Eman Hamad

Mitral valve repair at the time of continuous-flow left ventricular assist device implantation confers meaningful decrement in pulmonary vascular resistance

We hypothesized that the addition of mitral valve replacement or repair (MVR) to implantation of continuous-flow left ventricular assist device (cf-LVAD) may further decrease pulmonary vascular resistance (PVR) over Heartmate II (HMII) implantation alone. Patients undergoing MVR with concomitant HMII implantation were compared with those undergoing HMII implantation alone. Of the 57 patients undergoing cf-LVAD implantation, 21 (36.8%) underwent concomitant MVR and 36 (63.2%) underwent cf-LVAD implantation alone. Patients receiving MVR had greater decrement in PVR (59.4% vs. 35.2%, p = 0.01). Decrease in end-diastolic diameter was greater for patients receiving MVR but did not reach statistical significance (18.2 vs. 13.5 mm, p = 0.33). Duration of mechanical ventilation (121.6 vs. 181.4 hours, p = 0.45) and inotropic support (162.4 vs. 153.2 hours, p = 0.86), change in creatinine (0.19 vs. −0.26 mg/dl, p = 0.34), increase in bilirubin (2.54 vs. 1.55 mg/dl, p = 0.63), intensive care unit stay (168.0 vs. 231.5 hours, p = 0.38), and overall length of stay (32.0 vs. 42.5 days, p = 0.75) were similar. There was no difference in survival at 3 months (89.7% vs. 83.3%) and 1 year (83.7 vs. 67.3%, p = 0.34). Addition of MVR may result in greater decrement of PVR than HMII implantation alone. This may permit certain patients thought to be ineligible for transplantation to become candidates.

Cardioprotection of Controlled and Cardiac-Specific Over-Expression of A2A-Adenosine Receptor in the Pressure Overload

Adenosine binds to three G protein-coupled receptors (R) located on the cardiomyocyte (A1-R, A2A-R and A3-R) and provides cardiac protection during both ischemic and load-induced stress. While the role of adenosine receptor-subtypes has been well defined in the setting of ischemia-reperfusion, far less is known regarding their roles in protecting the heart during other forms of cardiac stress. Because of its ability to increase cardiac contractility and heart rate, we hypothesized that enhanced signaling through A2A-R would protect the heart during the stress of transverse aortic constriction (TAC). Using a cardiac-specific and inducible promoter, we selectively over-expressed A2A-R in FVB mice. Echocardiograms were obtained at baseline, 2, 4, 8, 12, 14 weeks and hearts were harvested at 14 weeks, when WT mice developed a significant decrease in cardiac function, an increase in end systolic and diastolic dimensions, a higher heart weight to body weight ratio (HW/BW), and marked fibrosis when compared with sham-operated WT. More importantly, these changes were significantly attenuated by over expression of the A2A-R. Furthermore, WT mice also demonstrated marked increases in the hypertrophic genes β-myosin heavy chain (β-MHC), and atrial natriuretic factor (ANF) – changes that are mediated by activation of the transcription factor GATA-4. Levels of the mRNAs encoding β-MHC, ANP, and GATA-4 were significantly lower in myocardium from A2A-R TG mice after TAC when compared with WT and sham-operated controls. In addition, three inflammatory factors genes encoding cysteine dioxygenase, complement component 3, and serine peptidase inhibitor, member 3N, were enhanced in WT TAC mice, but their expression was suppressed in A2A-R TG mice. A2A-R over-expression is protective against pressure-induced heart failure secondary to TAC. These cardioprotective effects are associated with attenuation of GATA-4 expression and inflammatory factors. The A2A-R may provide a novel new target for pharmacologic therapy in patients with cardiovascular disease.

Vasopressin Antagonists for Patients With Acute Heart Failure: Interpreting New Clinical and Translational Data

Elevated levels of arginine vasopressin (AVP) are associated with a worse prognosis and the development of hyponatremia in patients with heart failure (HF). This observation led to the development of AVP receptor antagonists for the treatment of HF patients. Although AVP receptor antagonists increase serum sodium, their overall benefits in patients with HF have been at best modest, and recent data raise concerns about their safety in patients with acute HF and low serum sodium.

Strongyloides stercoralis and Organ Transplantation

Strongyloides is a parasite that is common in tropical regions. Infection in the immunocompetent host is usually associated with mild gastrointestinal symptoms. However, in immunosuppressed individuals it has been known to cause a “hyperinfection syndrome” with fatal complications. Reactivation of latent infection and rarely transmission from donor organs in transplanted patients have been suggested as possible causes. Our case highlights the importance suspecting Strongyloides in transplant recipients with atypical presentations and demonstrates an incidence of donor derived infection. We also review the challenges associated with making this diagnosis.

Long-term outcomes in heart transplantation using donors with a history of past and present cocaine use

OBJECTIVES Organ donors with a history of cocaine use are thought to be less favourable for orthotopic heart transplantation (OHT). This study examined long-term survival in OHT using donors with a history of cocaine use. METHODS The United Network for Organ Sharing (UNOS) database was examined for primary, adult heart transplants from 2000 to 2010. Cox proportional hazards analysis using covariates associated with mortality was used to examine survival. RESULTS There were 19 636 total OHTs with 2274 (11.6%) using donors with a history of dependent cocaine use (DCU). Of these, 1008 (44.3%) donors were current cocaine users. Recipients of DCU were more likely to be male (79.0 vs 75.7%, P < 0.001), more likely diabetic (16.5 vs 14.8%, P = 0.003) and were less likely to be sex mismatched (23.0 vs 28.6%, P < 0.001). DCU donors were older (32.5 vs 31.4 years, P < 0.001), more likely male (79.7 vs 69.8%, P < 0.001) and had higher ischaemic times (3.27 vs 3.20 h, P = 0.001). On multivariate analysis, DCU was not associated with mortality [hazard ratio (HR): 0.95, 95% CI: 0.87-1.03, P = 0.22]. Variables associated with mortality included recipient body mass index, sex mismatch, race mismatch, black race, ischaemic time, recipient creatinine, donor age, donor smoking history and mechanical ventilation or extracorporeal membrane oxygen as a bridge to transplantation. On subset analysis, CCU was not associated with mortality (HR: 0.97, 95% CI: 0.89-1.05, P = 0.42). On Kaplan-Meier analysis, median survival was not different when comparing current (3890.0 days), past (3,889.0 days) and non-cocaine using donors (4165.0 days); P = 0.54. CONCLUSIONS Use of carefully selected donors with a history of past and current cocaine use does not result in worse outcomes.

Whole transcriptome microarrays identify long non-coding RNAs associated with cardiac hypertrophy.

Long non-coding RNAs (lncRNAs) have recently emerged as a novel group of non-coding RNAs able to regulate gene expression. While their role in cardiac disease is only starting to be understood, their involvement in cardiac hypertrophy is poorly known. We studied the association between lncRNAs and left ventricular hypertrophy using whole transcriptome microarrays. Wild-type mice and mice overexpressing the adenosine A2A receptor were subjected to transverse aortic constriction (TAC) to induce left ventricular hypertrophy. Expression profiles of lncRNAs in the heart were characterized using genome-wide microarrays. An analytical pipeline was specifically developed to extract lncRNA data from microarrays. We identified 2 lncRNAs up-regulated and 3 lncRNAs down-regulated in the hearts of A2A-receptor overexpressing-mice subjected to TAC compared to wild-type mice. Differential expression of these 2 lncRNAs was validated by quantitative PCR. Complete microarray dataset is available at Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE45423. Here, we describe in details the experimental design, microarray performance and analysis.

Use of Heavy Drinking Donors in Heart Transplantation is Not Associated With Worse Mortality.

Background Although orthotopic heart transplantation (OHT) remains the preferred treatment for end-stage heart failure, there continues to be a critical shortage of organ donors. The goal of this study is to examine outcomes after orthotopic OHT using heavy drinking donors (HDDs) in a large, national database. Methods The United Network for Organ Sharing database was examined for all primary, adult OHT carried out from 2005 to 2012. Results There were 14,928 total OHT performed during the study period with 2,274 (15.2%) using HDD. Recipients of HDD were older (53.4 vs. 51.9 years, P < 0.001), more likely men (80.7 vs 74.4%, P < 0.001), less likely sex mismatched (21.5 vs 27.5%, P < 0.001), more likely race mismatched (57.4 vs 52.4%, P < 0.001), and had less total HLA mismatches (4.55 vs 4.65, P < 0.001). The HDD were older (37.0 vs 30.5 years, P < 0.001), more likely men (82.2 vs 69.9%, P < 0.001), and more likely to have heavy cigarette use (38.1 vs 13.2%, P < 0.001). Length of stay was not different (20.3 vs 19.7 days, P = 0.02). On multivariate analysis, use of HDD was not associated with mortality at 30 days (hazards ratio [HR], 1.12; 95% confidence interval [95% CI], 0.90–1.39; P = 0.30), 1 year (HR, 0.96; 95% CI, 0.83–1.11; P = 0.56), and at 5 years (HR, 1.02; 95% CI, 0.91–1.13; P = 0.79). Variables associated with mortality at 5 years included increasing donor age, prolonged ischemic time, worsening recipient creatinine, recipient black race, sex mismatch, and extracorporeal membrane oxygenation or mechanical ventilation as a bridge to transplantation. Conclusion Heart transplantation can be performed using carefully selected HDDs with good outcomes.

Mo1174 Age Is a Predictor of Recurrent Gastrointestinal Bleeding in Patients With Left Ventricular Assist Devices: Results From an Urban Tertiary Care Center

Background: Re-bleeding after initial hemostasis in peptic ulcer bleeding can be life threatening. Identifying factors associated with re-bleeding in patient with peptic ulcer bleeding is important. The aims of our study was to evaluate factors related with re-bleeding and to identify incidence rate of rebleeding in patients with high risk peptic ulcer bleeding. Method: Among patients diagnosed as upper gastrointestinal hemorrhage at seven hospitals in DaeguGyeongbuk, and one hospital in Gyeongnam, South korea, from Feb 2011 to Dec 2013, 699 patients diagnosed as high risk peptic ulcer bleeding with Forrest classification above llb were included. The data were obtained in a prospective manner. Results: Among 699 patients, 500 (71.5%) patients had gastric ulcer, 199 (28.5%), duodenal ulcer. Re-bleeding of high risk peptic ulcer occurred in 64 (9.2%) patients. Age, sex, ulcer type, Forrest classification and treatment modalities were not significantly different between re-bleeding and non-rebleeding group. Second look endoscopy was significantly more performed in non-rebleeding group than rebleeding group (81.8% vs 62.5%, P=<0.001). Transfusion volume was significantly higher in rebleeding group than non-rebleeding group (7.9 vs 3.1, p=<0.001). On multivariate analysis, performance of transfusion, larger transfusion volume and non-performance of second look endoscopy were found as risk factors for rebleeding in high risk peptic ulcer bleeding. Conclusion: In our study, incidence rate of rebleeding was 9.2% and non-performance of second look endoscopy, performance of transfusion and larger transfusion volume were found as risk factors for rebleeding in patients with high risk peptic ulcer bleeding.

Response to “Clarification of Enrolled Subjects in Tolvaptan HF Trials”

We appreciate the efforts of Blais et al.1 in their letter, “Clarification of Enrolled Subjects in Tolvaptan HF Trials,” to correct factual errors in our recent article that discussed the role of V2-selective arginine vasopressin receptor (AVPV2-R) antagonists in the treatment of heart failure (HF).2 We agree that we erred by not counting the patients with hyponatremia in both SALT-1 and SALT-2 who received the AVP-V2-R antagonist tolvaptan. We also agree that, in contrast to the time line provided by Finley et al.,3 two of the dose-ranging studies with tolvaptan were performed prior to rather than “subsequent to” the completion of the SALT trials. Finally, as Blais et al. point out, the information presented regarding serum sodium levels in patients with HF enrolled in the EVEREST trial (tolvaptan) was derived from Lanfear et al.4 The initial report from the EVEREST trial5 provided only the number of patients with a serum sodium level ≤137. Lanfear et al. provided far more useful data—both the median serum sodium level and the interquartile range (140 mEq/dl: 137, 142)—all of which were within the normal range. Thus, we stand by our original contention that only a small number of patients enrolled in studies with tolvaptan had an acute exacerbation of HF accompanied by clinically significant hyponatremia (<135 mEq/l). Unfortunately, Blais et al. missed the primary point of our discussion: can we use available data to reconcile the neutral effects of tolvaptan on clinical outcomes with the increased mortality seen early after the administration of lixivaptan in the BALANCE trial? We posit three explanations for this disparity: (i) lixivaptan-specific maladaptive off-target effects; (ii) the statistical vagaries associated with an underpowered clinical trial; and/or (iii) substantive differences in the demographics of patients in the various trials. We stand by our hypothesis that the increased mortality in the BALANCE trial was due to enrichment for patients with an acute exacerbation of HF and significant hyponatremia. This hypothesis is supported by the data we presented originally but is now supported by new preclinical data demonstrating that activation of the cardiac AVP-V1A-R significantly attenuates the ability of β-adrenergic receptor agonists to increase cardiac contractility in vitro, ex vivo, and in vivo.6 These results, if applicable to humans, suggest that an increase in circulating AVP, now recognized to occur with the administration of all AVP-V2-R antagonists, could limit the ability of endogenous or exogenous adrenergic drive to increase contractility in patients with an acute exacerbation of HF and compromised cardiac reserve. Until this hypothesis is tested in humans, we remain concerned about the use of these agents in this fragile patient population.