Kaleigh L. Evans

Reduction of Na/K-ATPase affects cardiac remodeling and increases c-kit cell abundance in partial nephrectomized mice

The current study examined the role of Na/K-ATPase α1-subunit in animals subjected to 5/6th partial nephrectomy (PNx) using Na/K-ATPase α1-heterozygous (α1(+/-)) mice and their wild-type (WT) littermates. After PNx, both WT and α1(+/-) animals displayed diastolic dimension increases, increased blood pressure, and increased cardiac hypertrophy. However, in the α1(+/-) animals we detected significant increases in cardiac cell death in PNx animals. Given that reduction of α1 elicited increased cardiac cell death with PNx, while at the same time these animals developed cardiac hypertrophy, an examination of cardiac cell number, and proliferative capabilities of those cells was carried out. Cardiac tissues were probed for the progenitor cell marker c-kit and the proliferation marker ki-67. The results revealed that α1(+/-) mice had significantly higher numbers of c-kit-positive and ki-67-positive cells, especially in the PNx group. We also found that α1(+/-) mice express higher levels of stem cell factor, a c-kit ligand, in their heart tissue and had higher circulating levels of stem cell factor than WT animals. In addition, PNx induced significant enlargement of cardiac myocytes in WT mice but has much less effect in α1(+/-) mice. However, the total cell number determined by nuclear counting is higher in α1(+/-) mice with PNx compared with WT mice. We conclude that PNx induces hypertrophic growth and high blood pressure regardless of Na/K-ATPase content change. However, total cardiac cell number as well as c-kit-positive cell number is increased in α1(+/-) mice with PNx.

Effects of Na/K-ATPase and its ligands on bone marrow stromal cell differentiation.

Endogenous ligands of Na/K-ATPase have been demonstrated to increase in kidney dysfunction and heart failure. It is also reported that Na/K-ATPase signaling function effects stem cell differentiation. This study evaluated whether Na/K-ATPase activation through its ligands and associated signaling functions affect bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) differentiation capacity. BMSCs were isolated from male Sprague-Dawley rats and cultured in minimal essential medium alpha (MEM-α) supplemented with 15% Fetal Bovine serum (FBS). The results showed that marinobufagenin (MBG), a specific Na/K-ATPase ligand, potentiated rosiglitazone-induced adipogenesis in these BMSCs. Meanwhile, it attenuated BMSC osteogenesis. Mechanistically, MBG increased CCAAT/enhancer binding protein alpha (C/EBPα) protein expression through activation of an extracellular regulated kinase (ERK) signaling pathway, which leads to enhanced rosiglitazone-induced adipogenesis. Inhibition of ERK activation by U0126 blocks the effect of MBG on C/EBPα expression and on rosiglitazone-induced adipogenesis. Reciprocally, MBG reduced runt-related transcription factor 2 (RunX2) expression, which resulted in the inhibition of osteogenesis induced by β-glycerophosphate/ascorbic acid. MBG also potentiated rosiglitazone-induced adipogenesis in 3T3-L1 cells and in mouse BMSCs. These results suggest that Na/K-ATPase and its signaling functions are involved in the regulation of BMSCs differentiation.

Use of Renin-Angiotensin Inhibitors in People with Renal Artery Stenosis

BACKGROUND AND OBJECTIVES People with atherosclerotic renal artery stenosis may benefit from renin-angiotensin inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers, but little is known about the factors associated with their use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Cardiovascular Outcomes in Renal Atherosclerotic Lesions study (ClinicalTrials.gov identified: NCT00081731) is a prospective, international, multicenter clinical trial that randomly assigned participants with atherosclerotic renal artery stenosis who received optimal medical therapy to stenting versus no stenting from May 2005 through January 2010. At baseline, medication information was available from 853 of 931 randomly assigned participants. Kidney function was measured by serum creatinine-based eGFR at a core laboratory. RESULTS Before randomization, renin-angiotensin inhibitors were used in 419 (49%) of the 853 participants. Renin-angiotensin inhibitor use was lower in those with CKD (eGFR<60 ml/min per 1.73 m(2)) (58% versus 68%; P=0.004) and higher in individuals with diabetes (41% versus 27%; P<0.001). Presence of bilateral renal artery stenosis or congestive heart failure was not associated with renin-angiotensin inhibitor use. Although therapy with renin-angiotensin inhibitors varied by study site, differences in rates of use were not related to the characteristics of the site participants. Participants receiving a renin-angiotensin inhibitor had lower systolic BP (mean ± SD, 148 ± 23 versus 152 ± 23 mmHg; P=0.003) and more often had BP at goal (30% versus 22%; P=0.01). CONCLUSIONS Kidney function and diabetes were associated with renin-angiotensin inhibitor use. However, these or other clinical characteristics did not explain variability among study sites. Patients with renal artery stenosis who received renin-angiotensin inhibitor treatment had lower BP and were more likely to be at treatment goal.

Henry Ford HEART Score Randomized Trial: Rapid Discharge of Patients Evaluated for Possible Myocardial Infarction

Background— Hospital evaluation of patients with chest pain is common and costly. The HEART score risk stratification tool that merges troponin testing into a clinical risk model for evaluation emergency department patients with possible acute myocardial infarction (AMI) has been shown to effectively identify a substantial low-risk subset of patients possibly safe for early discharge without stress testing, a strategy that could have tremendous healthcare savings implications. Method and Results— A total of 105 patients evaluated for AMI in the emergency departments of 2 teaching hospitals in the Henry Ford Health System (Detroit and West Bloomfield, MI), between February 2014 and May 2015, with a modified HEART score ⩽3 (which includes cardiac troponin I <0.04 ng/mL at 0 and 3 hours) were randomized to immediate discharge (n=53) versus management in an observation unit with stress testing (n=52). The primary end points were 30-day total charges and length of stay. Secondary end points were all-cause death, nonfatal AMI, rehospitalization for evaluation of possible AMI, and coronary revascularization at 30 days. Patients randomized to early discharge, compared with those who were admitted for observation and cardiac testing, spent less time in the hospital (median 6.3 hours versus 25.9 hours; P<0.001) with an associated reduction in median total charges of care (

Regional and physician specialty–associated variations in the medical management of atherosclerotic renal–artery stenosis

2953 versus

THE PROGNOSTIC UTILITY OF A MODIFIED HEART SCORE IN PATIENTS WITH CHEST PAIN IN THE EMERGENCY DEPARTMENT APPLIED TO THE TRAPID-AMI STUDY

9616; P<0.001). There were no deaths, AMIs, or coronary revascularizations in either group. One patient in each group was lost to follow-up. Conclusions— Among patients evaluated for possible AMI in the emergency department with a modified HEART score ⩽3, early discharge without stress testing as compared with transfer to an observation unit for stress testing was associated with significant reductions in length of stay and total charges, a finding that has tremendous potential national healthcare expenditure implications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT03058120

Endovascular Versus Medical Therapy for Atherosclerotic Renovascular Disease

For people enrolled in Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), we sought to examine whether variation exists in the baseline medical therapy of different geographic regions and if any variations in prescribing patterns were associated with physician specialty. Patients were grouped by location within the United States (US) and outside the US (OUS), which includes Canada, South America, Europe, South Africa, New Zealand, and Australia. When comparing US to OUS, participants in the US took fewer anti-hypertensive medications (1.9 ± 1.5 vs. 2.4 ± 1.4; P < .001) and were less likely to be treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (46% vs. 62%; P < .001), calcium channel antagonist (37% vs. 58%; P < .001), and statin (64% vs. 75%; P < .05). In CORAL, the identification of variations in baseline medical therapy suggests that substantial opportunities exist to improve the medical management of patients with atherosclerotic renal-artery stenosis.

Mechanisms and treatments for renal artery stenosis.

The TRAPID-AMI study was a multicenter trial evaluating the high sensitivity cardiac troponin T (hs-cTnT) assay in a rapid “rule-out” acute myocardial infarction (AMI) strategy in the Emergency Department (ED). We evaluated a modified HEART score (HS) to identify a low-risk group that involves