Left Ventricular Assist Devices: A Primer for the Non-Mechanical Circulatory Support Provider

Survival after implant of a left ventricular assist device (LVAD) continues to improve for patients with end-stage heart failure. Meanwhile, more patients are implanted with a destination therapy, rather than bridge-to-transplant, indication, meaning the population of patients living long-term on LVADs will continue to grow. Non-LVAD healthcare providers will encounter such patients in their scope of practice, and familiarity and comfort with the physiology and operation of these devices and common problems is essential. This review article describes the history, development, and operation of the modern LVAD. Common LVAD-related complications such as bleeding, infection, stroke, and right heart failure are reviewed and an approach to the patient with an LVAD is suggested. Nominal operating parameters and device response to various physiologic conditions, including hypo- and hypervolemia, hypertension, and device failure, are reviewed

Early Cardiopulmonary Fitness after Heart Transplantation as a Determinant of Post-Transplant Survival

Background: Decreased peak oxygen consumption during exercise (peak Vo2) is a well-established prognostic marker for mortality in ambulatory heart failure. After heart transplantation, the utility of peak Vo2 as a marker of post-transplant survival is not well established. Methods and Results: We performed a retrospective analysis of adult heart transplant recipients at the Hospital of the University of Pennsylvania who underwent cardiopulmonary exercise testing within a year of transplant between the years 2000 to 2011. Using time-to-event models, we analyzed the hazard of mortality over nearly two decades of follow-up as a function of post-transplant percent predicted peak Vo2 (%Vo2). A total of 235 patients met inclusion criteria. The median post-transplant %Vo2 was 49% (IQR 42 to 60). Each standard deviation (±14%) increase in %Vo2 was associated with a 32% decrease in mortality in adjusted models (HR 0.68, 95% CI 0.53 to 0.87, p = 0.002). A %Vo2 below 29%, 64% and 88% predicted less than 80% survival at 5, 10, and 15 years, respectively. Conclusions: Post-transplant peak Vo2 is a highly significant prognostic marker for long-term post-transplant survival. It remains to be seen whether decreased peak Vo2 post-transplant is modifiable as a target to improve post-transplant longevity

Association Between Sleep Disordered Breathing and Left Ventricular Function: A Cross-Sectional Analysis of the ECHO-SOL Ancillary Study

Prior studies have found that sleep-disordered breathing (SDB) is common among those with left ventricular (LV) dysfunction and heart failure. Few epidemiological studies have examined this association, especially in US Hispanic/Latinos, who may be at elevated risk of SDB and heart failure. We examined associations between SDB and LV diastolic and systolic function using data from 1506 adults aged 18 to 64 years in the Hispanic Community Health Study/Study of Latinos ECHO-SOL Ancillary Study (2011-2014). Home sleep testing was used to measure the apnea-hypopnea index, a measure of SDB severity. Echocardiography was performed a median of 2.1 years later to quantify LV diastolic function, systolic function, and structure. Multivariable linear regression was used to model the association between apnea-hypopnea index and echocardiographic measures while accounting for the complex survey design, demographics, body mass, and time between sleep and echocardiographic measurements. Each 10-unit increase in apnea-hypopnea index was associated with 0.2 (95% CI, 0.1-0.3) lower E', 0.3 (0.1-0.5) greater E/E' ratio, and 1.07-fold (1.03-1.11) higher prevalence of diastolic dysfunction as well as 1.3 (0.3-2.4) g/m greater LV mass index. These associations persisted after adjustment for hypertension and diabetes mellitus. In contrast, no association was identified between SDB severity and subclinical markers of LV systolic function. Greater SDB severity was associated with LV hypertrophy and subclinical markers of LV diastolic dysfunction. These findings suggest SDB in Hispanic/Latino men and women may contribute to the burden of heart failure in this population

Distinct plasma gradients of microRNA-204 in the pulmonary circulation of patients suffering from WHO Groups I and II pulmonary hypertension

Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n = 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope = 0.22 [95% CI = 0.06-0.37], P = 0.008). PBMCs revealed insignificant miR-204 variations among PH groups ( P = 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 ( P = 0.0004), and a converse increase of extracellular miR-204 ( P = 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration

Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation

Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1, MSH2, and MSH6, including 12 missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants. Keywords: Lynch syndrome; mRNA splicing; mismatch repair genes; splicing aberrations; variant interpretation and classification; variant type

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome–associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases