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1. Deep phenotyping of cardiac function in heart transplant patients using cardiovascular system models

   https://doi.org/10.1113/JP279393  

   Colunga, Amanda L. ; Kim, Karam G. ; Woodall, N. Payton ; Dardas, Todd F. ; Gennari, John H. ; Olufsen, Mette S. ; Carlson, Brian E. ( June 2020 , The Journal of Physiology)

   Right heart catheterization data from clinical records of heart transplant patients are used to identify patient‐specific models of the cardiovascular system.

   These patient‐specific cardiovascular models represent a snapshot of cardiovascular function at a given post‐transplant recovery time point.

   This approach is used to describe cardiac function in 10 heart transplant patients, five of which had multiple right heart catheterizations allowing an assessment of cardiac function over time.

   These patient‐specific models are used to predict cardiovascular function in the form of right and left ventricular pressure‐volume loops and ventricular power, an important metric in the clinical assessment of cardiac function.

   Outcomes for the longitudinally tracked patients show that our approach was able to identify the one patient from the group of five that exhibited post‐transplant cardiovascular complications.

   Heart transplant patients are followed with periodic right heart catheterizations (RHCs) to identify post‐transplant complications and guide treatment. Post‐transplant positive outcomes are associated with a steady reduction of right ventricular and pulmonary arterial pressures, toward normal levels of right‐side pressure (about 20 mmHg) measured by RHC. This study shows that more information about patient progression is obtained by combining standard RHC measures with mechanistic computational cardiovascular system models. The purpose of this study is twofold: to understand how cardiovascular system models can be used to represent a patient's cardiovascular state, and to use these models to track post‐transplant recovery and outcome. To obtain reliable parameter estimates comparable within and across datasets, we use sensitivity analysis, parameter subset selection, and optimization to determine patient‐specific mechanistic parameters that can be reliably extracted from the RHC data. Patient‐specific models are identified for 10 patients from their first post‐transplant RHC, and longitudinal analysis is carried out for five patients. Results of the sensitivity analysis and subset selection show that we can reliably estimate seven non‐measurable quantities; namely, ventricular diastolic relaxation, systemic resistance, pulmonary venous elastance, pulmonary resistance, pulmonary arterial elastance, pulmonary valve resistance and systemic arterial elastance. Changes in parameters and predicted cardiovascular function post‐transplant are used to evaluate the cardiovascular state during recovery of five patients. Of these five patients, only one showed inconsistent trends during recovery in ventricular pressure–volume relationships and power output. At the four‐year post‐transplant time point this patient exhibited biventricular failure along with graft dysfunction while the remaining four exhibited no cardiovascular complications.

    

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2. Decellularization Following Fixation of Explanted Aortic Valves as a Strategy for Preserving Native Mechanical Properties and Function

   https://doi.org/10.3389/fbioe.2021.803183  

   Singh, Manisha ; Park, Clara ; Roche, Ellen T. ( January 2022 , Frontiers in Bioengineering and Biotechnology)

   Mechanical or biological aortic valves are incorporated in physical cardiac simulators for surgical training, educational purposes, and device testing. They suffer from limitations including either a lack of anatomical and biomechanical accuracy or a short lifespan, hence limiting the authentic hands-on learning experience. Medical schools utilize hearts from human cadavers for teaching and research, but these formaldehyde-fixed aortic valves contort and stiffen relative to native valves. Here, we compare a panel of different chemical treatment methods on explanted porcine aortic valves and evaluate the microscopic and macroscopic features of each treatment with a primary focus on mechanical function. A surfactant-based decellularization method after formaldehyde fixation is shown to have mechanical properties close to those of the native aortic valve. Valves treated in this method were integrated into a custom-built left heart cardiac simulator to test their hemodynamic performance. This decellularization, post-fixation technique produced aortic valves which have ultimate stress and elastic modulus in the range of the native leaflets. Decellularization of fixed valves reduced the valvular regurgitation by 60% compared to formaldehyde-fixed valves. This fixation method has implications for scenarios where the dynamic function of preserved valves is required, such as in surgical trainers or device test rigs. 

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3. Predictive Modeling of Secondary Pulmonary Hypertension in Left Ventricular Diastolic Dysfunction

   https://doi.org/10.1101/2020.04.23.20073601  

   Harrod, Karlyn K. ; Rogers, Jeffrey L. ; Feinstein, Jeffrey A. ; Marsden, Alison L. ; Schiavazzi, Daniele E. ( July 2021 , Frontiers in physiology)

   null (Ed.)

   Diastolic dysfunction is a common pathology occurring in about one third of patients affected by heart failure. This condition may not be associated with a marked decrease in cardiac output or systemic pressure and therefore is more difficult to diagnose than its systolic counterpart. Compromised relaxation or increased stiffness of the left ventricle induces an increase in the upstream pulmonary pressures, and is classified as secondary or group II pulmonary hypertension (2018 Nice classification). This may result in an increase in the right ventricular afterload leading to right ventricular failure. Elevated pulmonary pressures are therefore an important clinical indicator of diastolic heart failure (sometimes referred to as heart failure with preserved ejection fraction, HFpEF), showing significant correlation with associated mortality. However, accurate measurements of this quantity are typically obtained through invasive catheterization and after the onset of symptoms. In this study, we use the hemodynamic consistency of a differential-algebraic circulation model to predict pulmonary pressures in adult patients from other, possibly non-invasive, clinical data. We investigate several aspects of the problem, including the ability of model outputs to represent a sufficiently wide pathologic spectrum, the identifiability of the model's parameters, and the accuracy of the predicted pulmonary pressures. We also find that a classifier using the assimilated model parameters as features is free from the problem of missing data and is able to detect pulmonary hypertension with sufficiently high accuracy. For a cohort of 82 patients suffering from various degrees of heart failure severity, we show that systolic, diastolic, and wedge pulmonary pressures can be estimated on average within 8, 6, and 6 mmHg, respectively. We also show that, in general, increased data availability leads to improved predictions. 

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4. Pulmonary vascular distensibility with passive leg raise is comparable to exercise and predictive of clinical outcomes in pulmonary hypertension

   https://doi.org/10.1002/pul2.12029  

   Kozitza, Callyn J. ; Dharmavaram, Naga ; Tao, Ran ; Tabima, Diana M. ; Chesler, Naomi C. ; Raza, Farhan ( January 2022 , Pulmonary Circulation)

   Pulmonary vascular distensibility (α) is a marker of the ability of the pulmonary vasculature to dilate in response to increases in cardiac output, which protects the right ventricle from excessive increases in afterload. α measured with exercise predicts clinical outcomes in pulmonary hypertension (PH) and heart failure. In this study, we aim to determine if α measured with a passive leg raise (PLR) maneuver is comparable to α with exercise. Invasive cardiopulmonary exercise testing (iCPET) was performed with hemodynamics recorded at three stages: rest, PLR and peak exercise. Four hemodynamic phenotypes were identified (2019 ECS guidelines): pulmonary arterial hypertension (PAH) (n = 10), isolated post‐capillary (Ipc‐PH) (n = 18), combined pre‐/post‐capillary PH (Cpc‐PH) (n = 15), and Control (no significant PH at rest and exercise) (n = 7). Measurements of mean pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output at each stage were used to calculate α. There was no statistical difference between α‐exercise and α‐PLR (0.87 ± 0.68 and 0.78 ± 0.47% per mmHg, respectively). The peak exercise‐ and PLR‐based calculations of α among the four hemodynamic groups were: Ipc‐PH = Ex: 0.94 ± 0.30, PLR: 1.00 ± 0.27% per mmHg; Cpc‐PH = Ex: 0.51 ± 0.15, PLR: 0.47 ± 0.18% per mmHg; PAH = Ex: 0.39 ± 0.23, PLR: 0.34 ± 0.18% per mmHg; and the Control group: Ex: 2.13 ± 0.91, PLR: 1.45 ± 0.49% per mmHg. Patients withα ≥ 0.7% per mmHg had reduced cardiovascular death and hospital admissions at 12‐month follow‐up. In conclusion, α‐PLR is feasible and may be equally predictive of clinical outcomes as α‐exercise in patients who are unable to exercise or in programs lacking iCPET facilities.

    

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5. Type IV Pili of Streptococcus sanguinis Contribute to Pathogenesis in Experimental Infective Endocarditis

   https://doi.org/10.1128/Spectrum.01752-21  

   Martini, Anthony M. ; Moricz, Bridget S. ; Woods, Laurel J. ; Jones, Bradley D. ( December 2021 , Microbiology Spectrum)

   LaRock, Christopher N. (Ed.)

   ABSTRACT Streptococcus sanguinis is a common cause of infective endocarditis (IE). Efforts by research groups are aimed at identifying and characterizing virulence factors that contribute to the ability of this organism to cause IE. This Gram-positive pathogen causes heart infection by gaining access to the bloodstream, adhering to host extracellular matrix protein and/or platelets, colonizing the aortic endothelium, and incorporating itself into the aortic vegetation. While many virulence factors have been reported to contribute to the ability of S. sanguinis to cause IE, it is noteworthy that type IV pili (T4P) have not been described to be a virulence factor in this organism, although S. sanguinis strains typically encode these pili. Type IV pili are molecular machines that are capable of mediating diverse virulence functions and surface motility. T4P have been shown to mediate twitching motility in some strains of S. sanguinis , although in most strains it has been difficult to detect twitching motility. While we found that T4P are dispensable for direct in vitro platelet binding and aggregation phenotypes, we show that they are critical to the development of platelet-dependent biofilms representative of the cardiac vegetation. We also observed that T4P are required for in vitro invasion of S. sanguinis into human aortic endothelial cells, which indicates that S. sanguinis may use T4P to take advantage of an intracellular niche during infection. Importantly, we show that T4P of S. sanguinis are critical to disease progression (vegetation development) in a native valve IE rabbit model. The results presented here expand our understanding of IE caused by S. sanguinis and identify T4P as an important virulence factor for this pathogen. IMPORTANCE This work provides evidence that type IV pili produced by Streptococcus sanguinis SK36 are critical to the ability of these bacteria to attach to and colonize the aortic heart valve (endocarditis). We found that an S. sanguinis type IV pili mutant strain was defective in causing platelet-dependent aggregation in a 24-h infection assay but not in a 1-h platelet aggregation assay, suggesting that the type IV pili act at later stages of vegetation development. In a rabbit model of disease, a T4P mutant strain does not develop mature vegetations that form on the heart, indicating that this virulence factor is critical to disease and could be a target for IE therapy. 

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