C-reactive protein induces expression of matrix metalloproteinase-9: a possible link between inflammation and plaque rupture.

BACKGROUND: Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of acute coronary syndromes (ACS). However, little is known about the mechanisms responsible for MMP expression in ACS. C-reactive protein (CRP) not only is an independent risk factor for cardiovascular events, but also may exert direct pro-atherosclerotic effects. Therefore, we aimed at determining whether CRP might induce MMP-9 in two different experimental conditions: 1) smooth muscle cells (SMCs) in vitro, and 2) patients with ACS. METHODS AND RESULTS: Effects of increasing concentrations of CRP on MMP-9 expression were evaluated in vitro in human SMCs. TIMP-1 protein expression, the selective inhibitor of MMP-9, was also evaluated. CRP dose-dependently induced MMP-9 expression in SMCs by promoting MMP-mRNA transcription, as well as MMP-9 secretion. In contrast, no differences were found for TIMP-1 protein expression. In vivo, MMP-9 and CRP levels were measured in blood samples obtained from the aorta (Ao) and the coronary sinus (Cs) of patients with normal coronary arteries (controls, n=21), stable angina (n=24), and ACS (n=30). Both MMP-9 and CRP plasma levels were significantly increased across the coronary circulation only in patients with ACS. Interestingly, a significant correlation between MMP-9 and CRP plasma levels was found. CONCLUSIONS: CRP induced MMP-9 expression and activity in human SMCs in culture; patients presenting with ACS have increased transcoronary plasma levels of MMP-9 and CRP with a significant correlation between these two markers. This may explain the heightened risk of coronary events in subjects with elevated levels of CRP.

The adipokine visfatin induces tissue factor expression in human coronary artery endothelial cells: another piece in the adipokines puzzle.

INTRODUCTION: Adipocytes are nowadays recognized as cells able to produce and secrete a large variety of active substances with direct effects on vascular cells, known as adipokines. Visfatin is a recently identified adipokine not yet completely characterized for its pathophysiological role in cardiovascular disease. Increased levels of visfatin are measurable in the plasma of patients with coronary artery disease and specifically in those with acute coronary syndromes (ACS). Several studies have indicated that Tissue Factor (TF) plays a pivotal role in the pathophysiology of ACS by triggering the formation of intracoronary thrombi following endothelial injury. This study investigates the effects of visfatin on TF in human coronary endothelial cells (HCAECs). METHODS: HCAECs were stimulated with visfatin in a concentration range usually measurable in plasma of patients with ACS and than processed to evaluate TF-mRNA levels as well as TF expression/activity. Finally, the role of NF-κB pathway was investigated. RESULTS: We demonstrate that visfatin induces transcription of mRNA for TF by Real Time PCR. In addition, we show that this adipokine promotes surface expression of TF that is functionally active since we measured increased procoagulant activity. Visfatin effects on TF appear modulated by the activation of the transcription factor, NF-κB, since NF-κB inhibitors suppressed TF expression. Finally, we show that the nicotinamide phopsphoribosyltransferase enzymatic activity of visfatin seems to play a pivotal role in modulating the NF-κB driven regulation of TF. DISCUSSION: Data of the present study, although in vitro, indicate that visfatin, at doses measurable in ACS patient plasma, induces a procoagulant phenotype in human coronary endothelial cells by promoting TF expression. These observations support the hypothesis that this adipokine might play a relevant role as an active partaker in athero-thrombotic disease.

Regional and global ventricular systolic function in isolated ventricular non-compaction: pathophysiological insights from magnetic resonance imaging.

BACKGROUND: Isolated ventricular non-compaction (IVNC) is frequently, but not invariably, associated with left ventricular (LV) systolic dysfunction. Factors impacting on regional and global LV function are unknown. The aim of the study was to apply magnetic resonance imaging (MRI) to evaluate the impact of extent and severity of ventricular non-compaction on LV systolic function in patients with IVNC. METHODS: Sixteen adult patients with IVNC as defined by previously validated MRI criteria [ratio between end-diastolic thickness of non-compacted and compacted myocardium (NC/C ratio)> 2.3 in ≥ 1 LV segment] were enrolled. Short-axis cine images were employed for analysis. Applying a 16-segment LV model, regional systolic performance was assessed qualitatively (wall motion score, WMS; 1 = normal, 2 = mild hypokinesia, 3 = moderate-to-severe hypokinesia, and 4 = a/dyskinesia) as well as quantitatively [fractional wall thickening, FWT (%)=100 × (end-diastolic wall thickness-end-systolic wall thickness)/end-diastolic wall thickness)]. RESULTS: Mean LV ejection fraction was 43.8 ± 15.4% (range, 17-68%). Regional disease severity, as expressed by the NC/C ratio, revealed a significant correlation with WMS (r=0.26; p=0.018) and FWT (r=-0.30; p=0.006). The total number of non-compacted segments/patient (NoNC) as an index of disease extent was a significant independent correlate of LV ejection fraction by multivariate regression analysis (ß=-5.24; p=0.038) and an excellent predictor of global LV dysfunction (ROC analysis, AUC=0.98; p<0.0001). CONCLUSIONS: In patients with IVNC, disease severity correlates with the degree of LV dysfunction at a regional level. The extent of myocardial non-compaction is an independent predictor of global LV dysfunction.

Acquired left coronary artery fistula draining to the cardiac vein system after acute myocardial infarction revealed by CT scan.

Coronary artery fistula (CAF) is a congenital condition characterized by a pathological communication between a coronary artery and a systemic vein or one of the cardiac chambers. Iatrogenic CAFs were reported to develop secondary to the rupture of coronary aneurysm. Instances of acquired CAF draining into the cardiac chambers have been described after acute myocardial infarction. Angiography is the gold standard in diagnosing CAF. We describe the case of a patient who developed a fistula draining into the middle cardiac vein on the posterior interventricular sulcus, after acute myocardial infarction, revealed by CT scan.

EGFR trans-activation by urotensin II receptor is mediated by ß-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy.

Urotensin II (UTII) and its seven trans-membrane receptor (UTR) are up-regulated in the heart under pathological conditions. Previous in vitro studies have shown that UTII trans-activates the epidermal growth factor receptor (EGFR), however, the role of such novel signalling pathway stimulated by UTII is currently unknown. In this study, we hypothesized that EGFR trans-activation by UTII might exert a protective effect in the overloaded heart. To test this hypothesis, we induced cardiac hypertrophy by transverse aortic constriction (TAC) in wild-type mice, and tested the effects of the UTII antagonist Urantide (UR) on cardiac function, structure, and EGFR trans-activation. After 7 days of pressure overload, UR treatment induced a rapid and significant impairment of cardiac function compared to vehicle. In UR-treated TAC mice, cardiac dysfunction was associated with reduced phosphorylation levels of the EGFR and extracellular-regulated kinase (ERK), increased apoptotic cell death and fibrosis. In vitro UTR stimulation induced membrane translocation of ß-arrestin 1/2, EGFR phosphorylation/internalization, and ERK activation in HEK293 cells. Furthermore, UTII administration lowered apoptotic cell death induced by serum deprivation, as shown by reduced TUNEL/Annexin V staining and caspase 3 activation. Interestingly, UTII-mediated EGFR trans-activation could be prevented by UR treatment or knockdown of ß-arrestin 1/2. Our data show, for the first time in vivo, a new UTR signalling pathway which is mediated by EGFR trans-activation, dependent by ß-arrestin 1/2, promoting cell survival and cardioprotection.

Effects of exercise training on high-mobility group box-1 levels after acute myocardial infarction.

BACKGROUND: High-mobility group box-1 (HMGB1) is a novel predictor of adverse postinfarction clinical outcomes, playing a crucial role in the appropriate postinfarction healing process. METHODS AND RESULTS: Seventy-five postinfarction patients were enrolled in a single-center randomized study (clinicaltrial.gov identifier: NCT00755131). Group T patients (training, n = 37) underwent 6-month exercise-based cardiac rehabilitation (CR) program, whereas group C patients (controls, n = 38) were discharged with generic instructions for maintaining physical activity and a correct lifestyle. After 6 months, HMGB1 levels were significantly reduced in the total population (26.1 ± 23.5 vs. 16.2 ± 12.9 ng/mL; P = .0006). After adjusting for several confounders, linear regression analysis showed that the inclusion in the training group (ß = -10.54, P = .043) was associated with marked reduction of HMGB1 levels. After 6 months, HMGB1 levels were significantly lower in trained patients compared to controls (11.7 ± 7.0 vs. 20.5 ± 15.6 ng/mL, P = .0027, respectively). In trained patients, decreased HMGB1 levels were significantly associated with the improvement in peak oxygen consumption (ß = -3.879, P = .003) and heart rate recovery (ß = -2.492, P = .002), and with reduced left ventricular end-diastolic volume (ß = 1.412, P = .001) and wall motion score index (ß = 1.138, P = .002). CONCLUSIONS: The decrease in HMGB1 levels after anterior myocardial infarction was associated with exercise training and with the improvement of cardiopulmonary and autonomic function, and with favorable cardiac remodeling.

Neopterin: from forgotten biomarker to leading actor in cardiovascular pathophysiology.

Inflammation plays a role at all stages of atherosclerosis. Neopterin, a pteridine mainly synthesized by activated macrophages, is a marker of inflammation, immune system activation and an active participant in cardiovascular disease. Measurement of neopterin levels may help follow the evolution of specific inflammatory conditions (e.g. viral infection, renal transplant rejection, systemic inflammatory diseases, nephritic syndrome and autoimmune diseases). Serum levels of neopterin are elevated also in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). Moreover, plasma levels of this molecule might predict adverse cardiovascular events in patients with CAD, acute coronary syndromes or severe PAD. In addition, neopterin levels are related to the development of heart failure. We provide an updated overview on neopterin and, its links with CAD, left ventricular dysfunction, and PAD. We also describe its potential role in cardiac regenerative strategies with using bone marrow cells.

Molecular imaging of atherosclerosis in translational medicine.

Functional characterization of atherosclerosis is a promising application of molecular imaging. Radionuclide-based techniques for molecular imaging in the large arteries (e.g. aorta and carotids), along with ultrasound and magnetic resonance imaging (MRI), have been studied both experimentally and in clinical studies. Technical factors including cardiac and respiratory motion, low spatial resolution and partial volume effects mean that noninvasive molecular imaging of atherosclerosis in the coronary arteries is not ready for prime time. Positron emission tomography imaging with fluorodeoxyglucose can measure vascular inflammation in the large arteries with high reproducibility, and signal change in response to anti-inflammatory therapy has been described. MRI has proven of value for quantifying carotid artery inflammation when iron oxide nanoparticles are used as a contrast agent. Macrophage accumulation of the iron particles allows regression of inflammation to be measured with drug therapy. Similarly, contrast-enhanced ultrasound imaging is also being evaluated for functional characterization of atherosclerotic plaques. For all of these techniques, however, large-scale clinical trials are mandatory to define the prognostic importance of the imaging signals in terms of risk of future vascular events.

Multiple MGuard stent implantation to treat massive right coronary artery dissection during primary coronary angioplasty.

Here we report a case of a 79-year-old woman with inferior myocardial infarction, transferred to our cath lab to perform a primary percutaneous coronary intervention (PPCI). During the procedure, a massive dissection complicated the thrombotic lesion of the right coronary artery (RCA). In this case, we decided to use the MGuard stent to treat both the large dissection and the thrombotic lesion. MGuard stent is a combination of a coronary stent merged with an embolic protection device. After multiple MGuard stent implantation we obtained a complete resolution of the coronary dissection obtaining a patent RCA with normal antegrade flow.

Balancing hemorrhagic and thrombotic complications in a patient with a very late paclitaxel-eluting stent thrombosis: a clinical case report.

Stent thrombosis is a rare but potentially fatal complication of percutaneous treatment of coronary disease. Its occurrence after placement of drug eluting stents (DES) has raised concerns, as this event may occur very late after stent implantation. Here, we report a case of very late stent thrombosis (VLST) experienced 1462 days after DES deployment in a patient with challenging clinical status, requiring counterbalancing hemorrhagic and thrombotic risk factors.

A new approach to percutaneous coronary revascularization in patients requiring undeferrable non-cardiac surgery.

BACKGROUND: Optimal strategy for patients who need coronary revascularization before undeferrable non-cardiac surgery is still unknown. We performed a pilot study of dual antiplatelet therapy discontinuation followed by major non-cardiac surgery and endovascular aortic repair early after successful endothelial-progenitor cell-capture coronary stent deployment. METHODS AND RESULTS: Thirty consecutive patients underwent coronary angioplasty plus stenting, before upcoming endovascular or surgical procedures requiring early interruption of antiplatelet therapy. An optimal acute procedural result was observed in all patients. Antiplatelet therapy was stopped before surgery in all patients, achieving an average antiplatelet therapy time of 12.2 ± 3.9 days. Surgery was performed after antiplatelet therapy interruption at an average time interval from revascularization of 17.2 ± 3.9 days. No patient suffered cardiac events during the perioperative period. At thirty day follow-up after surgery there were no cardiac events in all patients. CONCLUSIONS: Our preliminary data might suggest a role for EPC-capture stent in patients requiring surgical procedures early after coronary stent placement. Further studies on larger population are needed to confirm the clinical impact of our findings.

Calcified anterior myocardial infarction depicted by cardiac MRI.

We present the case of a 68-year-old man with previous history of myocardial infarction and coronary artery bypass grafting. An initial chest X-ray showed a curvilinear calcification involving the left-sided profile of the mediastinal shadow. Cardiac MRI cine images demonstrated findings compatible with a calcified anterior myocardial infarction.

The extent of irreversible myocardial damage and the potential for left ventricular repair after primary percutaneous coronary intervention.

Primary percutaneous coronary intervention (PCI) is currently recognized as a highly effective therapy for acute myocardial infarction (AMI) and has been shown to decrease myocardial damage and improve prognosis. Several diagnostic tools have been proposed to evaluate the myocardium at risk, the occurrence of no-reflow, the final scar size, and the presence of residual viable myocardium in patients treated by primary PCI. A large body of literature documents the relevant impact of each of these variables on outcomes in patients treated for AMI. In patients undergoing primary PCI, a number of treatment approaches have been proposed recently to improve efficacy by increasing myocardial salvage. This article describes the principal diagnostic tools (ie, serum biochemical markers, electrocardiography, echocardiography, nuclear imaging techniques, magnetic resonance imaging, and multidetector computed tomography) applicable for evaluation of the size and severity of myocardial damage in patients with AMI undergoing primary PCI. Proposed therapeutic strategies to repair irreversible myocardial damage in patients treated with primary PCI are also considered, with particular focus on the value of stem cell therapy in this specific setting.

Does carotid intima-media thickness regression predict reduction of cardiovascular events? A meta-analysis of 41 randomized trials.

OBJECTIVES: the purpose of this study was to verify whether intima-media thickness (IMT) regression is associated with reduced incidence of cardiovascular events. BACKGROUND: Carotid IMT increase is associated with a raised risk of coronary heart disease (CHD) and cerebrovascular (CBV) events. However, it is undetermined whether favorable changes of IMT reflect prognostic benefits. METHODS: the MEDLINE database and the Cochrane Database were searched for articles published until August 2009. All randomized trials assessing carotid IMT at baseline, at end of follow-up, and reporting clinical end points were included. A weighted random-effects meta-regression analysis was performed to test the relationship between mean and maximum IMT changes and outcomes. The influence of baseline patients' characteristics, cardiovascular risk profile, IMT at baseline, follow-up, and quality of the trials was also explored. Overall estimates of effect were calculated with a fixed-effects model, random-effects model, or Peto method. RESULTS: forty-one trials enrolling 18,307 participants were included. Despite significant reduction in CHD, CBV events, and all-cause death induced by active treatments (for CHD events, odds ratio [OR]: 0.82, 95% confidence interval [CI]: 0.69 to 0.96, p = 0.02; for CBV events, OR: 0.71, 95% CI: 0.51 to 1.00, p = 0.05; and for all-cause death, OR: 0.71, 95% CI: 0.53 to 0.96, p = 0.03), there was no significant relationship between IMT regression and CHD events (tau(2)0.91, p = 0.37), CBV events (tau(2)-0.32, p = 0.75), and all-cause death (tau(2)-0.41, p = 0.69). In addition, subjects' baseline characteristics, cardiovascular risk profile, IMT at baseline, follow-up, and quality of the trials did not significantly influence the association between IMT changes and clinical outcomes. CONCLUSIONS: regression or slowed progression of carotid IMT, induced by cardiovascular drug therapies, do not reflect reduction in cardiovascular events.

Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure.

AIMS: Several studies have shown that muscle mass loss is an important pathogenic issue in heart failure (HF). Atrogin-1 is a F-box protein selectively expressed in cardiac and skeletal muscle tissue, which plays a pivotal role in muscle wasting regulation. The aim of this study was to investigate the expression of Atrogin-1 and the molecular pathway involved in Atrogin-1 regulation in human HF. METHODS AND RESULTS: Cardiac tissue from patients with HF (HF group: n=10) or with normal left ventricular function (control group: n=9) was studied by western blot and real time-PCR analysis. Linear regression analysis between patients left ventricular ejection fraction (LVEF) and Atrogin1 or its regulator Forkhead box O 3a (Foxo3a) myocardial expression was performed to test correlations between protein expression and LVEF. Western blot analysis revealed that the myocardial expression of Atrogin-1 in the HF group was 2.5-fold increased compared with controls (P=0.007). Accordingly, Atrogin-1 mRNA was 1.5 higher than in controls (P=0.003). The expression of Foxo3a and its up-stream regulator AKT were also measured. Western blot analysis demonstrated in the HF group a 2.56-fold reduction of AKT phosphorylation and a 3.32-fold increase of Foxo3a as compared with controls (P=0.002 and P=0.001, respectively). Finally, linear regression showed a significant relationship between Foxo3a or Atrogin-1 expression and LVEF (R=0.976, P<0.0001 and R=0.895, P=0.003, respectively). CONCLUSION: Our results suggest that in human HF, the activity of AKT decreases, with activation of Foxo3a and induction of Atrogin-1, thereby leading to a molecular state that favours heart muscle loss and left ventricular dysfunction.

Successful use of the Cardiva Boomerang™ vascular closure device to close a brachial artery puncture site after emergency PTCA.

Brachial artery access is a good alternative for performing percutaneous transluminal angioplasty when femoral access is contraindicated or not feasible. Although several closure devices are available for femoral access, haemostasis for brachial artery access is still achieved by manual compression with several potential complications, such as bleeding, pseudo-aneurysm formation, especially in patients in which heparin is administered, or thrombotic vessel occlusion. This first-in-human report describes the off-label brachial use of the Cardiva Boomerang™, a novel vascular closure device, which provides haemostasis using a temporary intravascular tampon, thus permitting the easier physiological closure of the puncture site without any important complications.

The GPIIIA PlA2 polymorphism is associated with an increased risk of cardiovascular adverse events.

BACKGROUND: The clinical impact of PlA2 polymorphism has been investigated in several diseases, but the definition of its specific role on thrombotic cardiovascular complications has been challenging. We aimed to explore the effect of PlA2 polymorphism on outcome in patients with atherosclerosis. METHODS: We studied 400 consecutive patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention. A replication study was conducted in 74 hypertensive patients with cerebrovascular events while a group of 100 healthy subjects was included as control population. PlA genotype was determined by PCR-RFLP on genomic DNA from peripheral blood cells. Major adverse cardiac events (MACE), were considered as end points, and recorded at a mean follow up of 24 ± 4.3 months. RESULTS: The frequencies of PlA2 polymorphism was similar between groups and genotype distribution was in Hardy-Weinberg equilibrium. In patients with CAD, the presence of PlA2 allele was associated with higher incidence of cardiac death (13.1% vs. 1.5%, p = 0.0001), myocardial infarction (10.7% vs. 2.6%, p = 0.004) and needs of new revascularization (34.8% vs. 17.7%, p = 0.010). Accordingly, the Kaplan-Meier analysis for event free survival in patients harboring the PlA2 allele showed worse long-term outcome for these patients (p = 0.015). Cox regression analysis identified the presence of PlA2 as an independent predictor of cardiac death (OR: 9.594, 95% CI: 2.6 to 35.3, p = 0.002) and overall MACE (OR: 1.829, 95% CI: 1.054 to 3.176, p = 0.032). In the replication study, the PlA2 polymorphism increased the risk of stroke (OR: 4.1, 95% CI: 1.63-12.4, p = 0.02) over TIA and was identified as an independent risk factor for stroke (B:-1.39; Wald: 7.15; p = 0.001). CONCLUSIONS: Our study demonstrates that in patients with severe atherosclerosis the presence of PlA2 allele is associated with thrombotic cardiovascular complications.

AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress.

AIMS: The aim of the present study was to determine the function and the role of the scaffold protein AKAP121, tethering cAMP dependent protein kinase A to the outer wall of mitochondria, in neonatal ventricular myocytes and the heart. METHODS AND RESULTS: Competitive peptides displacing AKAP121 from mitochondria in the tissue and in the cells were used to investigate the role of AKAP121 in mitochondrial function, reactive oxygen species (ROS) generation, and cell survival. Displacement of AKAP121 from mitochondria by synthetic peptides triggers the death program in cardiomyocytes. Under pathological conditions in vivo, in a rat model of cardiac hypertrophy induced by ascending aorta banding, the levels of AKAP121 are significantly down-regulated. Disappearance of AKAP121 is associated with mitochondrial dysfunction, high oxidative stress, and apoptosis. In vivo delocalization of AKAP121 by competitive peptides replicates some of the molecular signatures induced by pressure overload: mitochondrial dysfunction, increased mitochondrial ROS, and apoptosis. CONCLUSION: These data suggest that AKAP121 regulates the response to stress in cardiomyocytes, and therefore AKAP121 downregulation might represent an important event contributing to the development of cardiac dysfunction.

[Novel concepts in beta-adrenergic receptor signaling: therapeutic options for heart failure]. / Nuovi concetti nella segnalazione beta-adrenergica: prospettive terapeutiche per lo scompenso cardiaco.

Heart failure is a common and complex clinical syndrome characterized by progressive ventricular dilatation, depressed contractile function and premature death. Abnormalities in the beta-adrenergic receptor (betaAR) signaling such as betaAR down-regulation and desensitization are hallmarks of heart failure. Results from previous studies suggest that chronic betaAR dysfunction in the failing heart is maladaptive and contributes to the deterioration in cardiac function. In this review we will discuss a number of recent studies on betaAR signaling and addressing the role of phosphoinositide-3 kinase (PI3K) in the development of betaAR dysfunction and the progression of heart failure. Novel possible strategies to ameliorate cardiac dysfunction in heart failure through the competitive inhibition of PI3K are also described.

Aortic valve sclerosis in patients with peripheral and/or coronary arterial disease.

BACKGROUND: Aortic valve sclerosis (AVS) is a marker of cardiovascular risk; its prevalence increases in elderly and in patients with hypertension and/or coronary arterial disease (CAD). There are no data available in patients with peripheral arterial disease (PAD) and with both CAD and PAD. METHODS: To investigate the presence of AVS, 57 patients with stable CAD, 38 with PAD, and 62 with CAD + PAD where studied by echocardiography. RESULTS: The prevalence of AVS progressively increased within groups (P = 0.005). The prevalence of AVS in PAD doubled that in CAD group (42.1% vs. 22.8%, P < 0.05). PAD patients had a 4.634 (95% CI: 1.02-17.88; P = 0.026) fold increased risk of AVS compared to CAD. Also CAD + PAD group had a higher prevalence of aortic sclerosis when compared to CAD group (50.8% vs. 22.8%, P = 0.001). CAD + PAD showed a 3.799 (95% CI: 1.26-11.45; P < 0 .01) fold greater risk of aortic sclerosis than CAD group. There were no differences in AVS prevalence between CAD + PAD and PAD group (50.8% vs. 42.1%; P = 0.36). Age was related to AVS in both analysis (PAD vs. CAD and CAD + PAD vs. CAD: OR = 1.09, 95% CI: 1.02-1.16, P = 0.011 and OR = 1.13, 95% CI: 1.07-1.21; P < 0.001) but no classical cardiovascular risk factors. CONCLUSIONS: PAD patients have an elevated prevalence of AVS greater than CAD patients. In patients with both disease, the prevalence of AVS is similar to that of patients with PAD alone.