Echocardiographic evaluation of cardiac function in cynomolgus monkeys over a wide age range.
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ABSTRACT:
SUBMITTER: Nakayama S
PROVIDER: S-EPMC7445060 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Multimodal imaging has allowed cardiac amyloidosis (CA) to be increasingly recognised as a treatable cause of heart failure with preserved ejection fraction, but its prognosis remains poor due to late diagnosis. To assess the left ventricular diastolic function (LVDF) patterns in a large contemporary CA cohort according to the current recommendations and to identify their determinants. We conducted a monocentric, observational study on a cohort of CA patients from a tertiary CA referral centre. Diastolic function was analysed using standard echocardiography and clinical, laboratory and survival parameters were collected. Four hundred and sixty-four patients with one of the three main type of CA were included: 41% had grade III diastolic dysfunction (restrictive mitral pattern), 25% had grade II diastolic dysfunction, and 25% had grade I diastolic dysfunction; 9% were unclassified. No difference was found between the main CA types. After multivariate analyses, grades II and III were independently associated with dyspnoea, elevated NT-proBNP, cardiac infiltration and systolic dysfunction (global longitudinal strain). Grade I patients had a better prognosis. All LVDF patterns can be observed in CA. One quarter of CA patients have grade I LVDF, reflecting the emergence of earlier stage-related phenotypes with a better prognosis.
| S-EPMC8584963 | biostudies-literature
Project description:BACKGROUND:Cardiac power output (CPO), derived from the product of cardiac output and mean aortic pressure, is an important yet underexploited parameter for hemodynamic monitoring of critically ill patients in the intensive-care unit (ICU). The conductance catheter-derived pressure-volume loop area reflects left ventricular stroke work (LV SW). Dividing LV SW by time, a measure of LV SW min-?1 is obtained sharing the same unit as CPO (W). We aimed to validate CPO as a marker of LV SW min-?1 under various inotropic states. METHODS:We retrospectively analysed data obtained from experimental studies of the hemodynamic impact of mild hypothermia and hyperthermia on acute heart failure. Fifty-nine anaesthetized and mechanically ventilated closed-chest Landrace pigs (68?±?1?kg) were instrumented with Swan-Ganz and LV pressure-volume catheters. Data were obtained at body temperatures of 33.0?°C, 38.0?°C and 40.5?°C; before and after: resuscitation, myocardial infarction, endotoxemia, sevoflurane-induced myocardial depression and beta-adrenergic stimulation. We plotted LVSW min-?1 against CPO by linear regression analysis, as well as against the following classical indices of LV function and work: LV ejection fraction (LV EF), rate-pressure product (RPP), triple product (TP), LV maximum pressure (LVPmax) and maximal rate of rise of LVP (LV dP/dtmax). RESULTS:CPO showed the best correlation with LV SW min-?1 (r2?=?0.89; p?<?0.05) while LV EF did not correlate at all (r2?=?0.01; p?=?0.259). Further parameters correlated moderately with LV SW min-?1 (LVPmax r2?=?0.47, RPP r2?=?0.67; and TP r2?=?0.54). LV dP/dtmax correlated worst with LV SW min-?1 (r2?=?0.28). CONCLUSION:CPO reflects external cardiac work over a wide range of inotropic states. These data further support the use of CPO to monitor inotropic interventions in the ICU.
| S-EPMC6792198 | biostudies-literature
Project description:Aging per se is a major risk factor for cardiovascular diseases and is associated with progressive changes in cardiac structure and function. Rodent models are commonly used to study cardiac aging, but do not closely mirror differences as they occur in humans. Therefore, we performed a 2D echocardiographic study in non-human primates (NHP) to establish age- and sex-associated differences in cardiac function and morphometry in this animal model. M mode and 2D echocardiography and Doppler analyses were performed cross-sectionally in 38 healthy rhesus monkeys (20 females and 18 males), both young (age 7-12 years; n = 20) and old (age 19-30 years; n = 18). The diameters of the cardiac chambers did not differ significantly by age group, but males had larger left ventricular diameters (2.43 vs 2.06 cm in diastole and 1.91 vs 1.49 cm in systole, p = 0.0004 and p = 0.0001, respectively) and left atrial diameter (1.981 vs 1.732 cm; p = 0.0101). Left ventricular mass/body surface area did not vary significantly with age and sex. Ejection fraction did not differ by age and females presented a higher ejection fraction than males (54.0 vs 50.8%, p = 0.0237). Diastolic function, defined by early to late mitral peak flow velocity ratio (E/A), was significantly lower in old rhesus monkeys (2.31 vs 1.43, p = 0.0020) and was lower in females compared to males (1.595 vs 2.230, p = 0.0406). Right ventricular function, evaluated by measuring the Tricuspid Annular Plane Systolic Excursion, did not differ by age or sex, and Right Ventricular Free Wall Longitudinal Strain, did not differ with age but was lower in males than in females (-22.21 vs -17.95%, p = 0.0059). This is the first echocardiographic study to evaluate age- and sex-associated changes of cardiac morphometry and function in young and old NHP. The findings of this work will provide a reference to examine the effect of age and sex on cardiac diseases in NHP.
| S-EPMC11335998 | biostudies-literature
Project description:Background and purposeDrug candidates must be thoroughly investigated for their potential cardiac side effects. During the course of routine toxicological assessment, the compound RO5657, a CCR5 antagonist, was discovered to have the rare liability of inducing torsades de pointes (polymorphic ventricular arrhythmia) in normal, healthy animals. Studies were conducted to determine the molecular mechanism of this arrhythmia.Experimental approachToxicological effects of repeat dosing were assessed in naïve monkeys. Cardiovascular effects were determined in conscious telemetry-implanted monkeys (repeat dosing) and anaesthetized instrumented dogs (single doses). Mechanistic studies were performed in guinea-pig isolated hearts and in cells recombinantly expressing human cardiac channels.Key resultsIn cynomolgus monkeys, RO5657 caused a low incidence of myocardial degeneration and a greater incidence of ECG abnormalities including prolonged QT/QTc intervals, QRS complex widening and supraventricular tachycardia. In telemetry-implanted monkeys, RO5657 induced arrhythmias, including torsades de pointes and in one instance, degeneration to fatal ventricular fibrillation. RO5657 also depressed both heart rate (HR) and blood pressure (BP), with no histological evidence of myocardial degeneration. In the anaesthetized dog and guinea-pig isolated heart studies, RO5657 induced similar cardiovascular effects. RO5657 also inhibited Kv11.1 and sodium channel currents.Conclusions and implicationsThe molecular mechanism of RO5657 is hypothesized to be due to inhibition of cardiac sodium and Kv11.1 potassium channels. These results indicate that RO5657 is arrhythymogenic due to decreased haemodynamic function (HR/BP), decreased conduction and inhibition of multiple cardiac channels, which precede and are probably the causative factors in the observed myocardial degeneration.
| S-EPMC3423261 | biostudies-literature
Project description:Common polygenic diseases result from compounded risk contributed by multiple genetic variants, meaning that simultaneous correction or introduction of single nucleotide variants is required for disease modeling and gene therapy. Here, we show precise, efficient, and simultaneous multiplex base editing of up to three target sites across 11 genes/loci in cynomolgus monkey embryos using CRISPR-based cytidine- and adenine-base editors. Unbiased whole genome sequencing demonstrates high specificity of base editing in monkey embryos. Our data demonstrate feasibility of multiplex base editing for polygenic disease modeling in primate zygotes.
| S-EPMC7214463 | biostudies-literature
Project description:ObjectiveThe aim of this study was to investigate differentially expressed genes and their functions in the hippocampus and striatum after heroin administration in cynomolgus macaques of different ages.MethodsCynomolgus monkeys were divided by age as follows: 1 year (A1, n = 2); 3 to 4 years (A2, n = 2); 6 to 8 years (A3, n = 2); and older than 11 years (A4, n = 2). After heroin was injected intramuscularly into the monkeys (0.6 mg/kg), we performed large-scale transcriptome profiling in the hippocampus (H) and striatum (S) using RNA sequencing technology. Some genes were validated with real-time quantitative PCR.ResultsIn the hippocampus, the gene expression of A1H was similar to that of A4H, while the gene expression of A2H was similar to that of A3H. Genes associated with the mitogen-activated protein kinase signaling pathway (STMN1, FGF14, and MAPT) and γ-aminobutyric acid-ergic synapses (GABBR2 and GAD1) were differentially expressed among control and heroin-treated animals. Differential gene expression between A1S and A4S was the least significant, while differential gene expression between A3S and A2S was the most significant. Genes associated with the neurotrophin signaling pathway (NTRK1 and NGFR), autophagy (ATG5), and dopaminergic synapses (AKT1) in the striatum were differentially expressed among control and heroin-treated animals.ConclusionThese results suggest that even a single heroin exposure can cause differential gene expression in the hippocampus and striatum of nonhuman primates at different ages.
| S-EPMC7006971 | biostudies-literature
Project description:BACKGROUND AND PURPOSE: The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. EXPERIMENTAL APPROACH: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. KEY RESULTS: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. CONCLUSIONS AND IMPLICATIONS: The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.
| S-EPMC2492091 | biostudies-other
Project description:BACKGROUND:The distribution of cranio-spinal compliance (CSC) in the brain and spinal cord is a fundamental question, as it would determine the overall role of the compartments in modulating ICP in healthy and diseased states. Invasive methods for measurement of CSC using infusion-based techniques provide overall CSC estimate, but not the individual sub-compartmental contribution. Additionally, the outcome of the infusion-based method depends on the infusion site and dynamics. This article presents a method to determine compliance distribution between the cranium and spinal canal non-invasively using data obtained from patients. We hypothesize that this CSC distribution is indicative of the ICP. METHODS:We propose a lumped-parameter model representing the hydro and hemodynamics of the cranio-spinal system. The input and output to the model are phase-contrast MRI derived volumetric transcranial blood flow measured in vivo, and CSF flow at the spinal cervical level, respectively. The novelty of the method lies in the model mathematics that predicts CSC distribution (that obeys the physical laws) from the system dc gain of the discrete-domain transfer function. 104 healthy individuals (48 males, 56 females, age 25.4?±?14.9 years, range 3-60 years) without any history of neurological diseases, were used in the study. Non-invasive MR assisted estimate of ICP was calculated and compared with the cranial compliance to prove our hypothesis. RESULTS:A significant negative correlation was found between model-predicted cranial contribution to CSC and MR-ICP. The spinal canal provided majority of the compliance in all the age groups up to 40 years. However, no single sub-compartment provided majority of the compliance in 41-60 years age group. The cranial contribution to CSC and MR-ICP were significantly correlated with age, with gender not affecting the compliance distribution. Spinal contribution to CSC significantly positively correlated with CSF stroke volume. CONCLUSIONS:This paper describes MRI-based non-invasive way to determine the cranio-spinal compliance distribution in the brain and spinal canal sub-compartments. The proposed mathematics makes the model always stable and within the physiological range. The model-derived cranial compliance was strongly negatively correlated to non-invasive MR-ICP data from 104 patients, indicating that compliance distribution plays a major role in modulating ICP.
| S-EPMC6236958 | biostudies-other
Project description:Age can significantly affect human physiology and disease risk. Recent studies have shown that age may affect the composition and function of the gut microbiota, but the underlying mechanisms remain largely unknown. Non-human primates are an ideal model for uncovering how age shapes the gut microbiota, as their microbial composition is highly similar to that of humans and is not easily affected by confounding factors. Here, using the 16S rRNA and metagenomic sequencing methods, we characterized the microbial phenotypes of 16 female cynomolgus macaques from three age groups (young, adult and old). Our findings revealed significant differences in microbial composition among the three groups. With increased age, the relative abundances of Veillonellaceae, Coriobacteriaceae and Succinivibrionaceae were significantly increased, Ruminococcaceae and Rikenellaceae were significantly decreased at the family level. Functional enrichment showed that genes that differed among the three groups were mainly involved in arginine biosynthesis, purine metabolism and microbial polysaccharides metabolism. Moreover, CAZymes corresponding to polysaccharide degrading activities were also observed among the three groups. In conclusion, we characterized the composition and function of the gut microbiota at different ages, and our findings provide a new entry point for understanding the effects of age on the human body.
| S-EPMC6949106 | biostudies-literature
Project description:BackgroundChange in glomerular filtration rate (GFR) is important for clinical decision making. GFR estimates from serum creatinine level provide an unbiased but imprecise estimate of GFR at single time points. However, the accuracy of estimated GFR over time is not well known.Study designLongitudinal study of diagnostic test accuracy.Settings & participants4 clinical trials with longitudinal measurements of GFR and serum creatinine on the same day, including individuals with and without kidney disease with a wide range of kidney function, diverse racial backgrounds, and varied clinical characteristics.Index testGFR estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.Reference testGFR measured using urinary clearance of (125)I-iothalamate.ResultsData included 19,735 GFR measurements in 3,531 participants during a mean follow-up of 2.6 years. Mean values at baseline for measured and estimated GFR and error (measured GFR - estimated GFR) were 73.1 (95% CI, 71.6 to 74.5), 72.7 (95% CI, 71.5 to 74.0), and 0.14 (95% CI, -0.35 to 0.63) mL/min/1.73 m(2), respectively. Mean rates of change in measured and estimated GFR and error were -2.3 (95% CI, -2.4 to -2.1), -2.2 (95% CI, -2.4 to -2.1), and -0.09 (95% CI, -0.24 to 0.05) mL/min/1.73 m(2) per year (P < 0.001, P < 0.001, and P = 0.2, respectively). Variability (ie, standard deviation) among participants in rate of change in measured GFR, estimated GFR, and error was 4.3, 3.4, and 3.3 mL/min/1.73 m(2) per year, respectively. Only 15% of participants had a rate of change in error >3 mL/min/1.73 m(2) per year, and only 2% had a rate of change in error >5% per year.LimitationsParticipants' characteristics were not available over time.ConclusionThe accuracy of GFR estimates did not change over time. Clinicians should interpret changes in estimated GFR over time as reflecting changes in measured GFR rather than changes in errors in the GFR estimates in most individuals.
| S-EPMC3399947 | biostudies-literature