Evaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention.

Abnormal platelet reactivity is associated with recurrent ischemia and bleeding following percutaneous coronary intervention (PCI). Protease-activated receptor-1 (PAR1), encoded by F2R, is a high affinity thrombin receptor on platelets and the target of the antiplatelet drug vorapaxar. The intronic single nucleotide polymorphism F2R IVS-14 A/T affects PAR1 receptor density and function. We hypothesized that carriers of the T allele, who have been shown to have decreased platelet reactivity, would be at lower risk for thrombotic events, but higher risk for bleeding following PCI. Using BioVU, the Vanderbilt DNA repository linked to the electronic medical record, we studied 660 patients who underwent PCI for unstable or stable coronary artery disease. Primary outcome measures were major adverse cardiovascular events (MACE, composite of revascularization, MI, stroke, death) and bleeding (assessed by Bleeding Academic Research Consortium scale) over 24 months. The minor allele (T) frequency was 14.8 %. There were no genotypic differences in the frequency of MACE (33.7, 28.8, and 31.6 % for A/A, A/T, and T/T respectively, P = 0.50) or bleeding (15.7, 14.7, and 18.8 % for A/A, A/T, and T/T respectively, P = 0.90). In a Cox regression model, fully adjusted for age, race, sex, BMI, and smoking status, carrying a T allele was not associated with MACE (HR 1.19, 95 % CI 0.89-1.59, P = 0.23) or bleeding (HR 0.73, 95 % CI 0.37-1.4, P = 0.34). In conclusion, in our population, F2R IVS-14 PAR1 variability does not affect risk of MACE or bleeding following PCI.

Anti-remodeling and anti-fibrotic effects of the neuregulin-1ß glial growth factor 2 in a large animal model of heart failure.

BACKGROUND: Neuregulin-1ß (NRG-1ß) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 (GGF2) isoform of NRG-1ß improves cardiac function in rodents after myocardial infarction (MI), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF2 on ventricular remodeling, cardiac function, and global transcription in post-MI swine, as well as potential mechanisms for anti-remodeling effects. METHODS AND RESULTS: MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post-MI, survivors (n=13) received GGF2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post-MI, fractional shortening was higher (32.8% versus 25.3%, P=0.019), and left ventricular (LV) end-diastolic dimension lower (4.5 versus 5.3 cm, P=0.003) in GGF2-treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF2-treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG-1ß reduces myoFbs, and suppresses TGFß-induced phospho-SMAD3 as well as αSMA expression. CONCLUSIONS: These results suggest that GGF2/NRG-1ß prevents adverse remodeling after injury in part via anti-fibrotic effects in the heart.

Learning curve in transradial cardiac catheterization: procedure-related parameters stratified by operators' transradial volume.

OBJECTIVE: To determine whether radial artery access is associated with a reduction in fluoroscopy time, procedure time, and other procedural variables over a 27-month period during which the radial artery approach was incorporated in a single academic Medical Center. BACKGROUND: Although previous studies have demonstrated a relationship between increased volume and decreased procedural time, no studies have looked at the integration of radial access over time. METHODS: Data were collected from consecutive patients who presented to the Vanderbilt University Medical Center cardiac catheterization laboratory from January 1, 2009 to April 1, 2011. Patients who underwent radial access diagnostic catheterization with and without percutaneous coronary intervention were included in this study. A total of 1112 diagnostic cardiac catheterizations through the radial access site were analyzed. High-volume, intermediate-volume, and low-volume operators were grouped based on the percentage of procedures performed through a radial approach. RESULTS: From 2009 to 2011, there was a significant decrease in fluoroscopy time in all operator groups for diagnostic catheterization (P=.035). The high-volume operator group had 1.88 and 3.66 minute reductions in fluoroscopy time compared to the intermediate- and low-volume operator groups, respectively (both P<.001). Likewise, the intermediate-volume operator group had a 1.77 minute improvement compared to the low-volume operator group, but this did not reach statistical significance (P=.102). The improvement in fluoroscopy time and other procedure-related parameters was seen after approximately 25 cases with further improvement after 75 cases. CONCLUSIONS: The incorporation of the radial access approach in the cardiac catheterization laboratory led to a decrease in fluoroscopy time for each operator and operator group over the last 3 years. Our data demonstrated that higher-volume radial operators have better procedure, room, and fluoroscopy times when compared to intermediate- and low-volume operators. However, lower-volume operators have a reduction in procedure-related parameters with increased radial cases. Number of procedures needed to become sufficient was demonstrated in the current study.

Efficacy and safety of percutaneous life support during high-risk percutaneous coronary intervention, refractory cardiogenic shock and in-laboratory cardiopulmonary arrest.

BACKGROUND: High-risk percutaneous coronary interventions (PCI), refractory cardiogenic shock and in-lab cardiac arrest are all associated with significant mortality. Percutaneous left ventricular assist devices (pLVAD) and CPS (cardiopulmonary support) have been used to support such patients. However, the extent to which the use of these devices can improve outcomes in this patient subset is not known. METHODS: We evaluated clinical features, efficacy and safety outcomes in a retrospective cohort of 39 patients, treated either with pLVAD or CPS for support of high-risk PCI, cardiogenic shock or in-lab cardiac arrest. The Tandem-Heart and a new versatile Multifunctional Percutaneous Heart (MPH) system, with both CPS and LVAD capability, were used and assessed. RESULTS: 19 patients received the TandemHeart and 20 received the MPH system. The MPH system was used as a pLVAD in 12 and to provide CPS in 8 patients. Procedural efficacy was 100%. Emergent institution of CPS, in the setting of cardiac arrest, was able to support 7 out of 8 patients and resulted in a 50% survival to hospital discharge rate. Overall, in-hospital death and 30-day major adverse cardiac event rates were 28.2% and 35.9%, respectively. The risk of vascular complications and bleeding was relatively small. CONCLUSIONS: pLVADs are effective in supporting patients during high-risk cardiac (coronary and structural heart) interventions, with a low risk of device-related complications. Further, the expeditious use of CPS in the catheterization laboratory can improve survival in a selected subset of patients with refractory cardiogenic shock and cardiac arrest.

Novel multi-functional life support system.

UNLABELLED: Concepts of cardiopulmonary support (CPS), extracorporeal membrane oxygenation (ECMO), and ventricular support (VS) have been thoroughly studied and refined. These perfusion adjuncts often require multiple devices, skill sets, and significant financial burden to purchase, maintain, deploy, and use. We describe a novel system that is rapidly deployable, user-friendly, portable, safe, and economical. Over a 1-year period we have used a multi-functional life support system (MLS) in the cardiac catheterization laboratory, cardiovascular intensive care unit, and cardiac surgical suites. Further, we have conducted multiple transports within the hospital and one to an alternate facility. Applications have included ECMO, cardiopulmonary resuscitation-supported cardiogenic shock, high risk percutaneous coronary intervention (PCI), valvuloplasty, right ventricular assist device transition to ECMO post cardiotomy, left ventricular assist device transition to ECMO, ventricular septal defect closure, and ECMO transition to conventional cardiopulmonary bypass (CPB). Duration of support has ranged from approximately 39 minutes to several days. KEYWORDS: extracorporeal membrane oxygenation (ECMO), percutaneous ventricular assist device, cardiopulmonary support, portable cardiopulmonary life support, ventricular assist.

X-linked agammaglobulinemia diagnosed late in life: case report and review of the literature.

BACKGROUND: Common variable immune deficiency (CVID), one of the most common primary immunodeficiency diseases presents in adults, whereas X-linked agammaglobulinemia (XLA), an inherited humoral immunodeficiency, is usually diagnosed early in life after maternal Igs have waned. However, there have been several reports in the world literature in which individuals have either had a delay in onset of symptoms or have been misdiagnosed with CVID and then later found to have mutations in Bruton's tyrosine kinase (BTK) yielding a reclassification as adult-onset variants of XLA. The typical finding of absent B cells should suggest XLA rather than CVID and may be a sensitive test to detect this condition, leading to the more specific test (Btk mutational analysis). Further confirmation may be by mutational analyses. METHODS: The records of 2 patients were reviewed and appropriate clinical data collected. BTK mutational analysis was carried out to investigate the suspicion of adult-presentation of XLA. A review of the world literature on delayed diagnosis of XLA and mild or "leaky" phenotype was performed. RESULTS: 2 patients previously diagnosed with CVID associated with virtual absence of CD19+ B cells were reclassified as having a delayed diagnosis and adult-presentation of XLA. Patient 1, a 64 yr old male with recurrent sinobronchial infections had a low level of serum IgG of 360 mg/dl (normal 736-1900), IgA <27 mg/dl (normal 90-474), and IgM <25 mg/dl (normal 50-415). Patient 2, a 46 yr old male with recurrent sinopulmonary infections had low IgG of 260 mg/dl, low IgA <16 mg/dl, and normal IgM. Mutational analysis of BTK was carried out in both patients and confirmed the diagnosis of XLA CONCLUSION: These two cases represent an unusual adult-presentation of XLA, a humoral immunodeficiency usually diagnosed in childhood and the need to further investigate a suspicion of XLA in adult males with CVID particularly those associated with low to absent CD19+ B cells. A diagnosis of XLA can have significant implications including family counseling, detecting female carriers, and early intervention and treatment of affected male descendents.

Potential mechanisms connecting asthma, esophageal reflux, and obesity/sleep apnea complex--a hypothetical review.

Obstructive sleep apnea (OSA) and asthma are potentially linked at several levels. The pathophysiology of these two conditions seems to overlap significantly, as airway obstruction, inflammation, obesity, and several other factors are implicated in the development of both diseases. Gastroesophageal reflux disease (GERD), cardiovascular complications, obesity itself, and the underlying inflammatory processes are all complex contributory factors that provide hypothetical links. Furthermore, a collateral rise in prevalence of both OSA and asthma has been noticed during the past few years, occurring in association with the emerging epidemic of obesity, a common risk factor for both conditions. OSA and asthma share many other risk factors as well. We propose a hypothetical OSA-asthma relationship that has implications on the diagnosis and management of patients presenting with either condition singly. Clinicians should be aware that OSA might complicate asthma management. Based on this hypothesis, we suggest that the treatment of the individual patient who experiences both asthma and OSA needs to be multidisciplinary and comprehensive. This hypothetical association of asthma and OSA, though described anecdotally, has not been systematically studied. In particular, the influence of continuous positive airway pressure therapy (for sleep apnea) on asthma outcomes (such as quality of life, steroid utilization, emergency room visits) and fatality needs to be studied further.

Alveolar hemorrhage: an underdiagnosed complication of treatment with glycoprotein IIb/IIIa inhibitors.

OBJECTIVE: Alveolar hemorrhage (AH) is a rare complication of treatment with GP IIb/IIIa inhibitors. Hemoptysis, a constant sign, lacks in specificity, and may occur in confounding syndromes such as pulmonary edema, pulmonary infarction, and pneumonia. Nonspecific symptoms and signs often delay the diagnosis, thereby allowing serious or even fatal disease progression. Here, we performed a large-scale retrospective analysis to define the incidence and risk factors of AH in the setting of GP IIb/IIIa inhibitors therapy. BACKGROUND: Randomized controlled trials demonstrate that treatment with glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors may improve the outcome of acute myocardial infarction (AMI) and angioplastic procedures. However, this treatment may rarely lead to severe hemorrhagic complications, in particular AH. Unfortunately, the incidence and risk factors of AH remain poorly defined. METHODS: We reviewed for the period extending from August 1998 to January 2005 consecutive histories of AMI patients receiving coronary arteriography and treatment with either eptifibatide or abciximab. Concomitantly admitted AMI patients not treated with GP IIb/IIIa inhibitors were reviewed and served as a control group. The diagnosis of AH required the demonstration of typical symptoms and signs including dyspnea, hemoptysis, arterial hypoxemia, pulmonary radiographic changes, and, when available, bronchoscopic signs for AH. Potential covariates including pulmonary disease, pulmonary hypertension, smoking, and use of other anticoagulant or antiplatelet agents were evaluated. RESULTS: Six of 1,810 patients (0.33%) receiving eptifibatide and five of 3,648 patients (0.14%) receiving abciximab exhibited typical symptoms and signs of AH. Contrarily, only one of 4,136 patients (0.025%) receiving no GP IIb/IIIa inhibitors presented with similar symptoms and signs. There was no fatal outcome, though two patients required blood transfusions. Statistically significant differences were found between control patients and patients receiving eptifibatide alone (P = 0.004). There was also a significant difference between untreated patients and those receiving eptifibatide and abciximab (P = 0.017). No differences were found between eptifibatide and abciximab-treated patients (P = 0.19) or between abciximab and untreated control patients (P = 0.105). CONCLUSIONS: AH is a rare complication of treatment with GP IIb/IIIa inhibitors. Its incidence ranged from 0.14% in patients treated with abciximab to 0.33% in those receiving eptifibatide. Compared to a control group, patients treated with GP IIb/IIIa inhibitors had a statistically increased risk for AH.