Yaron D. Barac

The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion

Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S‐enantiomer of rasagiline, an anti‐Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats.

Shear stress-induced transcriptional regulation via hybrid promoters as a potential tool for promoting angiogenesis

Among the key effects of fluid shear stress on vascular endothelial cells is modulation of gene expression. Promoter sequences termed shear stress response elements (SSREs) mediate the responsiveness of endothelial genes to shear stress. While previous studies showed that shear stress responsiveness is mediated by a single SSRE, these endogenous promoters often encode for multiple SSREs. Moreover, hybrid promoters encoding a single SSRE rarely respond to shear stress at the same magnitude as the endogenous promoter. Thus, to better understand the interplay between the various SSREs, and between SSREs and endothelial-specific sequences (ESS), we generated a series of constructs regulated by SSREs cassettes alone, or in combination with ESS, and tested their response to shear stress and endothelial specific expression. Among these constructs, the most responsive promoter (NR1/2) encoded a combination of two GAGACC/SSREs, the Sp1/Egr1 sequence, as well as a TPA response element (TRE). This construct was four- to five-fold more responsive to shear stress than a promoter encoding a single SSRE. The expression of constructs containing other SSRE combinations was unaffected or suppressed by shear stress. Addition of ESS derived from the Tie2 promoter, either 5′ or 3′ to NR1/2 resulted in shear stress transcriptional suppression, yet retained endothelial specific expression. Thus, the combination and localization order of the various SSREs in a single promoter is crucial in determining the pattern and degree of shear stress responsiveness. These shear stress responsive cassettes may prove beneficial in our attempt to time the expression of an endothelial transgene in the vasculature.

TVP1022 Attenuates Cardiac Remodeling and Kidney Dysfunction in Experimental Volume Overload-Induced Congestive Heart Failure

Background—Despite the availability of many pharmacological and mechanical therapies, the mortality rate among patients with congestive heart failure (CHF) remains high. We tested the hypothesis that TVP1022 (the S-isomer of rasagiline; Azilect), a neuroprotective and cytoprotective molecule, is also cardioprotective in the settings of experimental CHF in rats. Methods and Results—In rats with volume overload-induced CHF, we investigated the therapeutic efficacy of TVP1022 (7.5 mg/kg) on cardiac function, structure, biomarkers, and kidney function. Treatment with TVP1022 for 7 days before CHF induction prevented the increase in left ventricular end-diastolic area and end-systolic area, and the decrease in fractional shortening measured 14 days after CHF induction. Additionally, TVP1022 pretreatment attenuated CHF-induced cardiomyocyte hypertrophy, fibrosis, plasma and ventricular B-type natriuretic peptide levels, and reactive oxygen species expression. Further, in CHF rats, TVP1022 decreased cytochrome c and caspase 3 expression, thereby contributing to the cardioprotective efficacy of the drug. TVP1022 also enhanced the urinary Na+ excretion and improved the glomerular filtration rate. Similar cardioprotective effects were obtained when TVP1022 was given to rats after CHF induction. Conclusions—TVP1022 attenuated the adverse functional, structural, and molecular alterations in CHF, rendering this drug a promising candidate for improving cardiac and renal function in this disease state.

I1 Imidazoline Receptor: Novel Potential Cytoprotective Target of TVP1022, the S-Enantiomer of Rasagiline

TVP1022, the S-enantiomer of rasagiline (Azilect®) (N-propargyl-1R-aminoindan), exerts cyto/cardio-protective effects in a variety of experimental cardiac and neuronal models. Previous studies have demonstrated that the protective activity of TVP1022 and other propargyl derivatives involve the activation of p42/44 mitogen-activated protein kinase (MAPK) signaling pathway. In the current study, we further investigated the molecular mechanism of action and signaling pathways of TVP1022 which may account for the cyto/cardio-protective efficacy of the drug. Using specific receptor binding and enzyme assays, we demonstrated that the imidazoline 1 and 2 binding sites (I1 & I2) are potential targets for TVP1022 (IC50 = 9.5E-08 M and IC50 = 1.4E-07 M, respectively). Western blotting analysis showed that TVP1022 (1–20 µM) dose-dependently increased the immunoreactivity of phosphorylated p42 and p44 MAPK in rat pheochromocytoma PC12 cells and in neonatal rat ventricular myocytes (NRVM). This effect of TVP1022 was significantly attenuated by efaroxan, a selective I1 imidazoline receptor antagonist. In addition, the cytoprotective effect of TVP1022 demonstrated in NRVM against serum deprivation-induced toxicity was markedly inhibited by efaroxan, thus suggesting the importance of I1imidazoline receptor in mediating the cardioprotective activity of the drug. Our findings suggest that the I1imidazoline receptor represents a novel site of action for the cyto/cardio-protective efficacy of TVP1022.

TVP1022: A Novel Cardioprotective Drug Attenuates Left Ventricular Remodeling After Ischemia/Reperfusion in Pigs.

Background: The current cornerstone treatment of myocardial infarction (MI) is restoration of coronary blood flow by means of thrombolytic therapy or primary percutaneous coronary intervention. However, reperfusion of ischemic myocardium can actually provoke tissue damage, defined as “ischemia–reperfusion (I/R) injury.” TVP1022 [the S-isomer of rasagiline (Azilect), FDA-approved anti-Parkinsons drug] was found to exert cardioprotective activities against various cardiac insults, such as chronic heart failure and I/R, in rat models. Therefore, we tested the hypothesis that TVP1022 will provide cardioprotection against I/R injury and post-MI remodeling in a pig model. Methods: For inducing MI, we used an I/R model of midleft anterior descending artery occlusion for 90 minutes followed by follow-up for 8 weeks in 18 farm pigs (9 pigs in each group, MI + TVP1022 or MI + Vehicle). Echocardiographic measurements were performed and cardiac scar size was calculated using histopathological methods. For fibrosis evaluation, we measured the interstitial collagen volume fraction in the remote noninfarcted tissue. Results: TVP1022 administration significantly decreased cardiac scar size, attenuated left ventricular dilation, and improved cardiac function assessed by segmental circumferential strain analysis. Furthermore, TVP1022 significantly reduced myocardial fibrosis 8 weeks post-MI. Conclusions: Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R pig model.

Using a Regent Aortic Valve in a Small Annulus Mitral Position Is a Viable Option

BACKGROUND Outcome of mitral valve replacement in extreme scenarios of small mitral annulus with the use of the Regent mechanical aortic valve is not well documented. METHODS Records were examined in 31 consecutive patients who underwent mitral valve replacement with the use of the aortic Regent valve because of a small mitral annulus. RESULTS Mean age was 60 ± 14 years. Mitral stenosis or mitral annulus calcification was present in 30 of 31 patients (97%). Concurrent procedures were performed in 17 of 31 patients (55%). Median valve size was 23 mm. Mean mitral gradient coming out of the operating room was 4.2 ± 1.5 mm Hg and at follow-up echocardiogram performed at a median of 32 months after the procedure was 5.8 ± 2.4 mm Hg. CONCLUSIONS A Regent aortic mechanical valve can be a viable option with a larger orifice area than the regular mechanical mitral valve in a problematic situation of a small mitral valve annulus. Moreover, the pressure gradients over the valve are acceptable intraoperatively and over time.

Monitoring platelet reactivity during prasugrel or ticagrelor washout before urgent coronary artery bypass grafting

Objectives Patients with acute myocardial infarction pretreated with prasugrel or ticagrelor may require urgent coronary artery bypass grafting (CABG). However, prasugrel and ticagrelor withdrawal period is recommended for 5–7 days before planned CABG to enable full platelet recovery. We hypothesized that monitoring sequential platelet reactivity (PR) could identify patients with early platelet recovery who may benefit from earlier surgery before the guideline-recommended 5–7 day delay. Patients and methods We performed preoperative PR assays in 35 patients with acute myocardial infarction who received prasugrel (60%) or ticagrelor (40%) and required an urgent CABG. When platelet inhibition levels were favorable, on the basis of the VerifyNow assay, surgery was endorsed. CABG-related bleeding parameters were collected and compared with two matched control groups composed of patients who received fewer potent antiplatelet regimens. Results On the basis of platelet function monitoring, we identified 21 (56.7%) patients with a relatively earlier platelet recovery who underwent CABG before the end of the conventional washout period (5–7 days). For these patients, the washout periods were shortened to an average time of 2.6±1.0 days for ticagrelor and 3.8±1.5 days for prasugrel. CABG-related bleeding parameters were comparable with the two matched control groups. Conclusion A strategy of performing preoperative PR assays can identify patients who recover platelet function in less than 5–7 days after ticagrelor or prasugrel discontinuation. This strategy may provide the basis for performing urgent CABGs earlier than the currently recommended delay. Future, larger studies are required to establish these preliminary findings.

Implications of blood group on lung transplantation rates: A propensity-matched registry analysis

BACKGROUND Blood type O lung allografts may be allocated to blood type identical (type O) or compatible (non-O) candidates. We tested the hypothesis that the current organ allocation schema in the United States-based on the Lung Allocation Score-prejudices against the allocation of allografts to type O candidates, given that the pool of potential donors is smaller. METHODS We performed a retrospective cohort review of the Organ Procurement and Transplantation Network/United Network of Organ Sharing registry from May 2005 to March 2017 for adult candidates on the waiting list for first-time isolated lung transplantation. Demographic data were compiled and described, and 1:1 nearest-neighbor propensity score matching was used to adjust for age and Lung Allocation Score at listing. RESULTS A total of 26,396 candidates met inclusion criteria: 14,329 type non-O and candidates and 12,068 type O candidates. After matching, 11,951 candidates were included in each group. Of these, 77.0% of type non-O underwent lung transplantation vs 73.1% type O (p < 0.001). At 1 year, the waiting list mortality was higher for type O candidates (12.5%) than for non-O candidates (10.1%, p < 0.001). Of those undergoing transplantation, 5-year survival rates were similar. CONCLUSIONS Type O candidates experience lower rates of transplantation and higher rates of waiting list mortality compared with matched type non-O candidates. Further evaluation of regional sharing of allografts to increase transplantation rates for type O candidates may be warranted to optimize equity in access to transplants.