Tricuspid regurgitation progression and regression in pulmonary arterial hypertension: implications for right ventricular and tricuspid valve apparatus geometry and patients outcome.

AIMS: The aim of this study was to determine the mechanism of tricuspid regurgitation (TR) progression in pulmonary arterial hypertension (PAH) and its effect on survival. METHODS AND RESULTS: We studied 88 patients with PAH and functional TR (mean pulmonary artery pressure 49 ± 14 mmHg; 43% idiopathic PAH) who had serial echocardiograms. TR progression (n = 35) was defined as ≤mild TR on Echo 1 and ≥moderate TR on Echo 2. TR regression (n = 17) was defined as ≥moderate TR on Echo 1 and ≤mild TR on Echo 2. Stable TR (n = 36) was defined as ≤mild TR on both echoes. TR progression was associated with an increase in pulmonary artery systolic pressure (PASP, 62 ± 22-92 ± 23 mmHg, P < 0.0001), right ventricular (RV) enlargement, mainly at mid-ventricular level, increased RV sphericity (6.1 ± 1.7-6.9 ± 1.8, P = 0.004), tricuspid annular (TA) dilatation (4.0 ± 0.7-4.6 ± 0.7 cm, P < 0.0001), and increased tricuspid valve (TV) tenting area (2.0 ± 0.7-2.5 ± 1.0 cm2, P = 0.0003). TR regression was associated with a reduction in PASP (84 ± 15-55 ± 18 mmHg, P < 0.0001), reverse RV remodelling with a reduction in RV sphericity (6.3 ± 1.4-5.5 ± 1.0, P = 0.02), and a reduction in TA size (4.1 ± 0.7-3.6 ± 0.7 cm, P = 0.02) and TV tenting (2.1 ± 0.7-1.3 ± 0.5 cm2, P = 0.0002). TR progression was associated with all-cause mortality (log-rank P = 0.0007). CONCLUSION: In PAH, TR progression was associated with worsening pulmonary hypertension and adverse RV and TV apparatus remodelling. TR progression is associated with poor outcome in PAH.

Phase I safety study of ranolazine in pulmonary arterial hypertension.

UNLABELLED: Pulmonary arterial hypertension (PAH) causes right ventricular ischemia, dysfunction, and failure. PAH patients may benefit from antianginal agents based on a shared pathophysiology with left ventricular ischemia. A single-center, randomized, placebo-controlled trial (1∶1) to assess the acute vasoreactivity and safety of ranolazine in PAH was conducted. Plasma samples for pharmacokinetic (PK) studies were drawn during hemodynamic measurements at 0, 60, 90, 120, 240, and 360 minutes from a Swan-Ganz catheter. All patients received 500-mg doses, uptitrated to 1,000 mg at week 4, monthly evaluations, and a complete objective assessment after 12 weeks, followed by an open-label extension. Thirteen patients were randomized and 12 enrolled (6 ranolazine, 6 placebo). All patients completed the acute phase; 10 completed the 12-week study. There were no acute changes in invasive hemodynamics. At 12 weeks ranolazine was well tolerated. Only 1 of the 5 patients on ranolazine had a serum concentration considered to be in the therapeutic range. Two serious adverse events required early withdrawal (both in the ranolazine group); gastrointestinal complaints were the most common adverse event. Efficacy measures did not demonstrate any differences between treatment groups. During the open-label trial, 2 additional patients reached a therapeutic concentration. Ranolazine in PAH appears safe, without acute hemodynamic effects after a 500-mg dose. Ranolazine administrated to PAH patients receiving background PAH therapies did not consistently reach therapeutic levels. Future studies should first perform PK analysis in PAH patients receiving PAH therapies and explore the safety and tolerability of the higher doses perhaps necessary to achieve therapeutic levels in PAH patients. ( TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01757808.).

Identification of a variant in KDR associated with serum VEGFR2 and pharmacodynamics of Pazopanib.

PURPOSE: VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors. EXPERIMENTAL DESIGN: We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy. RESULTS: rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10(-37)). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01). CONCLUSION: Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors.

Technical considerations in the development of circulating peptides as pharmacodynamic biomarkers for angiogenesis inhibitors.

To determine the biological reproducibility and estimate relevant covariates for candidate circulating biomarkers of angiogenesis, we conducted 3 sub-studies with ≤15 subjects each. In study 1, 6 healthy subjects provided 13 blood samples across 14-24 days. In study 2, 15 advanced solid tumor patients provided single blood samples before, and approximately 8 and 40 days after sorafenib treatment. In study 3, 4 healthy subjects provided blood samples on 3 occasions over 14 days, processed simultaneously in 2 different laboratories at a single institution. Vascular endothelial growth factor (VEGFA), soluble VEGF receptor-2 (sVEGFR2), and angiopoietin-2 (Ang2) concentrations in plasma and serum were determined by standard immunoassays. Ang2 and sVEGFR2 demonstrated low variance within and high variance across individuals reflected by the high intraclass correlation coefficient (for Ang2: 0.86 for plasma, 0.89 for serum; for sVEGFR2: 0.91 for plasma, 0.87 for serum). Repeated measures linear modeling from 15 patients demonstrated increased Ang2 (P ≤ 0.05) and decreased sVEGFR2 (P ≤ 0.05) after exposure to sorafenib. VEGFA had high intraindividual variance, and study 3 demonstrated the laboratory to have significant effects on plasma measurements (P ≤ 0.05). The biological reproducibility of sVEGFR2 and Ang2 support further use of these markers in studies of vasculature-targeted therapeutics.