Sickle cell disease is characterized by recurrent episodes of ischemia-reperfusion injury to multiple vital organ systems and a chronic hemolytic anemia, both contributing to progressive organ ...dysfunction. The introduction of treatments that induce protective fetal hemoglobin and reduce infectious complications has greatly prolonged survival. However, with increased longevity, cardiovascular complications are increasingly evident, with the notable development of a progressive proliferative systemic vasculopathy, pulmonary hypertension (PH), and left ventricular diastolic dysfunction. Pulmonary hypertension is reported in autopsy studies, and numerous clinical studies have shown that increased pulmonary pressures are an important risk marker for mortality in these patients. In epidemiological studies, the development of PH is associated with intravascular hemolysis, cutaneous leg ulceration, renal insufficiency, iron overload, and liver dysfunction. Chronic anemia in sickle cell disease results in cardiac chamber dilation and a compensatory increase in left ventricular mass. This is often accompanied by left ventricular diastolic dysfunction that has also been a strong independent predictor of mortality in patients with sickle cell disease. Both PH and diastolic dysfunction are associated with marked abnormalities in exercise capacity in these patients. Sudden death is an increasingly recognized problem, and further cardiac investigations are necessary to recognize and treat high-risk patients.
The accurate segmentation of cardiac images into anatomically meaningful regions is critical for the extraction of quantitative cardiac indices. The common pipeline for segmentation comprises regions ...of interest (ROIs) localization and segmentation stages that are independent of each other and typically performed using separate models. In this paper, we propose an end-to-end network, called Trilateral Attention Network (TaNet), for real-time region localization and segmentation. TaNet has a module for ROIs localization and three segmentation pathways: spatial pathway, handcrafted pathway, and context pathway. The localization module focuses segmentation attention on the desired region while learning the context relationship between different regions in the image. The localized regions are then sent to the three pathways for segmentation. The spatial pathway, which has regular convolutional kernels, is used to extract deep features at different levels of abstraction. The handcrafted pathway, which has hand-designed convolutional kernels, is used to extract a unique set of features complementary to the deep features. Finally, the context (or global) pathway is used to enlarge the receptive field. By jointly training TaNet for localization and segmentation, TaNet achieved superior performance, in terms of accuracy and speed, when evaluated on two echocardiography datasets for cardiac region segmentation.
Clinical application of cardiac magnetic resonance (CMR) is expanding but CMR assessment of LV diastolic function is still being validated. The purpose of this study was to validate assessments of ...left ventricular (LV) diastolic dysfunction (DD) using CMR by comparing with transthoracic echocardiography (TTE) performed on the same day. Patients with suspected or diagnosed cardiomyopathy (n = 63) and healthy volunteers (n = 24) were prospectively recruited and included in the study. CMR diastolic parameters were measured on cine images and velocity-encoded phase contrast cine images and compared with corresponding parameters measured on TTE. A contextual correlation feature tracking method was developed to calculate the mitral annular velocity curve. LV DD was classified by CMR and TTE following 2016 guidelines. Overall DD classification was 78.1% concordant between CMR and TTE (p < 0.0001). The trans-mitral inflow parameters correlated well between the two modalities (E, r = 0.78; A, r = 0.90; E/A, r = 0.82; all p < 0.0001) while the remaining diastolic parameters showed moderate correlation (e', r = 0.64; E/e', r = 0.54; left atrial volume index (LAVi), r = 0.61; all p < 0.0001). Classification of LV diastolic function by CMR showed good concordance with standardized grades established for TTE. CMR-based LV diastolic function may be integrated in routine clinical practice.Name of the registry: Technical Development of Cardiovascular Magnetic Resonance Imaging. Trial registration number: NCT00027170. Date of registration: November 26, 2001. URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT00027170.
BackgroundChimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies ...examining cardiac toxicity are limited.MethodsWe report on cardiac toxicity observed in children and young adults with hematologic malignancies enrolled in a CD19-28ζ CAR T-cell phase I trial (NCT01593696). All patients had a formal baseline echocardiogram. Real-time studies included echocardiograms on intensive care unit (ICU) transfer, and serial troponin and pro-B-type natriuretic peptide (pro-BNP) in the select patients.ResultsFrom July 2012 to March 2016, 52 patients, with a median age of 13.4 years (range 4.2–30.3) were treated. CRS developed in 37/52 (71%), which was grade 3–4 CRS in nine patients (17%). The median prior anthracycline exposure was 205 mg/m2 (range 70–620 mg/m2) in doxorubicin equivalents. The median baseline left ventricle ejection fraction (LVEF) and baseline LV global longitudinal strain (GLS) were 60% (range 50%–70%) and 16.8% (range 14.1%–23.5%, n=37) respectively. The majority, 78% (29/37), of patients had a reduced GLS <19% at baseline, and 6% (3/52) of patients had baseline LVEF <53%. ICU transfers occurred in 21 patients, with nine requiring vasoactive hemodynamic support and three necessitating >1 vasopressor. Six (12%) patients developed cardiac dysfunction (defined by >10% absolute decrease in LVEF or new-onset grade 2 or higher LV dysfunction, per CTCAE v4), among whom 4 had grade 3–4 CRS. Troponin elevations were seen in 4 of 13 patients, all of whom had low LVEF. Pro-BNP was elevated from baseline in 6/7 patients at the onset of CRS, with higher levels correlating with more severe CRS. Cardiac dysfunction fully resolved in all but two patients by day 28 post-CAR.ConclusionCardiac toxicity related to CD19-28ζ CAR T-cell-associated CRS was generally reversible by day 28 postinfusion. Implementation of more frequent monitoring with formal echocardiograms incorporating systemic analysis of changes in GLS, and cardiac biomarkers (troponin and proBNP) may help to earlier identify those patients at highest risk of severe cardiac systolic dysfunction, facilitating earlier interventions for CRS to potentially mitigate acute cardiac toxicity.
The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial.
We evaluated the relationship between an elevated estimated pulmonary artery systolic ...pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥ 3.0 m/s cuttof, which has a 67-75% positive predictive value for mean pulmonary artery pressure ≥ 25 mm Hg was used. Among 572 subjects, 11.2% had TRV ≥ 3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥ 160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV ≥ 3.0 m/sec. At 24 months the cumulative survival was 83% with TRV ≥ 3.0 m/sec and 98% with TRV < 3.0 m/sec (p < 0.0001). The hazard ratios for death were 11.1 (95% CI 4.1-30.1; p < 0.0001) for TRV ≥ 3.0 m/sec, 4.6 (1.8-11.3; p = 0.001) for NT-proBNP ≥ 160 pg/mL, and 14.9 (5.5-39.9; p < 0.0001) for both TRV ≥ 3.0 m/sec and NT-proBNP ≥ 160 pg/mL. Age > 47 years, male gender, chronic transfusions, WHO class III-IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death.
A TRV ≥ 3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable. The study is registered in ClinicalTrials.gov with identifier: NCT00492531.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This article describes the detailed phenotype of 15 children, 1 to 17 years of age, with Hutchinson–Gilford progeria syndrome, a rare, sporadic autosomal dominant premature aging syndrome causing ...death at approximately 13 years of age. Most cases are caused by an
LMNA
gene mutation that produces an abnormal lamin A, “progerin.” Since progerin accumulates in normal cells with age, understanding this syndrome may offer insight into normal aging.
This article describes the detailed phenotype of 15 children with Hutchinson–Gilford progeria syndrome, a rare, sporadic autosomal dominant premature aging syndrome causing death at approximately 13 years of age.
Some aspects of human aging appear to be dramatically accelerated in the Hutchinson–Gilford progeria syndrome, an extremely rare sporadic disorder (Figure 1).
1
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3
Within approximately 13 years after birth, affected children die from cardiovascular disease. The cause is abnormal lamin A (denoted “progerin,” to distinguish it from normal lamin A), which is produced by an activated cryptic splice donor site created by a change from glycine GGC to glycine GGT in codon 608 of exon 11 of the lamin A (
LMNA
) gene.
4
,
5
Progerin disrupts the structural integrity of the inner nuclear membrane in a dominant negative fashion. . . .
ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human ...subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data. In the initial phase of ClinSeq, we are enrolling roughly 1000 participants; the evaluation of each includes obtaining a detailed family and medical history, as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for whole-genome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits. The participants are also being consented to allow the contact of family members for additional studies of sequence variants to explore their potential association with specific phenotypes. Here, we present the general considerations in designing ClinSeq, preliminary results based on the generation of an initial 826 Mb of sequence data, the findings for several genes that serve as positive controls for the project, and our views about the potential implications of ClinSeq. The early experiences with ClinSeq illustrate how large-scale medical sequencing can be a practical, productive, and critical component of research in genomic medicine.
Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is ...excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3
years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis.
Aortic Valve Disease in Turner Syndrome Sachdev, Vandana, MD; Matura, Lea Ann, RNP, PhD; Sidenko, Stanislav, BA ...
Journal of the American College of Cardiology,
05/2008, Letnik:
51, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Aortic Valve Disease in Turner Syndrome Vandana Sachdev, Lea Ann Matura, Stanislav Sidenko, Vincent B. Ho, Andrew E. Arai, Douglas R. Rosing, Carolyn A. Bondy We used echocardiography and magnetic ...resonance imaging to examine aortic valve anatomy and ascending aorta diameter in 253 female subjects with Turner syndrome (TS). Aortic valves were bicuspid in 74 of 250 (30%) adequately imaged subjects. Most abnormal aortic valves resulted from fusion of right/left coronary leaflets. Ascending aortic diameters were significantly greater in the bicuspid aortic valve (BAV) group, with aortic root dilation in 25% of subjects with BAV versus 5% of those with tricuspid aortic valve. Girls and women with TS need focused screening of the aortic valve upon diagnosis to identify the 1 in 3, usually asymptomatic, individuals needing monitoring for aortic root dilation and aortic valve dysfunction.
Over the past decade, the field of valvular heart disease (VHD) has rapidly transformed, largely as a result of the development and improvement of less invasive transcatheter approaches to valve ...repair or replacement. This transformation has been supported by numerous well-designed randomized trials, but they have centered almost entirely on devices and procedures. Outside this scope of focus, however, myriad aspects of therapy and management for patients with VHD have either no guidelines or recommendations based only on expert opinion and observational studies. Further, research in VHD has often failed to engage patients to inform study design and identify research questions of greatest importance and relevance from a patient perspective. Accordingly, the National Heart, Lung, and Blood Institute convened a Working Group on Patient-Centered Research in Valvular Heart Disease, composed of clinician and research experts and patient advocacy experts to identify gaps and barriers to research in VHD and identify research priorities. While recognizing that important research remains to be done to test the safety and efficacy of devices and procedures to treat VHD, we intentionally focused less attention on these areas of research as they are more commonly pursued and supported by industry. Herein, we present the patient-centered research gaps, barriers, and priorities in VHD and organized our report according to the "patient journey," including access to care, screening and diagnosis, preprocedure therapy and management, decision making when a procedure is contemplated (clinician and patient perspectives), and postprocedure therapy and management. It is hoped that this report will foster collaboration among diverse stakeholders and highlight for funding bodies the pressing patient-centered research gaps, opportunities, and priorities in VHD in order to produce impactful patient-centered research that will inform and improve patient-centered policy and care.
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