Phenotyping heart failure using model-based analysis and physiology-informed machine learning.

To phenotype mechanistic differences between heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction, a closed-loop model of the cardiovascular system coupled with patient-specific transthoracic echocardiography (TTE) and right heart catheterization (RHC) data was used to identify key parameters representing haemodynamics. Thirty-one patient records (10 HFrEF, 21 HFpEF) were obtained from the Cardiovascular Health Improvement Project database at the University of Michigan. Model simulations were tuned to match RHC and TTE pressure, volume, and cardiac output measurements in each patient. The underlying physiological model parameters were plotted against model-based norms and compared between HFrEF and HFpEF. Our results confirm the main mechanistic parameter driving HFrEF is reduced left ventricular (LV) contractility, whereas HFpEF exhibits a heterogeneous phenotype. Conducting principal component analysis, k -means clustering, and hierarchical clustering on the optimized parameters reveal (i) a group of HFrEF-like HFpEF patients (HFpEF1), (ii) a classic HFpEF group (HFpEF2), and (iii) a group of HFpEF patients that do not consistently cluster (NCC). These subgroups cannot be distinguished from the clinical data alone. Increased LV active contractility ( p<0.001 ) and LV passive stiffness ( p<0.001 ) at rest are observed when comparing HFpEF2 to HFpEF1. Analysing the clinical data of each subgroup reveals that elevated systolic and diastolic LV volumes seen in both HFrEF and HFpEF1 may be used as a biomarker to identify HFrEF-like HFpEF patients. These results suggest that modelling of the cardiovascular system and optimizing to standard clinical data can designate subgroups of HFpEF as separate phenotypes, possibly elucidating patient-specific treatment strategies. KEY POINTS: Analysis of data from right heart catheterization (RHC) and transthoracic echocardiography (TTE) of heart failure (HF) patients using a closed-loop model of the cardiovascular system identifies key parameters representing haemodynamic cardiovascular function in patients with heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF). Analysing optimized parameters representing cardiovascular function using machine learning shows mechanistic differences between HFpEF groups that are not seen analysing clinical data alone. HFpEF groups presented here can be subdivided into three subgroups: HFpEF1 described as 'HFrEF-like HFpEF', HFpEF2 as 'classic HFpEF', and a third group of HFpEF patients that do not consistently cluster. Focusing purely on cardiac function consistently captures the underlying dysfunction in HFrEF, whereas HFpEF is better characterized by dysfunction in the entire cardiovascular system. Our methodology reveals that elevated left ventricular systolic and diastolic volumes are potential biomarkers for identifying HFrEF-like HFpEF patients.

Usefulness of Echocardiography/Doppler to Reliably Predict Elevated Left Ventricular End-Diastolic Pressure in Patients With Pulmonary Hypertension.

The ability of echocardiography (echo)/Doppler to predict elevated left ventricular (LV) end-diastolic pressure (EDP) specifically among patients with pulmonary hypertension is not well defined. This was a retrospective analysis of 161 patients referred to a specialized pulmonary hypertension clinic. A model based on an American Society of Echocardiography (ASE)/European Association of Echocardiography (EAE) joint statement was evaluated, and a new model was developed using univariate linear regression and multivariable logistic regression for potentially better prediction of elevated LVEDP. The study cohort had a median pulmonary arterial pressure was 34.0 mm Hg and pulmonary vascular resistance was 3.7 Wood units; 81 patients (51%) had LVEDP >15 mm Hg on invasive testing. Doppler E/A, E/e' (septal, lateral, and average), e'/a' (lateral and average), and left atrial volume and diameter all had significant correlation with LVEDP (p <0.05). The ASE/EAE model performed poorly (sensitivity 54% and specificity 66%) for detecting elevated LVEDP. Only echo/Doppler grade 3 diastolic dysfunction had an LVEDP significantly different from other grades (grade 0 to 2, median 15 mm Hg, interquartile range 13 to 22 mm Hg; grade 3, median 22 mm Hg, interquartile range 19 to 32 mm Hg; p <0.01). An experimental model was statistically significant in its prediction of elevated LVEDP (area under the receiver operating characteristic curve 0.7, p <0.001) but demonstrated poor performance (sensitivity 67% and specificity 61%). In conclusion, numerous echo/Doppler measurements correlate with elevated LV filling pressure. However, both the ASE/EAE model and our experimental model had poor test performance that did not permit confident identification of elevated LVEDP.

Testing the generality of above-ground biomass allometry across plant functional types at the continent scale.

Accurate ground-based estimation of the carbon stored in terrestrial ecosystems is critical to quantifying the global carbon budget. Allometric models provide cost-effective methods for biomass prediction. But do such models vary with ecoregion or plant functional type? We compiled 15 054 measurements of individual tree or shrub biomass from across Australia to examine the generality of allometric models for above-ground biomass prediction. This provided a robust case study because Australia includes ecoregions ranging from arid shrublands to tropical rainforests, and has a rich history of biomass research, particularly in planted forests. Regardless of ecoregion, for five broad categories of plant functional type (shrubs; multistemmed trees; trees of the genus Eucalyptus and closely related genera; other trees of high wood density; and other trees of low wood density), relationships between biomass and stem diameter were generic. Simple power-law models explained 84-95% of the variation in biomass, with little improvement in model performance when other plant variables (height, bole wood density), or site characteristics (climate, age, management) were included. Predictions of stand-based biomass from allometric models of varying levels of generalization (species-specific, plant functional type) were validated using whole-plot harvest data from 17 contrasting stands (range: 9-356 Mg ha(-1) ). Losses in efficiency of prediction were <1% if generalized models were used in place of species-specific models. Furthermore, application of generalized multispecies models did not introduce significant bias in biomass prediction in 92% of the 53 species tested. Further, overall efficiency of stand-level biomass prediction was 99%, with a mean absolute prediction error of only 13%. Hence, for cost-effective prediction of biomass across a wide range of stands, we recommend use of generic allometric models based on plant functional types. Development of new species-specific models is only warranted when gains in accuracy of stand-based predictions are relatively high (e.g. high-value monocultures).

Hind paw incision in the rat produces long-lasting colon hypersensitivity.

UNLABELLED: Visceral injury has been shown to alter somatic sensitivity, but little is known about the effect of somatic insult on the viscera. In the present study, we examined (1) the effect of colon inflammation on somatic sensitivity and (2) the affect of hind paw incision on colon sensitivity. After intracolonic administration of trinitrobenzene sulfonic acid (TNBS) or zymosan, visceromotor responses to colorectal distension were increased to post-treatment day 8. Mechanical withdrawal thresholds in the hind paw were decreased in TNBS- and in zymosan-treated rats until post-intracolonic treatment day 2. There was no change in hind paw heat withdrawal latency in either group. Plantar incision of the hind paw resulted in a decrease in both hind paw mechanical withdrawal threshold and heat withdrawal latency and significantly increased the visceromotor response to colorectal distension from postincision days 1 to 8. The colon hypersensitivity was of longer duration than hyperalgesia at the site of hind paw incision. These results support the hypothesis that somatic injury and visceral inflammation can alter central processing of visceral and somatic inputs, respectively. PERSPECTIVE: Surgical procedures are common and typically associated with hyperalgesia at and around the site of incision. This report establishes in a model of postsurgical pain and hyperalgesia that a long-lasting visceral hypersensitivity may also accompany postsurgical hyperalgesia.