In summary we here provide insights into questions raised as

In summary, we here provide insights into questions raised as a result of clinical experiences: How does clevidipine cause dyspnea relief in hypertensive AHF? What explains the specificity of this effect for clevidipine and not for other DHPs? What underlies the apparent potency differences between clevidipine effects on pulmonary and peripheral circulations? Could clevidipine cause dyspnea relief independent of any BP lowering effects? We here describe new CaV1.2 splice variants in human lung that have increased, selective affinity for clevidipine compared to other DHPs. Panx1 association with this high-affinity CaV1.2 variant further augments its affinity for clevidipine, but not for nicardipine. These observations could explain many of the clinical differences noted above. These experiments refine our understanding of how CaV1.2 alternative splicing produces specific molecular pharmacologic profiles among drugs of the same class. Because these pharmacologic profiles can explain important clinical observations, the possibility now exists to deploy more refined clinical trial designs and endpoints to better examine the role of DHP in the treatment of pulmonary hypertension and acute hypertensive heart failure.
Author Contributions
Acknowledgments
Introduction Pregnancy failure and placenta mediated pregnancy complications (PMPC), miscarriage, fetal growth restriction (FGR), pre-eclampsia (PE) and abruption, collectively affect over 25% of pregnancies. Fifteen per cent of clinically recognized pregnancies end in miscarriage, with 5% of women experiencing ≥2 losses, and 1–2% ≥3 losses (Rai and Regan, 2006). With assisted conception, 76.3% of all cycles (that include such PMPC) do not result in a live birth (Macaldowie et al., 2014). Diagnosis of PMPC is largely based on clinical outcome rather than cause, despite heterogeneous disease processes generating the same clinical pregnancy outcome (Greer et al., 2014). The largest single cause of first trimester miscarriage is due to Amyloid Beta-Peptide (1-40) Supplier aneuploidy. The remainder are unexplained, reflecting limited knowledge of implantation and placentation. The current focus on precision medicine (Collins and Varmus, 2015) emphasizes the need to stratify PMPC by mechanism, without which potential therapies may be rejected as ineffective when assessed in a heterogeneous patient group (Greer et al., 2014). For PMPC there is biological plausibility for coagulation activation being an underlying mechanism in a proportion of these events. The pathological features include deficient implantation, placental infarction, and microvascular thrombosis (Greer et al., 2014). The biological plausibility is enhanced by our knowledge of antiphospholipid syndrome, which is associated with thrombotic placental damage, and increased thrombin generation. Antithrombotic therapy guided by a biomarker, antiphospholipid antibodies, is associated with improved pregnancy outcome (Greer et al., 2014; Empson et al., 2005). In contrast, trials of antithrombotic intervention in unselected women at risk of PMPC, based on outcome of previous pregnancies, has been found to be ineffective (Greer et al., 2014; Kaandorp et al., 2010; Clark et al., 2010; Martinelli et al., 2012; Pasquier et al., 2015; Schleussner et al., 2015). However, an approach based on stratification for a specific thrombotic process underlying these PMPC, would be appropriate before discarding such treatment. This requires a biomarker. One possible biomarker is Annexin–A5 (ANXA5), an anticoagulant protein highly expressed on the apical surfaces of syncytiotrophoblasts, ANXA5 prevents coagulation processes by forming a two dimensional lattice which can be disrupted by antiphospholipid antibodies (Van Genderen et al., 2008), and has been reported to promote cell membrane repair in the syncytiotrophoblast layer (Bouter et al., 2015). The annexin A5 M2 haplotype (ANXA5 M2) is associated with reduced expression of ANXA5 in placentas from M2 haplotype carriers presenting with PE and FGR (Ota et al., 2013; Chinni et al., 2009; Markoff et al., 2010). Further, the M2 haplotype is associated with an increased risk of PMPCs: recurrent pregnancy loss (RPL) (Bogdanova et al., 2007; Tiscia et al., 2009; Miyamura et al., 2011; Rogenhofer et al., 2012; Tüttelmann et al., 2013; Hock et al., 2015; Demetriou et al., 2015), FGR (Tiscia et al., 2009) small for gestational age infants (Tiscia et al., 2012), and gestational hypertension (Tiscia et al., 2009). The haplotype is transmitted equally by males and females (Ota et al., 2013; Chinni et al., 2009; Markoff et al., 2010; Rogenhofer et al., 2012).