Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension.

RATIONALE: BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH. OBJECTIVES: To determine how an acquired deficiency of BMP9 signaling might contribute to PAH. METHODS: Plasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. MEASUREMENTS AND MAIN RESULTS: BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone. CONCLUSIONS: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

An audit of postoperative haemodynamic stability after intraoperative labetalol administration in non-cardiac surgery patients.

Anaesthesiologists commonly use intravenous labetalol to adjust patient haemodynamics during surgical procedures. Cases of profound hypotension after continuous labetalol infusions have been reported; however, there is limited evidence regarding the safety of intraoperative labetalol boluses. This audit examined the frequency of postoperative hypotension and bradycardia in 292 adult non-cardiac surgery patients treated with intraoperative labetalol boluses. Blood pressure and heart rate data were collected from the post-anaesthesia care unit and on the floor units for 24 hours after surgery. The median total intraoperative labetalol dose was 10mg. A total of 30/292 patients had all-cause postoperative hypotension within 24 hours of surgery, 26 of which had other medical or surgical precipitants. Fifteen patients developed bradycardia. There were no deaths or intensive care unit admissions attributed to labetalol. This audit demonstrates a low risk of all-cause postoperative hypotension (10%) and bradycardia (5%) after the use of small IV doses of intraoperative labetalol.

The role of bone morphogenetic protein signaling in vascular calcification.

Vascular calcification is associated with atherosclerosis, chronic kidney disease, and diabetes, and results from processes resembling endochondral or intramembranous ossification, or from processes that are distinct from ossification. Bone morphogenetic proteins (BMP), as well as other ligands, receptors, and regulators of the transforming growth factor beta (TGFß) family regulate vascular and valvular calcification by modulating the phenotypic plasticity of multipotent progenitor lineages associated with the vasculature or valves. While osteogenic ligands BMP2 and BMP4 appear to be both markers and drivers of vascular calcification, particularly in atherosclerosis, BMP7 may serve to protect against calcification in chronic kidney disease. BMP signaling regulators such as matrix Gla protein and BMP-binding endothelial regulator protein (BMPER) play protective roles in vascular calcification. The effects of BMP signaling molecules in vascular calcification are context-dependent, tissue-dependent, and cell-type specific. Here we review the current knowledge on mechanisms by which BMP signaling regulates vascular calcification and the potential therapeutic implications.

ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension.

Human genetics, biomarker, and animal studies implicate loss of function in bone morphogenetic protein (BMP) signaling and maladaptive transforming growth factor-ß (TGFß) signaling as drivers of pulmonary arterial hypertension (PAH). Although sharing common receptors and effectors with BMP/TGFß, the function of activin and growth and differentiation factor (GDF) ligands in PAH are less well defined. Increased expression of GDF8, GDF11, and activin A was detected in lung lesions from humans with PAH and experimental rodent models of pulmonary hypertension (PH). ACTRIIA-Fc, a potent GDF8/11 and activin ligand trap, was used to test the roles of these ligands in animal and cellular models of PH. By blocking GDF8/11- and activin-mediated SMAD2/3 activation in vascular cells, ACTRIIA-Fc attenuated proliferation of pulmonary arterial smooth muscle cells and pulmonary microvascular endothelial cells. In several experimental models of PH, prophylactic administration of ACTRIIA-Fc markedly improved hemodynamics, right ventricular (RV) hypertrophy, RV function, and arteriolar remodeling. When administered after the establishment of hemodynamically severe PH in a vasculoproliferative model, ACTRIIA-Fc was more effective than vasodilator in attenuating PH and arteriolar remodeling. Potent antiremodeling effects of ACTRIIA-Fc were associated with inhibition of SMAD2/3 activation and downstream transcriptional activity, inhibition of proliferation, and enhancement of apoptosis in the vascular wall. ACTRIIA-Fc reveals an unexpectedly prominent role of GDF8, GDF11, and activin as drivers of pulmonary vascular disease and represents a therapeutic strategy for restoring the balance between SMAD1/5/9 and SMAD2/3 signaling in PAH.

Responsiveness of 2 procedures for measurement of temporal and spatial gait parameters in older adults.

OBJECTIVE: To determine the responsiveness of the GAITRite system and a stopwatch-footfall count technique for measurement of walking speed, cadence, and stride length during comfortable and fast-paced walking. DESIGN: Criterion standard. SETTING: Research laboratory in a physical therapy education program. PARTICIPANTS: Twenty-four healthy volunteers (13 men, 11 women; mean age 74.5 years) without lower extremity injury or history of falls. INTERVENTIONS: Participants walked across a GAITRite mat with embedded pressure sensors at their self-selected comfortable and fast walking speeds. Simultaneously, an examiner, using a stopwatch, recorded the elapsed time necessary to cross the mat and counted the number of complete footfalls. MAIN OUTCOME MEASURE(S): Walking speed, cadence, and stride length were compared between the GAITRite system and the stopwatch-footfall count technique for both comfortable and fast walking speeds. Responsiveness values for each procedure were described by the 95% minimal detectable change (MDC). RESULTS: During comfortable self-paced walking, MDC values for the stopwatch-footfall count technique ranged from 10% to 65% greater than those obtained for the GAITRite system. During fast self-paced walking MDC values for the stopwatch-footfall count technique ranged from 26% to 65% larger than those measured by the GAITRite system for the temporal and spatial gait performance parameters. CONCLUSIONS: When measured by the GAITRite system, the 95% MDC values for temporal and spatial gait parameters of older community-dwelling adults were more responsive to change than those obtained by the stopwatch-footfall technique. Clinicians should recognize that self-selected walking speed, cadence, and stride length when obtained by an instrumented walkway must be equal to or exceed 12.6 cm/s, 8.4 steps/min, or 7 cm, respectively, for the change to be considered real change and not from measurement error.

Number of strides required for reliable measurements of pace, rhythm and variability parameters of gait during normal and dual task walking in older individuals.

The reliability with which spatiotemporal gait parameters are measured has neither been well-established for variability parameters nor during dual task walking. The purpose of this study was to examine test-retest reliability of three gait parameters representing pace, rhythm and variability in healthy older persons during normal and dual task walking and to determine the number of strides necessary to measure the parameters reliably. Twenty-four healthy adults aged 65 or older participated in the study. Subjects walked during normal and dual task (backward spelling) walking conditions at self-selected speeds and then repeated the tests. Velocity, cadence and variability in stride velocity were measured with GAITRite instrumentation. Intraclass correlation coefficients (ICCs) were calculated and the numbers of strides required to meet desired magnitudes of reliability were estimated with the Spearman-Brown prophecy formula. ICCs for velocity and cadence were high (>0.841) during normal and dual task walking, indicating strong test-retest reliability. Test-retest reliability for variability in stride velocity was moderate (ICC=0.656) in normal walking and poor (ICC=0.226) in dual task walking. While data collected from fewer than 10 to 20 strides may reliably measure velocity and cadence in either normal or dual task walking, measuring variability in stride velocity reliably may require that data be collected from hundreds of strides, particularly in dual task walking.