Impact of baseline hemodynamics on the effects of a transcatheter interatrial shunt device in heart failure with preserved ejection fraction

Background: Interatrial shunt device (IASD) effects have been described in patients with heart failure and ejection fractions (EFs) ≥40%. However, baseline characteristics that correlate with greatest hemodynamic effects are unknown. On the basis of fundamental principles, we hypothesized that larger pressure gradients between left and right atria would yield greater shunt flow and greater hemodynamic effects. Methods and Results: REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a multicenter study that investigated IASD safety and performance. Sixty-four patients with EF ≥40% underwent device implantation followed by hemodynamic assessments at rest and exercise, including pulmonary capillary wedge pressure (PCWP, surrogate for left atrial pressure) and central venous pressure (CVP). At 6 months, IASD resulted in an average pulmonary-to-systemic blood flow ratio of 1.27 and increased exercise tolerance. The PCWP-CVP gradient (ie, the driving pressure for shunt flow) decreased at peak exercise from 16.8±6.9 to 11.4±5.5 mm Hg, because of increased CVP (17.5±5.4 to 20.3±7.9 mm Hg; P=0.04) and decreased PCWP (34.1±7.6 to 31.6±8.0 mm Hg; P=0.025). Baseline PCWP-CVP gradient during exercise correlated with changes of both PCWP-CVP and PCWP: Δ(PCWP-CVP)=10.0−0.89·(PCWP-CVP)baseline (r2=0.56) and ΔPCWP=7.54−0.60·(PCWP-CVP)baseline (P=0.001). Hemodynamics of patients with EF ≥50% and those with EF <50% responded similarly to IASD. Conclusions: In heart failure patients with EF ≥40%, IASD significantly reduced PCWP and PCWP-CVP at peak exercise. Patients with higher baseline PCWP-CVP gradient had greater reductions in both parameters at follow-up. Results were sustained through 12 months and were independent of whether EF was ≥50% or between 40% and 49%. Additional studies will help further define the baseline hemodynamic predictors of exercise, hemodynamic, and clinical efficacy of the IASD. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01913613

Exceptional Diversity, Non-Random Distribution, and Rapid Evolution of Retroelements in the B73 Maize Genome

Recent comprehensive sequence analysis of the maize genome now permits detailed discovery and description of all transposable elements (TEs) in this complex nuclear environment. Reiteratively optimized structural and homology criteria were used in the computer-assisted search for retroelements, TEs that transpose by reverse transcription of an RNA intermediate, with the final results verified by manual inspection. Retroelements were found to occupy the majority (>75%) of the nuclear genome in maize inbred B73. Unprecedented genetic diversity was discovered in the long terminal repeat (LTR) retrotransposon class of retroelements, with >400 families (>350 newly discovered) contributing >31,000 intact elements. The two other classes of retroelements, SINEs (four families) and LINEs (at least 30 families), were observed to contribute 1,991 and ∼35,000 copies, respectively, or a combined ∼1% of the B73 nuclear genome. With regard to fully intact elements, median copy numbers for all retroelement families in maize was 2 because >250 LTR retrotransposon families contained only one or two intact members that could be detected in the B73 draft sequence. The majority, perhaps all, of the investigated retroelement families exhibited non-random dispersal across the maize genome, with LINEs, SINEs, and many low-copy-number LTR retrotransposons exhibiting a bias for accumulation in gene-rich regions. In contrast, most (but not all) medium- and high-copy-number LTR retrotransposons were found to preferentially accumulate in gene-poor regions like pericentromeric heterochromatin, while a few high-copy-number families exhibited the opposite bias. Regions of the genome with the highest LTR retrotransposon density contained the lowest LTR retrotransposon diversity. These results indicate that the maize genome provides a great number of different niches for the survival and procreation of a great variety of retroelements that have evolved to differentially occupy and exploit this genomic diversity

Detailed Analysis of a Contiguous 22-Mb Region of the Maize Genome

Most of our understanding of plant genome structure and evolution has come from the careful annotation of small (e.g., 100 kb) sequenced genomic regions or from automated annotation of complete genome sequences. Here, we sequenced and carefully annotated a contiguous 22 Mb region of maize chromosome 4 using an improved pseudomolecule for annotation. The sequence segment was comprehensively ordered, oriented, and confirmed using the maize optical map. Nearly 84% of the sequence is composed of transposable elements (TEs) that are mostly nested within each other, of which most families are low-copy. We identified 544 gene models using multiple levels of evidence, as well as five miRNA genes. Gene fragments, many captured by TEs, are prevalent within this region. Elimination of gene redundancy from a tetraploid maize ancestor that originated a few million years ago is responsible in this region for most disruptions of synteny with sorghum and rice. Consistent with other sub-genomic analyses in maize, small RNA mapping showed that many small RNAs match TEs and that most TEs match small RNAs. These results, performed on ∼1% of the maize genome, demonstrate the feasibility of refining the B73 RefGen_v1 genome assembly by incorporating optical map, high-resolution genetic map, and comparative genomic data sets. Such improvements, along with those of gene and repeat annotation, will serve to promote future functional genomic and phylogenomic research in maize and other grasses

Retrospective Outcome Data for Hematopoietic Stem Cell Transplantation in Patients with Concurrent Coronary Artery Disease

Hematopoietic stem cell transplantation (HSCT) represents an extended period of physiologic stress. It is unknown whether patients with pre-existing coronary artery disease (CAD) may be poor transplant candidates. There are no data analyzing the risk of transplantation in this population. Sixty-nine patients with CAD who underwent 72 transplantations, autologous and allogeneic, were identified retrospectively. Fifty-five percent of these patients had prior percutaneous coronary intervention, 42% had verifiable history of myocardial infarction, and 23% had prior coronary artery bypass grafting. Outcomes were compared to 1109 patients without established CAD who underwent 1183 transplants during the same time period. Cancer diagnoses in the 2 groups were similar, predominantly lymphoma, multiple myeloma, and leukemia. There was no significant difference between the CAD group and the control group with respect to type of transplant (autologous 68% versus 64%, P = .612, myeloablative 86% versus 85%, P = .867). Treatment-related mortality was no different in the CAD group versus the control group (5.6% versus 4.9%, P = .777), nor were there differences in mortality at 1 year (15.3% versus 16.6%, P = .871), urgent intensive care unit admission (11.1% versus 9.9%, P = .686), or length of stay (25.5 days versus 28.4 days, P = .195). These findings suggest many patients with underlying coronary artery disease may be safely managed through hematopoietic stem cell transplantation