Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

Elevated pulmonary arterial and systemic plasma aldosterone levels associate with impaired cardiac reserve capacity during exercise in left ventricular systolic heart failure patients: A pilot study.

BACKGROUND: Elevated levels of aldosterone are a modifiable contributor to clinical worsening in heart failure with reduced ejection fraction (HFrEF). Endothelin-1 (ET-1), which is increased in HFrEF, induces pulmonary endothelial aldosterone synthesis in vitro. However, whether transpulmonary aldosterone release occurs in humans or aldosterone relates to functional capacity in HFrEF is not known. Therefore, we aimed to characterize ET-1 and transpulmonary aldosterone levels in HFrEF and determine if aldosterone levels relate to peak volume of oxygen uptake (pVO2). METHODS: Data from 42 consecutive HFrEF patients and 18 controls referred for invasive cardiopulmonary exercise testing were analyzed retrospectively. RESULTS: Radial ET-1 levels (median [interquartile range]) were higher in HFrEF patients compared with controls (17.5 [11.5-31.4] vs 11.5 [4.4-19.0] pg/ml, p = 0.04). A significant ET-1 transpulmonary gradient (pulmonary arterial [PA] - radial arterial levels) was present in HFrEF (p < 0.001) but not in controls (p = 0.24). Compared with controls, aldosterone levels (median [interquartile range]) were increased in HFrEF patients in the PA (364 [250-489] vs 581 [400-914] ng/dl, p < 0.01) and radial compartments (366 [273-466] vs 702 [443-1223] ng/dl, p < 0.001). Akin to ET-1, a transpulmonary increase (median [interquartile range]) in aldosterone concentration was also observed between controls and HFrEF patients at rest (7.5 [-54 to 40] vs 61.6 [-13.6 to 165] ng/dl, p = 0.01) and peak exercise (-20.7 [-39.6 to 79.1] vs 25.8 [-29.2 to 109.3] ng/dl, p = 0.02). The adjusted pVO2 correlated inversely with aldosterone levels at peak activity in the PA (r = -0.31, p = 0.01) and radial artery (r = -0.32, p = 0.01). CONCLUSIONS: These data provide preliminary evidence in support of increased transpulmonary aldosterone levels in HFrEF and suggest an inverse relationship between circulating aldosterone and pVO2. Future prospective studies are needed to characterize the functional effects of transpulmonary and circulating aldosterone on cardiac reserve capacity in HFrEF.

Protocol for exercise hemodynamic assessment: performing an invasive cardiopulmonary exercise test in clinical practice.

Invasive cardiopulmonary exercise testing (iCPET) combines full central hemodynamic assessment with continuous measurements of pulmonary gas exchange and ventilation to help in understanding the pathophysiology underpinning unexplained exertional intolerance. There is increasing evidence to support the use of iCPET as a key methodology for diagnosing heart failure with preserved ejection fraction and exercise-induced pulmonary hypertension as occult causes of exercise limitation, but there is little information available outlining the methodology to use this diagnostic test in clinical practice. To bridge this knowledge gap, the operational protocol for iCPET at our institution is discussed in detail. In turn, a standardized iCPET protocol may provide a common framework to describe the evolving understanding of mechanism(s) that limit exercise capacity and to facilitate research efforts to define novel treatments in these patients.

Differences in mechanisms of failure, intraoperative findings, and surgical characteristics between single- and multiple-revision ACL reconstructions: a MARS cohort study.

BACKGROUND: The factors that lead to patients failing multiple anterior cruciate ligament (ACL) reconstructions are not well understood. HYPOTHESIS: Multiple-revision ACL reconstruction will have different characteristics than first-time revision in terms of previous and current graft selection, mode of failure, chondral/meniscal injuries, and surgical charactieristics. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A prospective multicenter ACL revision database was utilized for the time period from March 2006 to June 2011. Patients were divided into those who underwent a single-revision ACL reconstruction and those who underwent multiple-revision ACL reconstructions. The primary outcome variable was Marx activity level. Primary data analyses between the groups included a comparison of graft type, perceived mechanism of failure, associated injury (meniscus, ligament, and cartilage), reconstruction type, and tunnel position. Data were compared by analysis of variance with a post hoc Tukey test. RESULTS: A total of 1200 patients (58% men; median age, 26 years) were enrolled, with 1049 (87%) patients having a primary revision and 151 (13%) patients having a second or subsequent revision. Marx activity levels were significantly higher (9.77) in the primary-revision group than in those patients with multiple revisions (6.74). The most common cause of reruptures was a traumatic, noncontact ACL graft injury in 55% of primary-revision patients; 25% of patients had a nontraumatic, gradual-onset recurrent injury, and 11% had a traumatic, contact injury. In the multiple-revision group, a nontraumatic, gradual-onset injury was the most common cause of recurrence (47%), followed by traumatic noncontact (35%) and nontraumatic sudden onset (11%) (P < .01 between groups). Chondral injuries in the medial compartment were significantly more common in the multiple-revision group than in the single-revision group, as were chondral injuries in the patellofemoral compartment. CONCLUSION: Patients with multiple-revision ACL reconstructions had lower activity levels, were more likely to have chondral injuries in the medial and patellofemoral compartments, and had a high rate of a nontraumatic, recurrent injury of their graft.