How severity and classification of pulmonary hypertension affect pregnancy outcomes: a systematic review and timeline.

Women with pulmonary hypertension (PH) have increased mortality during pregnancy and the peripartum period. An increasing number of publications suggest improvements in maternal outcomes, so we conducted a systematic review focusing on disease severity and maternal survival. After screening 9097 potential studies from 1967 to 2021, we identified 66 relevant publications. Outcomes improved continuously over time and mortality fell from 11.6% in studies published before 2015 to 8.2% in studies published after 2015. Mortality was lower in patients with mild disease (0.8%) than in those with Eisenmenger syndrome (26.2%) or idiopathic pulmonary arterial hypertension (7.4-24.0%). One major drawback of the published studies is that they define severity using echocardiographic-estimated pulmonary artery pressures, without considering more contemporary parameters. This systematic review provides new insights for preconception counseling on pregnancy risks related to PH and suggests that PH classification and severity should be carefully considered in determining an individual's pregnancy-associated risk.

Analysis of the calcium paradox of renin secretion.

The secretion of the protease renin from renal juxtaglomerular cells is enhanced by subnormal extracellular calcium concentrations. The mechanisms underlying this atypical effect of calcium have not yet been unraveled. We therefore aimed to characterize the effect of extracellular calcium concentration on calcium handling of juxtaglomerular cells and on renin secretion in more detail. For this purpose, we used a combination of experiments with isolated perfused mouse kidneys and direct calcium measurements in renin-secreting cells in situ. We found that lowering of the extracellular calcium concentration led to a sustained elevation of renin secretion. Electron-microscopical analysis of renin-secreting cells exposed to subnormal extracellular calcium concentrations revealed big omega-shaped structures resulting from the intracellular fusion and subsequent emptying of renin storage vesicles. The calcium concentration dependencies as well as the kinetics of changes were rather similar for renin secretion and for renovascular resistance. Since vascular resistance is fundamentally influenced by myosin light chain kinase (MLCK), myosin light chain phosphatase (MLCP), and Rho-associated protein kinase (Rho-K) activities, we examined the effects of MLCK-, MLCP-, and Rho-K inhibitors on renin secretion. Only MLCK inhibition stimulated renin secretion. Conversely, inhibition of MCLP activity lowered perfusate flow and strongly inhibited renin secretion, which could not be reversed by lowering of the extracellular calcium concentration. Renin-secreting cells and smooth muscle cells of afferent arterioles showed immunoreactivity of MLCK. These findings suggest that the inhibitory effect of calcium on renin secretion could be explained by phosphorylation-dependent processes under control of the MLCK.