal failure after coronary artery bypass grafting.

OBJECTIVE: Our objective was to assess the effect of the timing of cardiac angiography, contrast media dose, and preoperative renal function on the prevalence of acute renal failure after cardiac surgery. METHODS: Data on 395 consecutive patients who underwent coronary artery bypass grafting were prospectively collected. Creatinine clearance was estimated by the Cockcroft-Gault equation. Patients were divided into 3 groups according to the time between cardiac angiography and surgery (group A, < or = 1 day; group B, > 1 day and < or = 5 days; group C, > 5 days). Patients who underwent a salvage operation or were receiving dialysis before surgery were excluded. Acute renal failure was defined as 25% decrease from baseline of estimated creatinine clearance and estimated creatinine clearance of 60 mL/min or less on postoperative day 3. Owing to differences in preoperative characteristics between groups, propensity score analysis was used to adjust those differences. RESULTS: Acute renal failure developed in 13.6% of patients. Hospital mortality was 3.3% and was higher in patients in whom acute renal failure developed (22%) versus those in whom it did not (0.3%; P < .001). Multivariable analysis identified preoperative estimated creatinine clearance of 60 mL/min or less (odds ratio [OR], 7.1), operation within 24 hours of catheterization (OR = 3.7), use of more than 1.4 mL/kg of contrast media (OR = 3.4), lower hemoglobin level (OR = 1.3), older age (OR = 1.1), and lower weight (OR = 0.95) as independent predictors of postoperative acute renal failure. Analysis of interaction between contrast dose and time of surgery revealed that high contrast dose (>1.4 mL/kg) predicted acute renal failure if surgery was performed up to 5 days after angiography. CONCLUSIONS: Whenever possible, coronary bypass grafting should be delayed for at least 5 days in patients who received a high contrast dose, especially if they also have preoperative reduced renal function.

Percutaneous aortic valve implantation: early clinical experience and future perspectives.

The incidence of aortic valve stenosis is growing rapidly in the elderly. Nonetheless, many symptomatic patients are not referred for surgery usually because of high surgical risk. Unfortunately, percutaneous balloon valvuloplasty is unsatisfactory due to high recurrence rates. In 2002, Cribier and colleagues were the first to describe percutaneous aortic valve implantation in a patient, opening a new era of aortic stenosis management. In the present review we report a patient treated by this novel method, discuss and assess how it is implanated, report the findings of studies conducted to date, and suggest future directions for percutaneous treatment of aortic valve disease.

The risk of cardiac complications following noncardiac surgery in patients with drug eluting stents implanted at least six months before surgery.

AIMS: Given the anecdotal reports and case series suggesting that drug-eluting coronary stents [DES] may be still vulnerable to coronary thrombosis after six months, we sought to assess this risk in patients undergoing non-cardiac surgery six months after stenting. METHODS AND RESULTS: Linking the Rabin Medical Centre interventional cardiology database with its non-cardiac surgical database, we identified 78 patients who underwent DES placement and subsequently [after six months] had noncardiac surgery [15-vascular, 37- abdominal and genitourinary and 26-others, excluding ophthalmic surgery]. Outcome measures included 30-day rate of postoperative myocardial infarction (MI), DES-related thrombosis, and cardiac mortality. Major adverse cardiac events [death and non-fatal MI] occurred in 6 (7.7%) patients including 2 cardiac deaths (2.6%), 4 (5.1%) non-fatal myocardial infarctions (MIs). Two patients (2.6%) sustained stent thrombosis [one patient had 'definite' and one 'probable' stent thrombosis]. All MIs [including stent thrombosis] occurred in the vascular and abdominal surgery group. Two of the MIs events occurred while the patients were on dual antiplatelet agents. IN CONCLUSIONS: Perioperative cardiac events during non cardiac surgery after six months of DES deployment still occur. These cardiac complications [not entirely prevented by continued dual antiplatelet agents] remain a matter of diagnostic and therapeutic challenge and concern.

Platelet reactivity in patients with a history of obstructive prosthetic valve thrombosis.

One of the most serious complications of mechanical valves is obstructive prosthetic valve thrombosis (OPVT or "stuck valve"). Some patients develop OPVT despite an international normalized ratio (INR) in the therapeutic recommended range. We hypothesized that patients who develop OPVT have hyper-reactive platelets. We, therefore, examined platelet reactivity in patients who developed OPVT, despite a therapeutic or near-therapeutic INR, compared with a matched control group. We compared platelet reactivity between patients who had had an OPVT episode, despite a therapeutic or near-therapeutic INR (n = 18), and a matched group of patients with mechanical valves who did not develop this complication (n = 18) from 1996 to 2007. Platelet reactivity was evaluated by platelet aggregation in response to various agonists, platelet deposition under flow conditions in the Impact-R system, and plasma levels of platelet activation markers (soluble CD40 ligand and P-selectin). In the OPVT group, the average INR during the index episode was 3.1 +/- 1.5, and 44.6 +/- 40 months had elapsed from the index episode to the present study. Both groups were matched for gender, age +/-10 years, valve position and type, active smoking, and diabetes. Patients with an OPVT history had a greater aggregation in response to collagen (p = 0.05), greater platelet deposition in the Impact-R system (p = 0.01), and tended to have higher levels of soluble P-selection and soluble CD40 ligand (p = 0.07) than their control counterparts. In conclusion, patients with a history of OPVT appear to have increased platelet reactivity, which might contribute to an increased risk of thrombotic complications. These patients would, therefore, likely benefit from the addition of antiplatelet therapy to their standard anticoagulant treatment.

Acute coronary syndromes in patients with prosthetic heart valves-a case-series.

BACKGROUND: There are few reports regarding acute coronary syndromes (ACS) in patients with prosthetic heart valves (PHV), mostly attributing the ACS to a PHV-derived coronary embolus. OBJECTIVE: To characterize a case-series of ACS patients with PHV. METHODS: All patients in our institution with previous PHV surgery and ACS during 1996-2005 were retrospectively analysed. RESULTS: We identified 40 patients from the 15,878 patient database, whose mean age was 72.5 +/- 12.5 years and of whom 21 were male. The majority (n=28) had mechanical valves; 24 patients (60%) had an aortic prosthetic valve, 9 patients (22.5%) had a mitral valve prosthesis and 7 patients (17.5%) had both. The majority of patients had > or = 2 risk factors for atherosclerotic disease. The median time from the PHV implantation to the subsequent ACS was 8.0 (4.7-12.1) years. Most patients had non-ST-segment elevation ACS rather than ST-segment elevation ACS (32 patients versus 8 patients). 12 patients (30%) had moderate to severe left ventricular dysfunction and 2 of them presented with cardiogenic shock. Atrial fibrillation on hospital admission was noted in 13 patients (32.5%). ACS management included coronary angiography in 32 patients (80%) which revealed coronary disease in 93%. Only 2 patients had normal coronary arteries and PHV-derived coronary emboli. The most frequent in-hospital complication was heart failure (n=11, 27.5%). CONCLUSIONS: Patients with PHV and ACS are a rare subgroup, more likely to be elderly with risk factors for atherosclerotic disease and to present with non-ST-segment-elevation ACS. The pathogenesis for ACS is commonly coronary atherosclerotic disease rather than PHV-derived emboli.

Therapeutic angiogenesis of mouse hind limb ischemia by novel peptide activating GRP78 receptor on endothelial cells.

Therapeutic angiogenesis emerged as a non-invasive mean of promoting neovascularization in ischemic tissues. We have searched for new molecules that induce angiogenesis by screening a phage display combinatory peptide library on endothelial cells. One of the selected peptides identified by binding to endothelial cells under hypoxic conditions was further studied. The aim of this study was to assess the therapeutic value of this peptide, RoY, in a mouse hind limb ischemia model and to identify it's receptor on endothelial cells. RoY, a 12 amino-acid synthetic peptide, induced in vitro angiogeneic activity under hypoxic conditions by increasing endothelial cell proliferation, migration and tube formation. In order to assess its therapeutic properties in ischemic tissues, a hind limb ischemia model was induced in C57BL mice by a femoral artery excision. A single local intramuscular injection of RoY peptide to the operated limb, significantly restored blood perfusion and alleviated hind limb ischemia as determined by a laser Doppler imager. Increased capillary density in histological sections corroborated these findings. Protein precipitation and mass spectroscopy studies identified GRP78, a heat shock protein, as the peptide-binding membrane receptor that was increased on endothelial cell membranes under hypoxic conditions. This study demonstrates the efficacy of RoY peptide in alleviation of hind limb ischemia. In addition, it provides evidence that GRP78 is an angiogenic receptor on hypoxic endothelial cells.

Inflammatory biomarkers are not predictive of intermediate-term risk of ventricular tachyarrhythmias in stable CHF patients.

BACKGROUND: Elevated levels of inflammatory biomarkers and brain natriuretic peptide (BNP) are associated with increased mortality in patients with heart failure (HF). HYPOTHESIS: : The aim of the current study was to assess the correlation between circulating biomarkers and ventricular tachyarrhythmias among patients with HF. METHODS: Blood samples from 50 stable ambulatory HF patients with moderate to severe systolic left ventricular (LV) dysfunction and an implantable cardioverter defibrillator (ICD) were analyzed for interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), high-sensitivity C-reactive protein (hsCRP) and BNP. Thereafter, the patients were followed for a mean period of 152 +/- 44 days, during which ventricular tachyarrhythmias were recorded by the ICDs. RESULTS: Follow-up data were obtained from 47 patients. Of them, 45 (96%) had ischemic cardiomyopathy, 38 (81%) had New York Heart Association class I-II, 43 (91%) were males, and the mean age was 68.6 +/- 11.1 years. During follow-up, 5 patients (11%) had nonsustained ventricular tachycardia (NSVT), 6 patients (13%) had sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and 36 patients (76%) had no events. The circulating biomarkers' levels upon enrollment were not significantly different between patients who subsequently had NSVT or VT/VF and patients who were free of events. CONCLUSIONS: No correlation was found between plasma levels of IL-6, TNF-alpha, hsCRP and BNP and ventricular arrhythmic events among stable HF patients during an intermediate term follow-up of 5.1 months. Further studies are still required to assess the association between these biomarkers and long-term risk of ventricular tachyarrhythmia.