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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. RVEX: Right Ventricular External Device for Biomimetic Support and Monitoring of the Right Heart

   https://doi.org/10.1002/admt.202101472  

   Pirozzi, Ileana ; Kight, Ali ; Shad, Rohan ; Han, Amy Kyungwon ; Dual, Seraina A. ; Fong, Robyn ; Jia, Allison ; Hiesinger, William ; Yock, Paul ; Cutkosky, Mark ( February 2022 , Advanced Materials Technologies)

   Right ventricular (RV) failure remains a significant burden for patients with advanced heart failure, especially after major cardiac surgeries such as implantation of left ventricular assist devices. Device solutions that can assist the complex biological function of heart muscle without the disadvantages of bulky designs and infection‐prone drivelines remain an area of pressing clinical need, especially for the right ventricle. In addition, devices that incur contact between blood and artificial surfaces mandate long‐term use of blood‐thinning medications, carrying increased risks for the patients. This work describes the design of a biomimetic, elastic sleeve to support RV‐specific motion via tuned regional mechanical properties. The RV external device (RVEX) in computational models as well as benchtop models and ex vivo (i.e., explanted heart) setups are evaluated to characterize the device and predict functional benefit. Additionally, long‐term implantation potential is demonstrated in mice. Finally, the ability to sensorize the RVEX device to yield resistive self‐sensing capabilities to continuously monitor ventricular deformation, as demonstrated in benchtop experiments and in live animal surgeries, is proposed.

    

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3. 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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4. 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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5. Angiotensin II type 1 receptor mediates pulmonary hypertension and right ventricular remodeling induced by inhaled nicotine

   https://doi.org/10.1152/ajpheart.00883.2020  

   Fried, Nicholas D. ; Morris, Tamara M. ; Whitehead, Anna ; Lazartigues, Eric ; Yue, Xinping ; Gardner, Jason D. ( April 2021 , American Journal of Physiology-Heart and Circulatory Physiology)

   null (Ed.)

   Use of electronic cigarettes is rapidly increasing among youth and young adults, but little is known regarding the long-term cardiopulmonary health impacts of these nicotine-containing devices. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension (PH) and right ventricular (RV) remodeling in mice. These changes were associated with upregulated RV angiotensin-converting enzyme (ACE). Angiotensin II receptor blockers (ARBs) have been shown to reverse cigarette smoking-induced PH in rats. ACE inhibitor and ARB use in a large retrospective cohort of patients with PH is associated with improved survival. Here, we utilized losartan (an ARB specific for angiotensin II type 1 receptor) to further explore nicotine-induced PH. Male C57BL/6 mice received nicotine vapor for 12 h/day, and exposure was assessed using serum cotinine to achieve levels comparable to human smokers or electronic cigarette users. Mice were exposed to nicotine for 8 wk and a subset was treated with losartan via an osmotic minipump. Cardiac function was assessed using echocardiography and catheterization. Although nicotine exposure increased angiotensin II in the RV and lung, this finding was nonsignificant. Chronic, inhaled nicotine significantly increased RV systolic pressure and RV free wall thickness versus air control. These parameters were significantly lower in mice receiving both nicotine and losartan. Nicotine significantly increased RV internal diameter, with no differences seen between the nicotine and nicotine-losartan group. Neither nicotine nor losartan affected left ventricular structure or function. These findings provide the first evidence that antagonism of the angiotensin II type 1 receptor can ameliorate chronic, inhaled nicotine-induced PH and RV remodeling. NEW & NOTEWORTHY Chronic, inhaled nicotine causes pulmonary hypertension and right ventricular remodeling in mice. Treatment with losartan, an angiotensin II type 1 receptor antagonist, ameliorates nicotine-induced pulmonary hypertension and right ventricular remodeling. This novel finding provides preclinical evidence for the use of renin-angiotensin system-based therapies in the treatment of pulmonary hypertension, particularly in patients with a history of tobacco-product use. 

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