Genetic and genomic basis of antibody response to porcine reproductive and respiratory syndrome (PRRS) in gilts and sows.

BACKGROUND: Our recent research showed that antibody response to porcine reproductive and respiratory syndrome (PRRS), measured as sample-to-positive (S/P) ratio, is highly heritable and has a high genetic correlation with reproductive performance during a PRRS outbreak. Two major quantitative trait loci (QTL) on Sus scrofa chromosome 7 (SSC7; QTLMHC and QTL130) accounted for ~40 % of the genetic variance for S/P. Objectives of this study were to estimate genetic parameters for PRRS S/P in gilts during acclimation, identify regions associated with S/P, and evaluate the accuracy of genomic prediction of S/P across populations with different prevalences of PRRS and using different single nucleotide polymorphism (SNP) sets. METHODS: Phenotypes and high-density SNP genotypes of female pigs from two datasets were used. The outbreak dataset included 607 animals from one multiplier herd, whereas the gilt acclimation (GA) dataset included data on 2364 replacement gilts from seven breeding companies placed on health-challenged farms. Genomic prediction was evaluated using GA for training and validation, and using GA for training and outbreak for validation. Predictions were based on SNPs across the genome (SNPAll), SNPs in one (SNPMHC and SNP130) or both (SNPSSC7) QTL, or SNPs outside the QTL (SNPRest). RESULTS: Heritability of S/P in the GA dataset increased with the proportion of PRRS-positive animals in the herd (from 0.28 to 0.47). Genomic prediction accuracies ranged from low to moderate. Average accuracies were highest when using only the 269 SNPs in both QTL regions (SNPSSC7, with accuracies of 0.39 and 0.31 for outbreak and GA validation datasets, respectively. Average accuracies for SNPALL, SNPMHC, SNP130, and SNPRest were, respectively, 0.26, 0.39, 0.21, and 0.05 for the outbreak, and 0.28, 0.25, 0.22, and 0.12, for the GA validation datasets. CONCLUSIONS: Moderate genomic prediction accuracies can be obtained for PRRS antibody response using SNPs located within two major QTL on SSC7, while the rest of the genome showed limited predictive ability. Results were obtained using data from multiple genetic sources and farms, which further strengthens these findings. Further research is needed to validate the use of S/P ratio as an indicator trait for reproductive performance during PRRS outbreaks.

Sex Differences in Systemic and Coronary Arterial Hemodynamics in Heart Failure With Preserved Ejection Fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) predominantly affects females. Systemic and coronary arterial abnormalities are present in HFpEF and may contribute to HFpEF in females. We performed a cross-sectional study of 32 participants with HFpEF and 26 controls. Arterial hemodynamics were noninvasively assessed by combining arterial tonometry with echocardiography. Coronary microvascular function was assessed by rubidium-82 positron emission tomography as the myocardial flow reserve. Coronary vascular resistance (CVR) at rest and vasodilator stress were calculated using positron emission tomography. CVR reserve was calculated as stress - rest CVR. Multivariable linear regression assessed the associations of female sex with arterial hemodynamics in participants with and without HF, and the association of HF with arterial hemodynamics within each sex stratum. Demographics and left ventricular systolic and diastolic function were similar between males and females. Among those with HFpEF, females had a higher steady and pulsatile arterial load and more impaired (less negative) CVR reserve than males. Conversely, in controls, females had similar hemodynamics to males. We then divided the sample based on sex. Femaleswith HFpEF had a higher pulsatile arterial load and higher stress CVR than control females. Among males, arterial hemodynamics were similar, regardless of HFpEF status. The measures of early pulsatile arterial load were independently associated with higher E/e' and lower myocardial flow reserve in females only. In conclusion, despite similar left ventricular function between sexes, older females with HFpEF are characterized by additional systemic and coronary arterial hemodynamic abnormalities compared with males with HFpEF and similarly aged females without HFpEF.

Purebred-crossbred genetic parameters for reproductive traits in swine.

For swine breeding programs, testing and selection programs are usually within purebred (PB) populations located in nucleus units that are generally managed differently and tend to have a higher health level than the commercial herds in which the crossbred (CB) descendants of these nucleus animals are expected to perform. This approach assumes that PB animals selected in the nucleus herd will have CB progeny that have superior performance at the commercial level. There is clear evidence that this may not be the case for all traits of economic importance and, thus, including data collected at the commercial herd level may increase the accuracy of selection for commercial CB performance at the nucleus level. The goal for this study was to estimate genetic parameters for five maternal reproductive traits between two PB maternal nucleus populations (Landrace and Yorkshire) and their CB offspring: Total Number Born (TNB), Number Born Alive (NBA), Number Born Alive > 1 kg (NBA > 1 kg), Total Number Weaned (TNW), and Litter Weight at Weaning (LWW). Estimates were based on single-step GBLUP by analyzing any two combinations of a PB and the CB population, and by analyzing all three populations jointly. The genomic relationship matrix between the three populations was generated by using within-population allele frequencies for relationships within a population, and across-population allele frequencies for relationships of the CB with the PB animals. Utilization of metafounders for the two PB populations had no effect on parameter estimates, so the two PB populations were assumed to be genetically unrelated. Joint analysis of two (one PB plus CB) vs. three (both PB and CB) populations did not impact estimates of heritability, additive genetic variance, and genetic correlations. Heritabilities were generally similar between the PB and CB populations, except for LWW and TNW, for which PB populations had about four times larger estimates than CB. Purebred-crossbred genetic correlations (rpc) were larger for Landrace than for Yorkshire, except for NBA > 1 kg. These estimates of rpc indicate that there is potential to improve selection of PB animals for CB performance by including CB information for all traits in the Yorkshire population, but that noticeable additional gains may only occur for NBA > 1 kg and TNW in the Landrace population.

Cardiac Sympathetic Positron Emission Tomography Imaging with Meta-[18F]Fluorobenzylguanidine is Sensitive to Uptake-1 in Rats.

Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias. Molecular imaging probes such as meta-[123I]iodobenzylguanidine have demonstrated the utility of assessing neuronal integrity by targeting norepinephrine transporter (NET, uptake-1). However, current radiotracers can report only on innervation due to suboptimal kinetics and lack sensitivity to NET in rodents, precluding mechanistic studies in these species. The objective of this work was to characterize myocardial sympathetic neuronal uptake mechanisms and kinetics of the positron emission tomography (PET) radiotracer meta-[18F]fluorobenzylguanidine ([18F]mFBG) in rats. Automated synthesis using spirocyclic iodonium(III) ylide radiofluorination produces [18F]mFBG in 24 ± 1% isolated radiochemical yield and 30-95 GBq/µmol molar activity. PET imaging in healthy rats delineated the left ventricle, with monoexponential washout kinetics (kmono = 0.027 ± 0.0026 min-1, Amono = 3.08 ± 0.33 SUV). Ex vivo biodistribution studies revealed tracer retention in the myocardium, while pharmacological treatment with selective NET inhibitor desipramine, nonselective neuronal and extraneuronal uptake-2 inhibitor phenoxybenzamine, and neuronal ablation with neurotoxin 6-hydroxydopamine reduced myocardial retention by 33, 76, and 36%, respectively. Clearance of [18F]mFBG from the myocardium was unaffected by treatment with uptake-1 and uptake-2 inhibitors following peak myocardial activity. These results suggest that myocardial distribution of [18F]mFBG in rats is dependent on both NET and extraneuronal transporters and that limited reuptake to the myocardium occurs. [18F]mFBG may therefore prove useful for imaging intraneuronal dysfunction in small animals.

Is ventilatory efficiency (VE/VCO(2) slope) associated with right ventricular oxidative metabolism in patients with congestive heart failure?

BACKGROUND: The relationship between minute ventilation and the rate of CO2 elimination (VE/VCO2 slope) is associated with mortality in patients with congestive heart failure (CHF). The VE/VCO2 slope > or =34 denotes a poor prognosis and has been proposed to reflect abnormalities in pulmonary perfusion. AIMS: To study whether increased VE/VCO2 slope is associated with elevated right ventricular (RV) oxidative metabolism relative to the left ventricle (LV). METHODS: 21 patients with stable NYHA II-III CHF underwent symptom limited cardiopulmonary exercise testing. Dynamic [(11)C]acetate positron emission tomography (PET) was used to measure oxidative metabolism (k(mono)) of the LV and RV. Corrected RV oxidative metabolism (RVOx) was calculated as RV/LV k(mono) ratio. RESULTS: Peak VO2 was 16.2+/-4.1 ml/min/kg and the VE/VCO2 slope was 33.4+/-6.1. LV and RV k(mono) were 0.046+/-0.009 and 0.037+/-0.007 min(-1), respectively, with a RVOx of 0.83+/-0.17. There was a good correlation between RVOx and the VE/VCO2 slope (r=0.61, p=0.0034). RVOx was 0.77+/-0.16 in patients with a VE/VCO2 slope <34 and 0.93+/-0.16 in patients with VE/VCO2 slope > or =34 (p=0.047). CONCLUSION: RVOx correlates with VE/VCO2 slope in CHF patients. This supports the hypothesis that pulmonary vascular resistance is a determinant of the VE/VCO2 slope.

Putative Loci Causing Early Embryonic Mortality in Duroc Swine.

Lethal recessive alleles that act prenatally may be detected from the absence of homozygous individuals in a population. However, these alleles may be maintained at relatively low frequencies in populations as heterozygotes. In pigs, they may reduce litter size. This study aimed to detect putative lethal variants in the Duroc breed. Phenotypes for the numbers of piglets born (TNB), born live (BA), alive at 24 h (L24), stillborn (SB), and born as mummified fetuses (MM) were available from 5340 recorded litters which resulted from mating of 192 genotyped boars with sows of unknown genotype (dataset 1). An additional 50 litters were produced from parents that were both genotyped (dataset 2). Imputed genotypes of 650K SNPs for 1359 Duroc boars were used in this study. One significant SNP (Bonferroni corrected P = 5.5E-06) was located on SSC14 with 45.3 homozygous individuals expected but none observed. This SNP was significant for mummified fetuses. One hundred fifty two haplotypes were also found to potentially harbor recessive lethal mutations. Twenty-one haplotypes had a significant harmful effect on at least one trait. Two regions, located on SSC8 (144.9-145.5 Mb) and SSC9 (19-19.4 Mb) had significant effects on fertility traits in both datasets. Additionally, regions on SSC1 (82.0-82.8 Mb), SSC3 (73.3-73.7 and 87.1-87.5 Mb) and SSC12 (35.8-36.2 and 50.0-50.5 Mb) had significant deleterious effects on TNB or BA or L24 in dataset 1. Finally, a region on SSC17 (28.7-29.3 Mb) had significant effects on TNB, BA and L24 in dataset 2. A few candidate genes identified within these regions were described as being involved in spermatogenesis and male fertility (TEX14, SEP4, and HSF5), or displayed recessive lethality (CYP26B1, SCD5, and PCF11) in other species. The putative loci detected in this study provide valuable information to potentially increase Duroc litter size by avoiding carrier-by-carrier matings in breeding programs. Further study of the identified candidate genes responsible for such lethal effects may lead to new insights into functions regulating pig fertility.

How common is isolated cardiac sarcoidosis? Extra-cardiac and cardiac findings on clinical examination and whole-body 18F-fluorodeoxyglucose positron emission tomography.

BACKGROUND: Sarcoidosis is a systemic inflammatory disease which can involve nearly any organ. Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. The reported prevalence of isolated cardiac sarcoidosis (CS) varies widely with reported rates of 27-54%. The explanation for this variability is likely multi-factorial but perhaps mostly related to the diagnostic method(s) for assessing extra-cardiac involvement. The primary aim of this study was to assess the rate of isolated CS in a homogeneous, prospectively recruited cohort of patients with clinically manifest CS, using whole body FDG PET-CT imaging as a gold standard. A secondary aim was to describe the extent and distribution of extra-cardiac sarcoidosis at the time of first presentation of clinically manifest CS. METHODS: Patients were prospectively recruited at the time of first presentation with cardiac symptoms. All patients underwent whole-body and cardiac 18F-FDG PET-CT. All patients were examined for presence of skin sarcoidosis and were assessed by an ophthalmologist. RESULTS: 31 patients were included (mean age 56±8years, 17 female, 100% Caucasian). Patients had limited extra-cardiac involvement (mean of 2.2 organs) however using the most precise definition, only 1/31 (3.2%) patients had isolated CS. There were marked differences in right ventricular (RV) and atrial involvement between patients presenting with CS as first presentation compared to patients presenting initially with extra-cardiac disease. CONCLUSIONS: Most patients had limited extra-cardiac involvement at the time of presentation of manifest CS however, isolated CS, using the proposed gold standard, was only observed in one patient.

Deterministic Encapsulation of Human Cardiac Stem Cells in Variable Composition Nanoporous Gel Cocoons To Enhance Therapeutic Repair of Injured Myocardium.

Although cocooning explant-derived cardiac stem cells (EDCs) in protective nanoporous gels (NPGs) prior to intramyocardial injection boosts long-term cell retention, the number of EDCs that finally engraft is trivial and unlikely to account for salutary effects on myocardial function and scar size. As such, we investigated the effect of varying the NPG content within capsules to alter the physical properties of cocoons without influencing cocoon dimensions. Increasing NPG concentration enhanced cell migration and viability while improving cell-mediated repair of injured myocardium. Given that the latter occurred with NPG content having no detectable effect on the long-term engraftment of transplanted cells, we found that changing the physical properties of cocoons prompted explant-derived cardiac stem cells to produce greater amounts of cytokines, nanovesicles, and microRNAs that boosted the generation of new blood vessels and new cardiomyocytes. Thus, by altering the physical properties of cocoons by varying NPG content, the paracrine signature of encapsulated cells can be enhanced to promote greater endogenous repair of injured myocardium.

Comparison of computed tomographic angiography versus rubidium-82 positron emission tomography for the detection of patients with anatomical coronary artery disease.

BACKGROUND: The present study compared computed tomographic coronary angiography (CTA) and positron emission tomography (PET) for the detection of significant anatomical coronary artery stenosis as defined by conventional invasive coronary angiography (CICA). METHODS: The study protocol was approved by the local ethics board, and informed consent was obtained from all patients. Of the 26 patients (mean age 57+/-9 years, 18 men) who prospectively underwent CTA and rubidium-82 PET before CICA, 24 patients had a history of chest pain. Images were interpreted by expert readers and assessed for the presence of anatomically significant coronary stenosis (50% luminal diameter stenosis or greater) or myocardial perfusion defects. Diagnostic test characteristics were analyzed using patient-based, territory-based, vessel-based and segment-based analyses. RESULTS: In the 24 patients referred for chest pain, CTA had similar sensitivity to PET, but was more specific (sensitivity 95% [95% CI 72% to 100%] versus 95% [95% CI 72% to 100%], respectively; specificity 100% [95% CI 46% to 100%] versus 60% [95% CI 17% to 93%], respectively) in the detection of patients with anatomical coronary artery stenosis of 50% or greater. On a per-segment basis of all 26 patients, CTA had a sensitivity, specificity, positive predictive value and negative predictive value of 72%, 99%, 91% and 95%, respectively, in all coronary segments. CONCLUSIONS: Coronary CTA has a similar sensitivity and specificity to rubidium-82 PET for the identification of patients with significant anatomical coronary artery disease.

Effect of cardiac resynchronization on myocardial efficiency and regional oxidative metabolism.

BACKGROUND: Recent studies have demonstrated increased left ventricular contractility with cardiac resynchronization therapy (CRT) using atriobiventricular stimulation. This study evaluated the effect of CRT on myocardial oxidative metabolism and efficiency. METHODS AND RESULTS: Eight patients with New York Heart Association functional class III-IV congestive heart failure were studied during atrial pacing (control) and atriobiventricular stimulation at the same rate. The monoexponential clearance rate of [11C]acetate (k(mono)) was measured with positron emission tomography to assess myocardial oxidative metabolism in the left and right ventricles (LV and RV, respectively). Myocardial efficiency was measured using the work metabolic index (WMI). Stroke volume index improved by 10% (P=0.011) with CRT, although both global LV and RV k(mono) were unchanged compared with control. Septal k(mono) increased by 15% (P=0.04), and the septal/lateral wall k(mono) ratio increased by 22% (P=0.01). WMI increased by 13% (P=0.024) with CRT. CONCLUSIONS: CRT improves LV function without increasing global LV oxidative metabolism, resulting in improved myocardial efficiency. Oxidative metabolism of the interventricular septum increases relative to the lateral wall, which suggests successful resynchronization.

Small-animal molecular imaging methods.

UNLABELLED: The ability to trace or identify specific molecules within a specific anatomic location provides insight into metabolic pathways, tissue components, and tracing of solute transport mechanisms. With the increasing use of small animals for research, such imaging must have sufficiently high spatial resolution to allow anatomic localization as well as sufficient specificity and sensitivity to provide an accurate description of the molecular distribution and concentration. METHODS: Imaging methods based on electromagnetic radiation, such as PET, SPECT, MRI, and CT, are increasingly applicable because of recent advances in novel scanner hardware and image reconstruction software and the availability of novel molecules that have enhanced sensitivity in these methodologies. RESULTS: Small-animal PET has been advanced by the development of detector arrays that provide higher resolution and positron-emitting elements that allow new molecular tracers to be labeled. Micro-MRI has been improved in terms of spatial resolution and sensitivity through increased magnet field strength and the development of special-purpose coils and associated scan protocols. Of particular interest is the associated ability to image local mechanical function and solute transport processes, which can be directly related to the molecular information. This ability is further strengthened by the synergistic integration of PET with MRI. Micro-SPECT has been improved through the use of coded aperture imaging approaches as well as image reconstruction algorithms that can better deal with the photon-limited scan data. The limited spatial resolution can be partially overcome by integrating SPECT with CT. Micro-CT by itself provides exquisite spatial resolution of anatomy, but recent developments in high-spatial-resolution photon counting and spectrally sensitive imaging arrays, combined with x-ray optical devices, hold promise for actual molecular identification by virtue of the chemical bond lengths of molecules, especially biopolymers. CONCLUSION: Given the increasing use of small animals for evaluating new clinical imaging techniques and providing more insight into pathophysiologic phenomena as well as the availability of improved detection systems, scanning protocols, and associated software, the sensitivity and specificity of molecular imaging are increasing.