Terlipressin Increases Systemic and Lowers Pulmonary Arterial Pressure in Experimental Acute Pulmonary Embolism.

OBJECTIVES: We investigated whether the vasopressin-analog, terlipressin induces systemic vasoconstriction and pulmonary vasodilation in a porcine model of acute pulmonary embolism. DESIGN: Controlled, animal study. SETTING: Tertiary medical center research laboratory. SUBJECTS: Female pigs (n = 12, Cross of Land Race, Duroc, and Yorkshire ~ 60 kg). INTERVENTIONS: Acute pulmonary embolism was induced by administration of three large autologous emboli. Animals then received four increasing doses of either terlipressin (n = 6) or vehicle (n = 6). MEASUREMENTS AND MAIN RESULTS: Effects were evaluated in vivo at baseline, after pulmonary embolism and after each dose by invasive hemodynamic measures, transesophageal echocardiography, and blood analysis. Isolated pulmonary arteries were evaluated ex vivo in a myograph. Pulmonary embolism caused a four-fold increase in pulmonary vascular resistance (p < 0.0001) and a two-fold increase in mean pulmonary arterial pressure (p < 0.0001) compared with baseline. Terlipressin increased mean systemic blood pressure (28 ± 5 mm Hg; p < 0.0001) and systemic vascular resistance (1,320 ± 143 dynes; p < 0.0001) compared with vehicle. In the pulmonary circulation, terlipressin decreased mean pulmonary arterial pressure (-6.5 ± 1.8 mm Hg; p = 0.005) and tended to decrease pulmonary vascular resistance (-83 ± 33 dynes; p = 0.07). Terlipressin decreased cardiac output (-2.5 ± 0.5 L/min; p < 0.0001) and increased plasma lactate (2.7 ± 0.2 mmol/L; p < 0.0001), possibly indicating systemic hypoperfusion. A biomarker of cerebral ischemia, S100b, remained unchanged, suggesting preserved cerebral perfusion (0.17 ± 0.11 µg/L; p = 0.51). Ex vivo, terlipressin relaxed pulmonary and constricted mesenteric arteries. CONCLUSIONS: Terlipressin caused systemic vasoconstriction and pulmonary vasodilation in a porcine in vivo model of acute pulmonary embolism and vasorelaxation in isolated pulmonary arteries. Despite positive vascular effects, cardiac output declined and plasma lactate increased probably due to a predominantly systemic vasoconstrictor effect of terlipressin. These findings should warrant careful translation to the clinical setting and does not suggest routine use in acute pulmonary embolism.

Transcriptional and posttranscriptional mechanisms contribute to the dysregulation of elastogenesis in Schimke immuno-osseous dysplasia.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.

The surviving monozygotic twin.

It has been suggested that because of vascular interchange between the monozygous twins vascular disruptions from a deceased cotwin with disseminated intravascular coagulation causes embolisation in the surviving twin. This study reports six cases in which all the surviving monozygous twins had central nervous system infarcts and three had multiple organ infarcts, including pulmonary and hepatic infarcts, which have not been reported previously. Fetal death in utero occurred 1-11 weeks before the live birth of the monozygous survivor. In three cases there was pathological confirmation of a continuing process with infarcts ranging in age from a few days to eight weeks. Four infants died in the early neonatal period, and the remaining two survived with considerable handicap. A review of the published reports confirmed the high risk of vascular disruption affecting many organ systems and the extremely poor prognosis for subsequent death or handicap. We recommend that after detection of fetal death in utero in a suspected monozygous twin pregnancy careful consideration should be given to prompt delivery of the survivor and investigations should be carried out to rule out infarction in the central nervous system and other organs that are at risk.