Transcatheter Aortic Valve Replacement and Impact of Subclinical Leaflet Thrombosis in Low-Risk Patients: LRT Trial 4-Year Outcomes.

BACKGROUND: The LRT trial (Low-Risk Transcatheter Aortic Valve Replacement [TAVR]) demonstrated the safety and feasibility of TAVR in low-risk patients, with excellent 1- and 2-year outcomes. The objective of the current study is to provide the overall clinical outcomes and the impact of 30-day hypoattenuated leaflet thickening (HALT) on structural valve deterioration at 4 years. METHODS: The prospective, multicenter LRT trial was the first Food and Drug Administration-approved investigational device exemption study to evaluate feasibility and safety of TAVR in low-risk patients with symptomatic severe tricuspid aortic stenosis. Clinical outcomes and valve hemodynamics were documented annually through 4 years. RESULTS: A total of 200 patients were enrolled, and follow-up was available on 177 patients at 4 years. The rates of all-cause mortality and cardiovascular death were 11.9% and 3.3%, respectively. The stroke rate rose from 0.5% at 30 days to 7.5% at 4 years, and permanent pacemaker implantation rose from 6.5% at 30 days to 11.7% at 4 years. Endocarditis was detected in 2.5% of the cohort, with no new cases reported between 2 and 4 years. Transcatheter heart valve hemodynamics remained excellent post-procedure and were maintained (mean gradient 12.56±5.54 mm Hg and aortic valve area 1.69±0.52 cm2) at 4 years. At 30 days, HALT was observed in 14% of subjects who received a balloon-expandable transcatheter heart valve. There was no difference in valve hemodynamics between patients with and without HALT (mean gradient 14.94±5.01 mm Hg versus 12.3±5.57 mm Hg; P=0.23) at 4 years. The overall rate of structural valve deterioration was 5.8%, and there was no impact of HALT on valve hemodynamics, endocarditis, or stroke at 4 years. CONCLUSIONS: TAVR in low-risk patients with symptomatic severe tricuspid aortic stenosis was found to be safe and durable at 4 years. Structural valve deterioration rates were low irrespective of the type of valve, and the presence of HALT at 30 days did not affect structural valve deterioration, transcatheter valve hemodynamics, and stroke rate at 4 years. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02628899.

Pulmonary artery smooth muscle cell HIF-1α regulates endothelin expression via microRNA-543.

Pulmonary artery smooth muscle cells (PASMCs) express endothelin (ET-1), which modulates the pulmonary vascular response to hypoxia. Although cross-talk between hypoxia-inducible factor-1α (HIF-1α), an O2-sensitive transcription factor, and ET-1 is established, the cell-specific relationship between HIF-1α and ET-1 expression remains incompletely understood. We tested the hypotheses that in PASMCs 1) HIF-1α expression constrains ET-1 expression, and 2) a specific microRNA (miRNA) links HIF-1α and ET-1 expression. In human (h)PASMCs, depletion of HIF-1α with siRNA increased ET-1 expression at both the mRNA and protein levels ( P < 0.01). In HIF-1α-/- murine PASMCs, ET-1 gene and protein expression was increased ( P < 0.0001) compared with HIF-1α+/+ cells. miRNA profiles were screened in hPASMCs transfected with siRNA-HIF-1α, and RNA hybridization was performed on the Agilent (Santa Clara, CA) human miRNA microarray. With HIF-1α depletion, miRNA-543 increased 2.4-fold ( P < 0.01). In hPASMCs, miRNA-543 overexpression increased ET-1 gene ( P < 0.01) and protein ( P < 0.01) expression, decreased TWIST gene expression ( P < 0.05), and increased ET-1 gene and protein expression, compared with nontargeting controls ( P < 0.01). Moreover, we evaluated low passage hPASMCs from control and patients with idiopathic pulmonary arterial hypertension (IPAH). Compared with controls, protein expression of HIF-1α and Twist-related protein-1 (TWIST1) was decreased ( P < 0.05), and miRNA-543 and ET-1 expression increased ( P < 0.001) in hPASMCs from patients with IPAH. Thus, in PASMCs, loss of HIF-1α increases miRNA-543, which decreases Twist expression, leading to an increase in PASMC ET-1 expression. This previously undescribed link between HIF-1α and ET-1 via miRNA-543 mediated Twist suppression represents another layer of molecular regulation that might determine pulmonary vascular tone.

Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia.

Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1(flox/flox) mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1(+/+) and ET-1(-/-) mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1(-/-) and SM22α-ET-1(+/+) (control) littermates. After exposure to hypoxia (10% O2, 21-24 days), RVSP was and vascular remodeling were less in SM22α-ET-1(-/-) mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC.

Saphenous vein graft disease: review of pathophysiology, prevention, and treatment.

Saphenous vein graft (SVG) disease after coronary artery bypass grafting (CABG) occurs in three phases: thrombosis, intimal hyperplasia, and atherosclerosis. Within the first month, thrombosis plays a major role. From month 1 to month 12, intimal hyperplasia occurs. Beyond 12 months, atherosclerosis becomes the primary cause for late graft failure. Endothelial damage has been shown to be the major underlying pathophysiology of SVG disease. Many factors contribute to endothelial damage from the moment the vein is harvested to when the vein is grafted into an arterial environment. To address this disease process, various therapeutic modalities, from surgical methods to medical treatment, have been evaluated. Surgically, the technical method of harvesting the vein has been shown to affect SVG patency. From a pharmacologic perspective, only two guideline class I recommended medications, aspirin and statins, have been shown to improve short- and long-term SVG patency after CABG. Despite these surgical and medical advances, SVG disease remains a significant problem with 1-year patency rates of 89% dropping to 61% after 10 years. This review discusses the pathogenesis of SVG disease, predictors of SVG failure, and current surgical and pharmacologic therapies to address SVG disease, including possible future treatment.

Recurrent orthostatic syncope due to left atrial and left ventricular collapse after a continuous-flow left ventricular assist device implantation.

Left ventricular assist devices (LVADs) have become an established treatment for patients with advanced heart failure as a bridge to transplantation or for permanent support as an alternative to heart transplantation. Continuous-flow LVADs have been shown to improve outcomes, including survival, and reduce device failure compared with pulsatile devices. Although LVADs have been shown to be a good option for patients with end-stage heart failure, unanticipated complications may occur. We describe dynamic left atrial and left ventricular chamber collapse related to postural changes in a patient with a recent continuous-flow LVAD implantation.

Renal hemodynamic and ureteral pressure changes in response to ureteral obstruction: the role of nitric oxide.

PURPOSE: Triphasic changes in renal blood flow and ureteral pressure after unilateral ureteral obstruction have long been known. The contribution of nitric oxide to the decline in renal blood flow and ureteral pressure in unilateral ureteral obstruction was studied in this model using arginine infusion and by studying the effect of 2 inhibitors of nitric oxide synthase (NOS). MATERIALS AND METHODS: Left ureteral obstruction was created in dogs. Renal blood flow and ureteral pressure were monitored. Groups 1 to 4 underwent unilateral ureteral obstruction and group 5 dogs underwent sham operation. Groups 2 to 5 received an infusion of arginine at hour 18 of obstruction that was sustained for 1 hour. In addition, NOS inhibitors were administered to dogs in groups 3 (N-monomethyl-L-arginine) and 4 (triamcinolone diacetate). RESULTS: Arginine administration at 18 hours of obstruction caused a significant increase in renal blood flow and ureteral pressure compared to sham operated animals. Triamcinolone diacetate eliminated the increase in renal blood flow and ureteral pressure, whereas N-monomethyl-L-arginine did not, reflecting the competitive nature of its inhibition of NOS. CONCLUSIONS: Arginine infusion 18 hours after unilateral ureteral obstruction led to increases in renal blood flow and ureteral pressure that were not seen in control animals. These results suggest that the nitric oxide system of the kidney is activated in unilateral ureteral obstruction. Since the addition of arginine is accompanied by an increase in renal blood flow and ureteral pressure, it further suggests that a lack of availability of substrate for NOS may explain the decrease in renal blood flow and ureteral pressure in obstruction. Providing substrate may be a way of maintaining renal blood flow in unilateral ureteral obstruction.

Bladder stone in a 3-year-old Dominican male.

Bladder stones forming in the absence of underlying uropathy are termed primary, or endemic, bladder stones. They are prevalent among children in certain developing nations of Asia and northern Africa. Dietary deficiencies have been implicated in the cause of such stones, because they occur in regions of malnutrition and poverty; yet studies remain inconclusive. Interestingly, reports are lacking of primary bladder stones occurring in Central and South America, as well as in the Caribbean and Pacific islands, where certainly there are areas of impoverishment. The reasons for this remain unclear. This article presents the case of a primary bladder stone occurring in a patient from the Dominican Republic.