[show abstract][hide abstract] ABSTRACT: Despite the exponential growth in medical knowledge, cardiovascular diseases (CVDs) contribute to more than one-third of worldwide morbidity and mortality. A range of therapies already exist for established CVDs, although there is significant interest in further understanding their pathogenesis. The urocortins (Ucns) are peptide members of the corticotrophin-releasing factor family, a group of evolutionary conserved peptides with homologues in fish, amphibians and mammals and considered to play a pivotal role in energy homeostasis and local tissue repair. A number of preclinical studies in vitro, in-vivo and ex-vivo have defined a multifaceted effect of Ucns on the cardiovascular system. Different G-protein coupled signaling and protein-kinase pathways have been shown to be activated by Ucns, together with different transcriptional and translational effects, all of which preferentially converge on the mitochondria, where the modulation of apoptosis is considered their principal action. It has been demonstrated in experimental models, and consequentially suggested in human diseases, that Ucn-mediated inhibition of apoptosis can be exploited for the improvement of both therapeutic and preventative strategies against CVDs. Specifically, some unavoidable iatrogenic ischemia/reperfusion (I/R) injuries, e.g. during cardiac surgery or percutaneous coronary angioplasty, may greatly benefit from the anti-apoptotic effect of Ucns. However, few studies on the topic have been employed in humans to date. Therefore, this review will focus on the different intra-cellular mechanisms of action of Urocortins, and detail the different Ucn-mediated pathways identified so far. It will also highlight the limited evidence already existing in human clinical and surgical settings, as well as emphasize the potential uses of Ucns in human cardiac pathology.
Cardiovascular Drugs and Therapy 07/2013; · 2.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: Src tyrosine kinase family was recently identified as a novel upstream modulator of MAP kinase subfamily, p42/p44, whose activation is required for urocortin (Ucn)-mediated cardioprotection. Src kinase was also shown to reduce apoptosis in different cancer cell lines, enhancing phosphorylation and DNA binding affinity of signal transducer and activator of transcription (STAT)3. In order to evaluate the effects of Ucn on the activation status of different STAT family members, HL-1 cardiac cells were incubated with Ucn (10 nM) for increasing periods of time. STAT3 was rapidly phosphorylated at Tyr705, while neither phosphorylation at Ser727 nor induction of total STAT3 was observed. Pretreatment with PP2, a selective inhibitor of Src tyrosine kinase, reduced the pSTAT(-T705) phosphorylation and transcriptional activity induced by Ucn in a dose-dependent manner. Overexpression of STAT3 in HL-1 cardiac myocytes pretreated with Ucn reduced the magnitude of cell death as compared with Ucn treatment alone, while transfection of HL-1 cells with a STAT3 mutant functionally inactive, acting as a dominant negative (DN-STAT3), enhanced the extent of cell death in a dose-dependent manner. In line with this finding, in HL-1 cardiac myocytes overexpressing STAT3 treated with Ucn, addition of the Src kinase inhibitor PP2 reversed the cytoprotective effects of Ucn, proving that the cytoprotective effects of Ucn are also mediated via the Src-pSTAT(-T705) phosphorylation pathway. By immunocytochemistry, Ucn induced nuclear translocation of pST3-T705, which was inhibited by pretreatment with PP2. Together, these data strongly suggest that Ucn can mediate cardioprotection by activating the Src-pSTAT-T705 phosphorylation pathway.
[show abstract][hide abstract] ABSTRACT: Background: Postoperative atrial fibrillation (POAF) is the most common arrhythmia after coronary artery bypass surgery (CABG) and is associated with an increased morbidity. Recently, it has been suggested that POAF is also associated with increased postoperative mortality.
Aim: To investigate whether POAF after isolated CABG was associated with a higher EuroSCORE, indicating greater in-hospital mortality risk.
Methods: We reviewed data from our prospective cardiac surgery database of all patients (n=2791) undergoing isolated CABG from January 2003 through December 2006 at a large university medical center. The Mann-Whitney test was used to test for differences in continuous variables between the POAF and non-POAF groups, while the Chi-square test was used for categorical variables. Cox proportional-hazards regression analysis was used to identify independent predictors of in-hospital mortality.
Results: The mean age was 68 ± 9.1yrs, and mean EuroSCORE was 6.91 ± 3.18. The overall incidence of POAF was 32.3%. The POAF group was older (70.5 ± 7.8 vs. 66.8 ± 9.5yrs non-POAF: p<0.0001), but there was no significant difference in ejection fraction (EF) between the two groups (p=0.13). There was a significant difference in the mean EuroSCORE (POAF, 7.6 ± 3.2 vs non-POAF, 6.6 ± 3.1, p<0.0001), indicating that the POAF group was at greater risk for postoperative mortality. Although, there was a significant association between EuroSCORE and POAF (p<0.0001), there was no significant difference in hospital mortality between the POAF and non-POAF groups. The overall hospital mortality was 1.9%, with no difference between the two groups (p=0.91). Furthermore, POAF was not predictive of hospital mortality after CABG.
Conclusion: POAF is associated with a higher EuroSCORE, but it is neither associated with, nor predictive of increased hospital mortality after CABG.
Journal of Clinical and Experimental Cardiology. 12/2012;
[show abstract][hide abstract] ABSTRACT: β-Adrenergic receptor antagonists (β-blockers) have been recognized for their cardioprotective properties, prompting use of these pharmacologic agents to become more mainstream in acute myocardial infarction (AMI) and congestive heart failure (CHF). Despite their popularity as a class, the ability to protect the myocardium varies significantly between different agents. Carvedilol is a non-selective β-blocker with α(1)-adrenergic receptor antagonism properties. It is unique among β-blockers because in addition to improving exercise tolerance and its anti-ischemic properties secondary to a reduction in heart rate and myocardial contractility, carvedilol exerts other beneficial effects including: antioxidant effects; reduction in neutrophil infiltration; apoptosis inhibition; reduction of vascular smooth muscle migration; and improvement of myocardial remodeling post-AMI. These properties, documented in animal models and subsequent clinical trials, are consistent with established evidence demonstrating decreased morbidity and mortality in patients with CHF and post-AMI. This article reviews the role of carvedilol compared with other β-blockers in the treatment of CHF and post-AMI management.
American Journal of Cardiovascular Drugs 10/2012; · 2.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: IL-17A and IL-17F are pro-inflammatory cytokines which induce the expression of several cytokines, chemokines and matrix metalloproteinases (MMPs) in target cells. IL-17 cytokines have recently attracted huge interest due to their pathogenic role in diseases such as arthritis and inflammatory bowel disease although a role for IL-17 cytokines in myocardial infarction (MI) has not previously been described. METHODS: In vivo MI was performed by coronary artery occlusion in the absence or presence of a neutralizing IL-17 antibody for blocking IL-17 actions in vivo. IL-17 signaling was also assessed in isolated primary cardiomyocytes by Western blot, mRNA expression and immunostaining. RESULTS: Expression of IL-17A, IL-17F and the IL-17 receptor (IL-17RA) were all increased following MI. Expression of several IL-17 target genes, including Cxcl1, Cxcl2, IL-1β, iNOS and IL-6 was also upregulated following MI. In addition, IL-17A promoted the expression of Cxcl1 and IL-6 in isolated cardiomyocytes in a MAPK and PI(3)K-dependent manner. IL-17A and ischaemia/reperfusion (I/R) injury were found to have an additive effect on Cxcl1 expression, suggesting that IL-17 may enhance myocardial neutrophil recruitment during MI. Moreover, protein levels of both IL-17R and IL-17A were enhanced following in vivo MI. Finally, blocking IL-17 signaling in vivo reduced the levels of apoptotic cell death markers following in vivo MI. CONCLUSIONS: These data imply that the expression of IL-17 cytokines and their receptor are elevated during myocardial I/R injury and may play a fundamental role in post infarct inflammatory and apoptotic responses.
International journal of cardiology 10/2011; · 7.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: We sought to prospectively evaluate long-term follow-up results of intracardiac echocardiography-aided transcatheter closure of interatrial shunts in adults.
Intracardiac echocardiography improves the safety and effectiveness of transcatheter device-based closure of interatrial shunts, but its impact on long-term follow-up is unknown.
Over a 5-year period, we prospectively enrolled 258 consecutive patients (mean age 48 ± 19.1 years, 169 females) who had been referred to our centre for catheter-based closure of interatrial shunts. All patients were screened with transesophageal echocardiography before the operation. Eligible patients underwent intracardiac echocardiography study and attempted closure.
After intracardiac echocardiography study and measurements, 18 patients did not proceed to transcatheter closure due to unsuitable rims, atrial myxoma not diagnosed by preoperative transesophageal echocardiography or inaccurate transesophageal echocardiography measurement of defects more than 40 mm. The remaining 240 patients underwent transcatheter closure: transesophageal echocardiography-planned device type and size were modified in 108 patients (45%). Rates of procedural success, predischarge occlusion and complication were 100%, 94.2% and 5%, respectively. On mean follow-up of 65 ± 15.3 months, the follow-up occlusion rate was 96.5%. There were no cases of aortic/atrial erosion, device thrombosis or atrioventricular valve inferences.
Intracardiac echocardiography-guided interatrial shunt transcatheter closure is safe and effective and appears to have excellent long-term results, potentially minimizing the complications resulting from incorrect device selection and sizing.
Cardiovascular revascularization medicine: including molecular interventions 06/2011; 12(6):355-61.
[show abstract][hide abstract] ABSTRACT: Minocycline is a semi-synthetic tetracycline that inhibits bacterial protein synthesis and hence is used for the treatment of many infectious diseases. Over the years, many other interesting properties of minocycline have been identified and been used to make patents which include anti-inflammatory, anti-apoptotic, matrix metalloproteinase inhibitor and free oxygen radical scavenger activity. Ischemia-reperfusion injury is a concern for almost every clinical specialty and minocycline seems to be an attractive cytoprotective agent that can ameliorate the damage due to these properties. Ischemia-reperfusion injury is a complex process and involves various pathways that lead to cell death. This review focuses on the body of evidence describing various proposed mechanisms of action of minocycline and its current experimental use in various animal models of ischemia-reperfusion injury.
Recent patents on cardiovascular drug discovery. 05/2011; 6(2):123-32.
[show abstract][hide abstract] ABSTRACT: Urocortin is a 40 amino acid peptide of the corticotrophin-releasing factor (CRF) family that is synthesized and released by cardiac myocytes. Endogenous urocortin expression is increased during ischemia/reperfusion (I/R) and addition of exogenous urocortin reduces cell death caused by I/R injury. Studies have also showed that the protective action of urocortin is mediated by the activation of ERK1/2. We discovered that a non-receptor tyrosine kinase, Src, is involved in the urocortin-induced activation of ERK1/2 in mouse atrial HL-1 myocytes. The selective Src family kinase inhibitor, PP2, reduced the urocortin-induced phosphorylation of ERK1/2, and so did the expression of a dominant-negative mutant of Src in transfected HL-1 cells. Inhibition of Src by PP2 also reduced urocortin's protective effects in HL-1 cells after hypoxia/reoxygenation (H/R), as assessed by flow cytometry and caspase-3 activation assay. Titration studies indicated that as little as 10(-8)M urocortin was sufficient to induce Src activation. Maximal phosphorylation/activation of Src and ERK1/2 were both detected after 5 min incubation with urocortin. These effects of urocortin were largely mediated by CRF receptor-1, although a minor contribution of CRF receptor-2 cannot be excluded. Here we report for the first time that short-term treatment with urocortin causes rapid phosphorylation of Src, and that the urocortin-activated Src kinase serves as an upstream modulator of ERK1/2 activation, playing an essential role in urocortin-mediated cardioprotection.
Molecular and Cellular Endocrinology 04/2010; 325(1-2):1-7. · 4.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: A 56-year-old Caucasian male was admitted to our hospital with complaints of shortness of breath, joint aches, and chills in the absence of fever. During his hospitalization, he remained afebrile, but developed multiple episodes of bradycardia and intermittent second degree atrioventricular (AV) block, with both Wenckebach and Mobitz type II episodes. Laboratory evaluation demonstrated a chronically elevated amylase, without any significant electrolyte abnormalities. Abdominal computed tomography scan revealed prominence of the pancreatic head without any discrete pancreatic mass, suggestive of chronic pancreatitis. Pancreatic disorders, including acute pancreatitis or exacerbation of chronic pancreatitis, may be associated with intermittent transient AV block conduction abnormalities. Although the pathophysiology remains unclear, awareness of this entity is important for clinicians for appropriate management. Progression to more severe, permanent AV block necessitating permanent pacemaker implant to our knowledge has not been reported.
[show abstract][hide abstract] ABSTRACT: Inappropriate implantable cardioverter-defibrillator (ICD) therapy of atrial tachycardia (AT) with 1:1 atrioventricular (AV) conduction is common because it is difficult to discriminate from ventricular tachycardia (VT) with 1:1 retrograde conduction. Tachycardia cycle length (CL) variability and the relationship between atrial and ventricular CLs may be useful in discriminating AT from VT with 1:1 retrograde conduction.
The purpose of this study was to evaluate the usefulness of the relationship between the atrial and ventricular CLs in differentiating AT with 1:1 conduction from VT with 1:1 retrograde conduction.
We studied 71 patients who had a tachycardia with a 1:1 AV relationship and significant CL variability. Thirty-nine patients had AT (21 inducible and 18 simulated), and 32 patients had VT (11 inducible and 21 simulated). The relationship between atrial and ventricular CLs was examined.
A change in atrial CL predicted the change in subsequent ventricular CL in 37 (95%) of 39 patients with AT and in none of the patients with VT. A change in preceding ventricular CL predicted the change in atrial CL in 31 (97%) of 32 patients with VT and in only one (3%) of 39 patients with AT. The sensitivity, specificity, and positive and negative predictive values of a change in atrial CL predicting the change in ventricular CL for AT with significant CL variability were 95%, 100%, 100%, and 94%, respectively. The corresponding values for the change in preceding ventricular CL predicting the change in atrial CL for AT with significant CL variability were 97%.
The relationship between atrial and ventricular CL is useful in differentiating AT from VT with retrograde conduction. A change in atrial CL that predicts the change in subsequent ventricular CL rules in AT and excludes VT.
Heart rhythm: the official journal of the Heart Rhythm Society 10/2009; 7(2):225-8. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: This article presents a case report of a 74-year-old man with T-wave inversion (TwI) in atrial fibrillation noted during routine pacemaker interrogation. The patient was seen for routine pacemaker interrogation, at which time he was noted to have underlying atrial fibrillation. A12-lead electrocardiogram of the atrial fibrillation revealed significant TwIs. He was subsequently worked up for myocardial ischemia and was found to have a moderate-sized,moderate-degree inferior wall myocardial perfusion defect. He was subsequently referred for a cardiac catheterization. The cardiac catheterization revealed nonobstructive coronary artery disease. The follow-up electrocardiogram revealed persistent but attenuated TwI.The TwIs were attributed to cardiac memory, a common but infrequently recognized phenomenon of which many clinical practitioners are unaware. Cardiac memory is due to the T wave tracking the preceding abnormal QRS complex and can be induced by right ventricular pacing or arrhythmias.
The American journal of emergency medicine 10/2009; 27(7):898.e1-4. · 1.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study investigates the cardioprotective role and mechanism of action of urocortin in patients undergoing cardiac surgery, with respect to protein kinase Cepsilon expression, activation, and relocation.
Cardioplegic arrest and subsequent reperfusion inevitably expose the heart to iatrogenic ischemia/reperfusion injury. We previously reported that iatrogenic ischemia/reperfusion injury caused myocyte induction of urocortin, an endogenous cardioprotective peptide.
Two sequential biopsies were obtained from the right atrium of 25 patients undergoing coronary artery bypass grafting at the start of grafting (internal control) and 10 minutes after release of the aortic clamp.
In hearts exposed to iatrogenic ischemia/reperfusion injury, induction of urocortin was documented at both the mRNA (255% of basic levels; P < .05) and the protein (4-fold increase; P < .01) levels. Iatrogenic ischemia/reperfusion injury also induced a selective increase of protein kinase Cepsilon mRNA (225% of internal control; P < .05) and a 2-fold overexpression of total protein kinase Cepsilon (P < .05), which paralleled a 2.9-fold increase in protein kinase Cepsilon phosphorylation (P < .01). Mitochondrial translocation of activated protein kinase Cepsilon was observed only in postcardioplegic samples, using both subcellular fractionation (P < .05) and immunostaining techniques (P < .05). Enhanced protein kinase Cepsilon/mitochondria colocalization was selectively observed in viable myocytes, showing concurrently positive staining for urocortin (P < .05). Finally, co immunoprecipitation experiments documented an iatrogenic ischemia/reperfusion injury-enhanced physical interaction of phosphorylated protein kinase Cepsilon with the 6.1 inwardly rectifying potassium channel subunit of the K(ATP) channels (P < .05).
After iatrogenic ischemia/reperfusion injury, urocortin expression in viable cells selectively colocalized with enhanced phosphorylation and mitochondrial relocation of protein kinase Cepsilon, suggesting a cardioprotective role for endogenous urocortin. The physical interaction of activated protein kinase Cepsilon with 6.1 inwardly rectifying potassium channel, enhanced by cardioplegic arrest, may represent a conjectural mechanism of urocortin-mediated cardioprotection.
The Journal of thoracic and cardiovascular surgery 06/2009; 138(5):1213-21. · 3.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: The small peptide urocortin (Ucn) has the ability to protect the heart by reducing cardiac cell loss during myocardial ischemia/reperfusion, and improving post-ischemic cardiac performance. Although its mechanism of action is not clearly defined, investigations have revealed that Ucn acts through several kinase pathways, and modulates a group of genes which synergistically minimize mitochondrial damage. Besides cardioprotection, most recent findings suggest a role for Ucn as a cardiac biomarker. Serum Ucn levels may be clinically useful to diagnose cases of mild sub-lethal ischemia, lacking elevation of cardiac enzymes and electrocardiogram changes. Infusion of Ucn may also help reduce the extent of the iatrogenic ischemic/reperfusion injury, associated with cardioplegic arrest.
International journal of cardiology 05/2009; 137(3):189-94. · 7.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Flavonoids exhibit a variety of beneficial effects in cardiovascular diseases. Although their therapeutic properties have been attributed mainly to their antioxidant action, they have additional protective mechanisms such as inhibition of signal transducer and activator of transcription 1 (STAT1) activation. Here, we have investigated the cardioprotective mechanisms of strong antioxidant flavonoids such as quercetin, myricetin and delphinidin. Although all of them protect the heart from ischemia/reperfusion-injury, myricetin and delphinidin exert a more pronounced protective action than quercetin by their capacity to inhibit STAT1 activation. Biochemical and computer modeling analysis indicated the direct interaction between STAT1 and flavonoids with anti-STAT1 activity.
[show abstract][hide abstract] ABSTRACT: Selecting the most relevant literature for a state-of-the-art review article may result in the unintentional exclusion of valuable contributions, despite the most genuine intention of comprehensiveness. Some of these omissions, however, can be sensibly justified by a number of factors, such as language barriers, lack of abstract and/or online full-text article, type of manuscript and date of publication, whose concurrence makes simply unfeasible the gathering of the most basic information, indispensable for the citation. In this case, even the oceanic collection of scientific contributions contained in the database Medline may become underpowered.
International journal of cardiology 07/2008; 127(1):144-5. · 7.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study evaluates whether cardiac ischemia induces release of urocortin, before and independently from myocyte cell death. Urocortin levels rose after 5-min ischemia and peaked after 10-min ischemia, when cell death was not detected. However, myocyte apoptosis and/or necrosis occurred following 20- and 30-min ischemia, which paralleled a fall in urocortin levels, suggesting that urocortin expression and release are mainly sustained by metabolically challenged, though still viable myocytes. Hence, since cardiac release of urocortin, unlike that of conventional biomarkers, occurs before and apart from cell death, urocortin levels may be clinically useful in the diagnosis of sublethal myocardial ischemia.