Publications by authors named "Naomi C Chesler"

91 Publications

Decreased ventricular size and mass mediate the reduced exercise capacity in adolescents and adults born premature.

Early Hum Dev 2021 Sep 24;160:105426. Epub 2021 Jul 24.

Department of Pediatrics, Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI, United States of America.

Background: Premature birth is associated with lower levels of cardiorespiratory fitness (CRF) but the underlying mechanisms responsible remain unclear. This study assessed whether differences in cardiac morphology or function mediate differences in CRF among adolescents and young adults born preterm.

Methods: Adolescents and young adults born moderately to extremely premature (gestational age ≤ 32 weeks or birth weight < 1500 g) and age-matched term born participants underwent resting cardiac MRI and maximal exercise testing. Mediation analysis assessed whether individual cardiovascular variables accounted for a significant proportion of the difference in maximal aerobic capacity between groups.

Results: Individuals born preterm had lower VO2max than those born term (41.7 ± 8.6 v 47.5 ± 8.7, p < 0.01). Several variables differed between term and preterm born subjects, including systolic and diastolic blood pressure, mean pulmonary artery pressure, indexed left ventricular end-diastolic volume (LVEDVi), right ventricular end-diastolic volume (RVEDVi), LV mass (LVMi), LV stroke volume index (LVSVi), and LV strain (p < 0.05 for all). Of these variables, LVEDVi, RVEDVi, LVSVi, LVMi, and LV longitudinal strain were significantly related to VO2max (p < 0.05 for all). Significant portions of the difference in VO2max between term and preterm born subjects were mediated by LVEDVi (74.3%, p = 0.010), RVEDVi (50.6%, p = 0.016), and LVMi (43.0%, p = 0.036).

Conclusions: Lower levels of CRF in adolescents and young adults born preterm are mediated by differences in LVEDVi, RVEDVi, and LVMi. This may represent greater risk for long-term cardiac morbidity and mortality in preterm born individuals.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105426DOI Listing
September 2021

Dynamic FDG PET Imaging to Probe for Cardiac Metabolic Remodeling in Adults Born Premature.

J Clin Med 2021 Mar 22;10(6). Epub 2021 Mar 22.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Individuals born very premature have an increased cardiometabolic and heart failure risk. While the structural differences of the preterm heart are now well-described, metabolic insights into the physiologic mechanisms underpinning this risk are needed. Here, we used dynamic fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET-MRI) in young adults born term and preterm during normoxic (N = 28 preterm; 18 term) and hypoxic exposure (12% O; N = 26 preterm; 17 term) to measure the myocardial metabolic rate of glucose (MMRglc) in young adults born term (N = 18) and preterm (N = 32), hypothesizing that young adults born preterm would have higher rates of MMRglc under normoxic conditions and a reduced ability to augment glucose metabolism under hypoxic conditions. MMRglc was calculated from the myocardial and blood pool time-activity curves by fitting the measured activities to the 3-compartment model of FDG kinetics. MMRglc was similar at rest between term and preterm subjects, and decreased during hypoxia exposure in both groups ( = 0.02 for MMRglc hypoxia effect). There were no differences observed between groups in the metabolic response to hypoxia, either globally (serum glucose and lactate measures) or within the myocardium. Thus, we did not find evidence of altered myocardial metabolism in the otherwise healthy preterm-born adult. However, whether subtle changes in myocardial metabolism may preceed or predict heart failure in this population remains to be determined.
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http://dx.doi.org/10.3390/jcm10061301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004130PMC
March 2021

Exaggerated Cardiac Contractile Response to Hypoxia in Adults Born Preterm.

J Clin Med 2021 Mar 10;10(6). Epub 2021 Mar 10.

Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53792, USA.

Individuals born prematurely have smaller hearts, cardiac limitations to exercise, and increased overall cardiometabolic risk. The cardiac effects of acute hypoxia exposure as another physiologic stressor remain under explored. The purpose of this study was to determine the effects of hypoxia on ventricular function in adults born preterm. Adults born moderately to extremely preterm (≤32 weeks gestation or <1500 g, = 32) and born at term ( = 18) underwent cardiac magnetic resonance imaging under normoxic (21% O) and hypoxic (12% O) conditions to assess cardiovascular function. In normoxia, cardiac function parameters were similar between groups. During hypoxia, the right ventricular (RV) contractile response was significantly greater in participants born premature, demonstrated by greater increases in RV ejection fraction (EF) ( = 0.002), ventricular-vascular coupling (VVC) ( = 0.004), and strain ( < 0.0001) measures compared to term-born participants, respectively. Left ventricular contractile reserve was similar to term-born participants. Adults born preterm exhibit an exaggerated contractile response to acute hypoxia, particularly in the RV. This suggests that adults born preterm may have contractile reserve, despite the lack of volume reserve identified in previous exercise studies. However, this exaggerated and hyper-adapted response may also increase their risk for late RV failure.
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http://dx.doi.org/10.3390/jcm10061166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999333PMC
March 2021

Fund Black scientists.

Cell 2021 02 26;184(3):561-565. Epub 2021 Jan 26.

Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Our nationwide network of BME women faculty collectively argue that racial funding disparity by the National Institutes of Health (NIH) remains the most insidious barrier to success of Black faculty in our profession. We thus refocus attention on this critical barrier and suggest solutions on how it can be dismantled.
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http://dx.doi.org/10.1016/j.cell.2021.01.011DOI Listing
February 2021

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin.

J Clin Invest 2021 03;131(6)

Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α-null or ER-β-null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.
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http://dx.doi.org/10.1172/JCI129433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968046PMC
March 2021

Estrogen receptor-α prevents right ventricular diastolic dysfunction and fibrosis in female rats.

Am J Physiol Heart Circ Physiol 2020 12 16;319(6):H1459-H1473. Epub 2020 Oct 16.

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.

Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-α (ERα) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERα (ERαMut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ERαMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ERαMut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERαMut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH. Using a novel loss-of-function mutation in estrogen receptor-α (ERα), we demonstrate that female, but not male, ERα mutant rats display right ventricular (RV)-vascular uncoupling, diastolic dysfunction, and fibrosis following pressure overload, indicating a sex-dependent role of ERα in protecting against adverse RV remodeling. TIMP metallopeptidase inhibitor 1 (Timp1), matrix metalloproteinase 9 (Mmp9), kallikrein-related peptidase 10 (), and Jun Proto-Oncogene () were identified as potential mediators in ERα-regulated pathways in RV pressure overload.
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http://dx.doi.org/10.1152/ajpheart.00247.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792707PMC
December 2020

Association Between Preterm Birth and Arrested Cardiac Growth in Adolescents and Young Adults.

JAMA Cardiol 2020 Aug;5(8):910-919

Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison.

Importance: Premature birth is associated with substantially higher lifetime risk for cardiovascular disease, including arrhythmia, ischemic disease, and heart failure, although the underlying mechanisms are poorly understood.

Objective: To characterize cardiac structure and function in adolescents and young adults born preterm using cardiac magnetic resonance imaging (MRI).

Design, Setting, And Participants: This cross-sectional cohort study at an academic medical center included adolescents and young adults born moderately to extremely premature (20 in the adolescent cohort born from 2003 to 2004 and 38 in the young adult cohort born in the 1980s and 1990s) and 52 age-matched participants who were born at term and underwent cardiac MRI. The dates of analysis were February 2016 to October 2019.

Exposures: Premature birth (gestational age ≤32 weeks) or birth weight less than 1500 g.

Main Outcomes And Measures: Main study outcomes included MRI measures of biventricular volume, mass, and strain.

Results: Of 40 adolescents (24 [60%] girls), the mean (SD) age of participants in the term and preterm groups was 13.3 (0.7) years and 13.0 (0.7) years, respectively. Of 70 adults (43 [61%] women), the mean (SD) age of participants in the term and preterm groups was 25.4 (2.9) years and 26.5 (3.5) years, respectively. Participants from both age cohorts who were born prematurely had statistically significantly smaller biventricular cardiac chamber size compared with participants in the term group: the mean (SD) left ventricular end-diastolic volume index was 72 (7) vs 80 (9) and 80 (10) vs 92 (15) mL/m2 for adolescents and adults in the preterm group compared with age-matched participants in the term group, respectively (P < .001), and the mean (SD) left ventricular end-systolic volume index was 30 (4) vs 34 (6) and 32 (7) vs 38 (8) mL/m2, respectively (P < .001). Stroke volume index was also reduced in adolescent vs adult participants in the preterm group vs age-matched participants in the term group, with a mean (SD) of 42 (7) vs 46 (7) and 48 (7) vs 54 (9) mL/m2, respectively (P < .001), although biventricular ejection fractions were preserved. Biventricular mass was statistically significantly lower in adolescents and adults born preterm: the mean (SD) left ventricular mass index was 39.6 (5.9) vs 44.4 (7.5) and 40.7 (7.3) vs 49.8 (14.0), respectively (P < .001). Cardiac strain analyses demonstrated a hypercontractile heart, primarily in the right ventricle, in adults born prematurely.

Conclusions And Relevance: In this cross-sectional study, adolescents and young adults born prematurely had statistically significantly smaller biventricular cardiac chamber size and decreased cardiac mass. Although function was preserved in both age groups, these morphologic differences may be associated with elevated lifetime cardiovascular disease risk after premature birth.
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http://dx.doi.org/10.1001/jamacardio.2020.1511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240643PMC
August 2020

Exercise-Induced Changes in Pulmonary Artery Stiffness in Pulmonary Hypertension.

Front Physiol 2019 2;10:269. Epub 2019 Apr 2.

College of Engineering, University of Wisconsin-Madison, Madison, WI, United States.

Pulmonary hypertension causes pulmonary artery (PA) stiffening, which overloads the right ventricle (RV). Since symptoms of pulmonary hypertension (PH) are exacerbated by exercise, exercise-induced PA stiffening is relevant to cardiopulmonary status. Here, we sought to demonstrate the feasibility of using magnetic resonance imaging (MRI) for non-invasive assessment of exercise-induced changes in PA stiffness in patients with PH. MRI was performed on 7 PH patients and 8 age-matched control subjects at rest and during exercise stress. Main pulmonary artery (MPA) relative area change (RAC) and pulse wave velocity (PWV) were measured from 2D-PC images. Invasive right heart catheterization (RHC) was performed on 5 of the PH patients in conjunction with exercise stress to measure MPA pressures and stiffness index (β). Heart rate and cardiac index (CI) were significantly increased with exercise in both groups. In controls, RAC decreased from 0.27 ± 0.05 at rest to 0.22 ± 0.06 with exercise ( < 0.05); a modest increase in PWV was not significant ( = 0.06). In PH patients, RAC decreased from 0.15 ± 0.02 to 0.11 ± 0.01 ( < 0.05) and PWV and β increased from 3.9 ± 0.54 m/s and 1.86 ± 0.12 at rest to 5.75 ± 0.70 m/s and 3.25 ± 0.26 with exercise ( < 0.05 for both), respectively. These results confirm increased MPA stiffness with exercise stress in both groups and the non-invasive metrics of MPA stiffness correlated well with β. Finally, as assessed by PWV but not RAC, PA stiffness of PH patients increased more than that of controls for comparable levels of moderate exercise. These results demonstrate the feasibility of using MRI for non-invasive assessment of exercise-induced changes in MPA stiffness in a small, heterogeneous group of PH patients in a research context. Similar measurements in a larger cohort are required to investigate differences between PWV and RAC for estimation of MPA stiffness.
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http://dx.doi.org/10.3389/fphys.2019.00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454859PMC
April 2019

Beneficial effects of mesenchymal stem cell delivery via a novel cardiac bioscaffold on right ventricles of pulmonary arterial hypertensive rats.

Am J Physiol Heart Circ Physiol 2019 05 1;316(5):H1005-H1013. Epub 2019 Mar 1.

Department of Biomedical Engineering, University of Wisconsin , Madison, Wisconsin.

Right ventricular failure (RVF) is a common cause of death in patients suffering from pulmonary arterial hypertension (PAH). The current treatment for PAH only moderately improves symptoms, and RVF ultimately occurs. Therefore, it is necessary to develop new treatment strategies to protect against right ventricle (RV) maladaptation despite PAH progression. In this study, we hypothesize that local mesenchymal stem cell (MSC) delivery via a novel bioscaffold can improve RV function despite persistent PAH. To test our hypothesis, we induced PAH in adult rats with SU5416 and chronic hypoxia exposure; treated with rat MSCs delivered by intravenous injection, intramyocardial injection, or epicardial placement of a bioscaffold; and then examined treatment effectiveness by in vivo pressure-volume measurement, echocardiography, histology, and immunohistochemistry. Our results showed that compared with other treatment groups, only the MSC-seeded bioscaffold group resulted in RV functional improvement, including restored stroke volume, cardiac output, and improved stroke work. Diastolic function indicated by end-diastolic pressure-volume relationship was improved by the local MSC treatments or bioscaffold alone. Cardiomyocyte hypertrophy and RV fibrosis were both reduced, and von Willebrand factor expression was restored by the MSC-seeded bioscaffold treatment. Overall, our study suggests a potential new regenerative therapy to rescue the pressure-overload failing RV with persistent pulmonary vascular disease, which may improve quality of life and/or survival of PAH patients. NEW & NOTEWORTHY We explored the effects of mesenchymal stem cell-seeded bioscaffold on right ventricles (RVs) of rats with established pulmonary arterial hypertension (PAH). Some beneficial effects were observed despite persistent PAH, suggesting that this may be a new therapy for RV to improve quality of life and/or survival of PAH patients.
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http://dx.doi.org/10.1152/ajpheart.00091.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580387PMC
May 2019

Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function.

Am J Physiol Heart Circ Physiol 2019 05 15;316(5):H1167-H1177. Epub 2019 Feb 15.

Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering , Madison, Wisconsin.

Left heart failure (LHF) is the most common cause of pulmonary hypertension, which confers an increase in morbidity and mortality in this context. Pulmonary vascular resistance has prognostic value in LHF, but otherwise the mechanical consequences of LHF for the pulmonary vasculature and right ventricle (RV) remain unknown. We sought to investigate mechanical mechanisms of pulmonary vascular and RV dysfunction in a rodent model of LHF to address the knowledge gaps in understanding disease pathophysiology. LHF was created using a left anterior descending artery ligation to cause myocardial infarction (MI) in mice. Sham animals underwent thoracotomy alone. Echocardiography demonstrated increased left ventricle (LV) volumes and decreased ejection fraction at 4 wk post-MI that did not normalize by 12 wk post-MI. Elevation of LV diastolic pressure and RV systolic pressure at 12 wk post-MI demonstrated pulmonary hypertension (PH) due to LHF. There was increased pulmonary arterial elastance and pulmonary vascular resistance associated with perivascular fibrosis without other remodeling. There was also RV contractile dysfunction with a 35% decrease in RV end-systolic elastance and 66% decrease in ventricular-vascular coupling. In this model of PH due to LHF with reduced ejection fraction, pulmonary fibrosis contributes to increased RV afterload, and loss of RV contractility contributes to RV dysfunction. These are key pathologic features of human PH secondary to LHF. In the future, novel therapeutic strategies aimed at preventing pulmonary vascular mechanical changes and RV dysfunction in the context of LHF can be tested using this model. In this study, we investigate the mechanical consequences of left heart failure with reduced ejection fraction for the pulmonary vasculature and right ventricle. Using comprehensive functional analyses of the cardiopulmonary system in vivo and ex vivo, we demonstrate that pulmonary fibrosis contributes to increased RV afterload and loss of RV contractility contributes to RV dysfunction. Thus this model recapitulates key pathologic features of human pulmonary hypertension-left heart failure and offers a robust platform for future investigations.
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http://dx.doi.org/10.1152/ajpheart.00319.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580389PMC
May 2019

A How-To Guide for Promoting Diversity and Inclusion in Biomedical Engineering.

Authors:
Naomi C Chesler

Ann Biomed Eng 2019 May 11;47(5):1167-1170. Epub 2019 Feb 11.

Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, 2146 Engineering Centers Building, 1550 Engineering Drive, Madison, WI, 53706, USA.

To accelerate the development of an inclusive culture in biomedical engineering (BME), we must accept complexity, seek to understand our own privilege, speak out about diversity, learn the difference between intent and impact, accept our mistakes, and learn how to engage in difficult conversations. In turn, we will be rewarded by the ideas, designs, devices and discoveries of a new generation of problem solvers and thought leaders who bring diverse experiences and perspectives.
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http://dx.doi.org/10.1007/s10439-019-02223-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456400PMC
May 2019

A Large Animal Model of Right Ventricular Failure due to Chronic Thromboembolic Pulmonary Hypertension: A Focus on Function.

Front Cardiovasc Med 2018 9;5:189. Epub 2019 Jan 9.

Department of Biomedical Engineering, Univeristy of Wisconsin-Madison, Madison, WI, United States.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease that progresses to right ventricular (RV) failure and death if left untreated. Little is known regarding the progression of RV failure in this disease, greatly limiting effective prognoses, and therapeutic interventions. Large animal models enable the use of clinical techniques and technologies to assess progression and diagnose failure, but the existing large animal models of CTEPH have not been shown to replicate the functional consequences of the RV, i.e., RV failure. Here, we created a canine embolization model of CTEPH utilizing only microsphere injections, and we used a combination of right heart catheterization (RHC), echocardiography (echo), and magnetic resonance imaging (MRI) to quantify RV function. Over the course of several months, CTEPH led to a 6-fold increase in pulmonary vascular resistance (PVR) in four adult, male beagles. As evidenced by decreased cardiac index (0.12 ± 0.01 v. 0.07 ± 0.01 [L/(minkg)]; < 0.05), ejection fraction (0.48 ± 0.02 v. 0.31 ± 0.02; < 0.05), and ventricular-vascular coupling ratio (0.95 ± 0.09 v. 0.45 ± 0.05; < 0.05), as well as decreased tricuspid annular plane systolic excursion (TAPSE) (1.37 ± 0.06 v. 0.86 ± 0.05 [cm]; < 0.05) and increased end-diastolic volume index (2.73 ± 0.06 v. 2.98 ± 0.02 [mL/kg]; < 0.05), the model caused RV failure. The ability of this large animal CTEPH model to replicate the hemodynamic consequences of the human disease suggests that it could be utilized for future studies to gain insight into the pathophysiology of CTEPH development, following further optimization.
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http://dx.doi.org/10.3389/fcvm.2018.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333696PMC
January 2019

MRI assessment of aortic flow in patients with pulmonary arterial hypertension in response to exercise.

BMC Med Imaging 2018 12 22;18(1):55. Epub 2018 Dec 22.

Department of Medical Physics, University of Wisconsin, 1111 Highland Avenue, Room 1005, Madison, WI, 53705, USA.

Background: While primarily a right heart disease, pulmonary arterial hypertension (PAH) can impact left heart function and aortic flow through a shifted interventricular septum from right ventricular pressure overload and reduced left ventricular preload, among other mechanisms. In this study, we used phase contrast (PC) MRI and a modest exercise challenge to examine the effects of PAH on systemic circulation. While exercise challenges are typically performed with ultrasound in the clinic, MRI exercise studies allow for more reproducible image alignment, more accurate flow quantification, and improved tissue contrast.

Methods: Six PAH patients and fifteen healthy controls (8 older age-matched, 7 younger) exercised in the magnet bore with an MRI-compatible exercise device that allowed for scanning immediately following cessation of exercise. PC scans were performed in the ascending aorta during a breath hold immediately after modest exercise to non-invasively measure stroke volume (SV), cardiac output (CO), aortic peak systolic flow (PSF), and aortic wall stiffness via relative area change (RAC).

Results: Images following exercise showed mild blurring, but were high enough quality to allow for segmentation of the aorta. While SV was approximately 30% lower in PAH patients (SV = 67 ± 16 mL; SV = 90 ± 42 mL) than age-matched controls (SV = 93 ± 16 mL; SV = 133 ± 40 mL) at both rest and following exercise, CO was similar for both groups following exercise (CO = 10.8 ± 5.7 L/min; CO = 11.8 ± 5.0 L/min). This was achieved through a compensatory increase in heart rate in the PAH subjects (74% increase as compared to 29% in age-matched controls). The PAH subjects also demonstrated reduced aortic peak systolic flow relative to the healthy controls (PSF, = 309 ± 52 mL/s; PSF, = 416 ± 114 mL/s; PSF, = 388 ± 113 mL/s; PSF, = 462 ± 176 mL/s). PAH patients and older controls demonstrated stiffer aortic walls when compared to younger controls (RAC = 0.15 ± 0.05; RAC = 0.17 ± 0.05; RAC = 0.28 ± 0.08).

Conclusions: PC MRI following a modest exercise challenge was capable of detecting differences in left heart dynamics likely induced from PAH. These results demonstrated that PAH can have a significant influence on systemic flow, even when the patient has no prior left heart disease. Image quantification following exercise could likely be improved in future studies through the implementation of free-breathing or real-time MRI acquisitions.

Trial Registration: Retrospectively registered on 02/26/2018 (TRN: NCT03523910 ).
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http://dx.doi.org/10.1186/s12880-018-0298-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303959PMC
December 2018

Cardiovascular function and structure are preserved despite induced ablation of BMP1-related proteinases.

Cell Mol Bioeng 2018 Aug 5;11(4):255-266. Epub 2018 Jun 5.

Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, WI 53706 USA.

Introduction: Bone morphogenetic protein 1 (BMP1) is part of an extracellular metalloproteinase family that biosynthetically processes procollagen molecules. BMP1- and tolloid-like (TLL1) proteinases mediate the cleavage of carboxyl peptides from procollagen molecules, which is a crucial step in fibrillar collagen synthesis. Ablating the genes that encode BMP1-related proteinases ( and ) post-natally results in brittle bones, periodontal defects, and thin skin in conditional knockout (BT) mice. Despite the importance of collagen to cardiovascular tissues and the adverse effects of and ablation in other tissues, the impact of and ablation on cardiovascular performance is unknown. Here, we investigated the role of - and -ablation in cardiovascular tissues by examining ventricular and vascular structure and function in BT mice.

Methods: Ventricular and vascular structure and function were comprehensively quantified in BT mice (n=9) and in age- and sex-matched controls (n=9). Echocardiography, cardiac catheterization, and biaxial arterial mechanical testing were performed to assess tissue function, and histological staining was used to measure collagen protein content.

Results: - and -ablation resulted in maintained hemodynamics and cardiovascular function, preserved biaxial arterial compliance, and comparable ventricular and vascular collagen protein content.

Conclusions: Maintained ventricular and vascular structure and function despite post-natal ablation of and suggests that there is an as-yet unidentified compensatory mechanism in cardiovascular tissues. In addition, these findings suggest that proteinases derived from and post-natally have less of an impact on cardiovascular tissues compared to skeletal, periodontal, and dermal tissues.
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http://dx.doi.org/10.1007/s12195-018-0534-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094387PMC
August 2018

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2018 08;198(4):e15-e43

Background: Right ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies.

Methods: A multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations.

Results: This document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes.

Conclusions: This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.
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http://dx.doi.org/10.1164/rccm.201806-1160STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835085PMC
August 2018

Multiscale Computational Analysis of Right Ventricular Mechanoenergetics.

J Biomech Eng 2018 08;140(8)

Fellow ASME Biomedical Engineering, University of Wisconsin-Madison Medicine, , 1550 Engineering Drive, Madison, WI 53706 e-mail: .

Right ventricular (RV) failure, which occurs in the setting of pressure overload, is characterized by abnormalities in mechanical and energetic function. The effects of these cell- and tissue-level changes on organ-level RV function are unknown. The primary aim of this study was to investigate the effects of myofiber mechanics and mitochondrial energetics on organ-level RV function in the context of pressure overload using a multiscale model of the cardiovascular system. The model integrates the mitochondria-generated metabolite concentrations that drive intracellular actin-myosin cross-bridging and extracellular myocardial tissue mechanics in a biventricular heart model coupled with simple lumped parameter circulations. Three types of pressure overload were simulated and compared to experimental results. The computational model was able to capture a wide range of cardiovascular physiology and pathophysiology from mild RV dysfunction to RV failure. Our results confirm that, in response to pressure overload alone, the RV is able to maintain cardiac output (CO) and predict that alterations in either RV active myofiber mechanics or RV metabolite concentrations are necessary to decrease CO.
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http://dx.doi.org/10.1115/1.4040044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056199PMC
August 2018

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions.

Front Physiol 2018 27;9:731. Epub 2018 Jun 27.

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States.

Pulmonary hypertension (PH) causes pressure overload leading to right ventricular failure (RVF). Myocardial structure and myocyte mechanics are altered in RVF but the direct impact of these cellular level factors on organ level function remain unclear. A computational model of the cardiovascular system that integrates cellular function into whole organ function has recently been developed. This model is a useful tool for investigating how changes in myocyte structure and mechanics contribute to organ function. We use this model to determine how measured changes in myocyte and myocardial mechanics contribute to RVF at the organ level and predict the impact of myocyte-targeted therapy. A multiscale computational framework was tuned to model PH due to bleomycin exposure in mice. Pressure overload was modeled by increasing the pulmonary vascular resistance (PVR) and decreasing pulmonary artery compliance (CPA). Myocardial fibrosis and the impairment of myocyte maximum force generation (Fmax) were simulated by increasing the collagen content (↑PVR + ↓CPA + fibrosis) and decreasing Fmax (↑PVR + ↓CPA + fibrosis + ↓Fmax). A61603 (A6), a selective α-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH. Increased afterload (RV systolic pressure and arterial elastance) in simulations matched experimental results for bleomycin exposure. Pressure overload alone (↑PVR + ↓CPA) caused decreased RV ejection fraction (EF) similar to experimental findings but preservation of cardiac output (CO). Myocardial fibrosis in the setting of pressure overload (↑PVR + ↓PAC + fibrosis) had minimal impact compared to pressure overload alone. Including impaired myocyte function (↑PVR + ↓PAC + fibrosis + ↓Fmax) reduced CO, similar to experiment, and impaired EF. Simulations predicted that A6 treatment preserves EF and CO despite maintained RV pressure overload. Multiscale computational modeling enabled prediction of the contribution of cellular level changes to whole organ function. Impaired Fmax is a key feature that directly contributes to RVF. Simulations further demonstrate the therapeutic benefit of targeting Fmax, which warrants additional study. Future work should incorporate growth and remodeling into the computational model to enable prediction of the multiscale drivers of the transition from dysfunction to failure.
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http://dx.doi.org/10.3389/fphys.2018.00731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030352PMC
June 2018

Know Your Limitations: Assumptions in the Single-Beat Method for Estimating Right Ventricular-Pulmonary Vascular Coupling.

Am J Respir Crit Care Med 2018 09;198(6):707-709

1 Department of Biomedical Engineering University of Wisconsin-Madison College of Engineering Madison, Wisconsin.

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http://dx.doi.org/10.1164/rccm.201805-1000EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222468PMC
September 2018

Early Pulmonary Vascular Disease in Young Adults Born Preterm.

Am J Respir Crit Care Med 2018 12;198(12):1549-1558

Department of Pediatrics.

Premature birth affects 10% of live births in the United States and is associated with alveolar simplification and altered pulmonary microvascular development. However, little is known about the long-term impact prematurity has on the pulmonary vasculature. Determine the long-term effects of prematurity on right ventricular and pulmonary vascular hemodynamics. Preterm subjects ( = 11) were recruited from the Newborn Lung Project, a prospectively followed cohort at the University of Wisconsin-Madison, born preterm with very low birth weight (≤1,500 g; average gestational age, 28 wk) between 1988 and 1991. Control subjects ( = 10) from the same birth years were recruited from the general population. All subjects had no known adult cardiopulmonary disease. Right heart catheterization was performed to assess right ventricular and pulmonary vascular hemodynamics at rest and during hypoxic and exercise stress. Preterm subjects had higher mean pulmonary arterial pressures (mPAPs), with 27% (3 of 11) meeting criteria for borderline pulmonary hypertension (mPAP, 19-24 mm Hg) and 18% (2 of 11) meeting criteria for overt pulmonary hypertension (mPAP ≥ 25 mm Hg). Pulmonary vascular resistance and elastance were higher at rest and during exercise, suggesting a stiffer vascular bed. Preterm subjects were significantly less able to augment cardiac index or right ventricular stroke work during exercise. Among neonatal characteristics, total ventilatory support days was the strongest predictor of adult pulmonary pressure. Young adults born preterm demonstrate early pulmonary vascular disease, characterized by elevated pulmonary pressures, a stiffer pulmonary vascular bed, and right ventricular dysfunction, consistent with an increased risk of developing pulmonary hypertension.
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http://dx.doi.org/10.1164/rccm.201710-2016OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298636PMC
December 2018

Multiscale structure-function relationships in right ventricular failure due to pressure overload.

Am J Physiol Heart Circ Physiol 2018 09 8;315(3):H699-H708. Epub 2018 Jun 8.

Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering , Madison, Wisconsin.

Right ventricular (RV) failure (RVF) is the major cause of death in pulmonary hypertension. Recent studies have characterized changes in RV structure in RVF, including hypertrophy, fibrosis, and abnormalities in mitochondria. Few, if any, studies have explored the relationships between these multiscale structural changes and functional changes in RVF. Pulmonary artery banding (PAB) was used to induce RVF due to pressure overload in male rats. Eight weeks postsurgery, terminal invasive measurements demonstrated RVF with decreased ejection fraction (70 ± 10 vs. 45 ± 15%, sham vs. PAB, P < 0.005) and cardiac output (126 ± 40 vs. 67 ± 32 ml/min, sham vs. PAB, P < 0.05). At the organ level, RV hypertrophy was directly correlated with increased contractility, which was insufficient to maintain ventricular-vascular coupling. At the tissue level, there was a 90% increase in fibrosis that had a direct correlation with diastolic dysfunction measured by reduced chamber compliance ( r = 0.43, P = 0.008). At the organelle level, transmission electron microscopy demonstrated an abundance of small-sized mitochondria. Increased mitochondria was associated with increased ventricular oxygen consumption and reduced mechanical efficiency ( P < 0.05). These results demonstrate an association between alterations in mitochondria and RV oxygen consumption and mechanical inefficiency in RVF and a link between fibrosis and in vivo diastolic dysfunction. Overall, this work provides key insights into multiscale RV remodeling in RVF due to pressure overload. NEW & NOTEWORTHY This study explores the functional impact of multiscale ventricular remodeling in right ventricular failure (RVF). It demonstrates correlations between hypertrophy and increased contractility as well as fibrosis and diastolic function. This work quantifies mitochondrial ultrastructural remodeling in RVF and demonstrates increased oxygen consumption and mechanical inefficiency as features of RVF. Direct correlation between mitochondrial changes and ventricular energetics provides insight into the impact of organelle remodeling on organ level function.
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http://dx.doi.org/10.1152/ajpheart.00047.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172642PMC
September 2018

Organ-level right ventricular dysfunction with preserved Frank-Starling mechanism in a mouse model of pulmonary arterial hypertension.

J Appl Physiol (1985) 2018 05 25;124(5):1244-1253. Epub 2018 Jan 25.

Department of Biomedical Engineering, University of Wisconsin-Madison , Madison, Wisconsin.

Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is due to right ventricular (RV) failure. It is unclear whether RV dysfunction initiates at the organ level or the subcellular level or both. We hypothesized that chronic pressure overload-induced RV dysfunction begins at the organ level with preserved Frank-Starling mechanism in myocytes. To test this hypothesis, we induced PAH with Sugen + hypoxia (HySu) in mice and measured RV whole organ and subcellular functional changes by in vivo pressure-volume measurements and in vitro trabeculae length-tension measurements, respectively, at multiple time points for up to 56 days. We observed progressive changes in RV function at the organ level: in contrast to early PAH (14-day HySu), in late PAH (56-day HySu) ejection fraction and ventricular-vascular coupling were decreased. At the subcellular level, direct measurements of myofilament contraction showed that RV contractile force was similarly increased at any stage of PAH development. Moreover, cross-bridge kinetics were not changed and length dependence of force development (Frank-Starling relation) were not different from baseline in any PAH group. Histological examinations confirmed increased cardiomyocyte cross-sectional area and decreased von Willebrand factor expression in RVs with PAH. In summary, RV dysfunction developed at the organ level with preserved Frank-Starling mechanism in myofilaments, and these results provide novel insight into the development of RV dysfunction, which is critical to understanding the mechanisms of RV failure. NEW & NOTEWORTHY A multiscale investigation of pulmonary artery pressure overload in mice showed time-dependent organ-level right ventricular (RV) dysfunction with preserved Frank-Starling relations in myofilaments. Our findings provide novel insight into the development of RV dysfunction, which is critical to understanding mechanisms of RV failure.
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http://dx.doi.org/10.1152/japplphysiol.00725.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008075PMC
May 2018

PBX transcription factors drive pulmonary vascular adaptation to birth.

J Clin Invest 2018 02 18;128(2):655-667. Epub 2017 Dec 18.

Laboratory of Genetics.

A critical event in the adaptation to extrauterine life is relaxation of the pulmonary vasculature at birth, allowing for a rapid increase in pulmonary blood flow that is essential for efficient gas exchange. Failure of this transition leads to pulmonary hypertension (PH), a major cause of newborn mortality associated with preterm birth, infection, hypoxia, and malformations including congenital diaphragmatic hernia (CDH). While individual vasoconstrictor and dilator genes have been identified, the coordination of their expression is not well understood. Here, we found that lung mesenchyme-specific deletion of CDH-implicated genes encoding pre-B cell leukemia transcription factors (Pbx) led to lethal PH in mice shortly after birth. Loss of Pbx genes resulted in the misexpression of both vasoconstrictors and vasodilators in multiple pathways that converge to increase phosphorylation of myosin in vascular smooth muscle (VSM) cells, causing persistent constriction. While targeting endothelin and angiotensin, which are upstream regulators that promote VSM contraction, was not effective, treatment with the Rho-kinase inhibitor Y-27632 reduced vessel constriction and PH in Pbx-mutant mice. These results demonstrate a lung-intrinsic, herniation-independent cause of PH in CDH. More broadly, our findings indicate that neonatal PH can result from perturbation of multiple pathways and suggest that targeting the downstream common effectors may be a more effective treatment for neonatal PH.
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http://dx.doi.org/10.1172/JCI93395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785269PMC
February 2018

Characteristic impedance: frequency or time domain approach?

Physiol Meas 2018 01 31;39(1):014004. Epub 2018 Jan 31.

Department of Mathematics, North Carolina State University, Raleigh, NC, 27695, United States of America. Author to whom any correspondence should be addressed.

Objective: Characteristic impedance (Zc) is an important component in the theory of hemodynamics. It is a commonly used metric of proximal arterial stiffness and pulse wave velocity. Calculated using simultaneously measured dynamic pressure and flow data, estimates of characteristic impedance can be obtained using methods based on frequency or time domain analysis. Applications of these methods under different physiological and pathological conditions in species with different body sizes and heart rates show that the two approaches do not always agree. In this study, we have investigated the discrepancies between frequency and time domain estimates accounting for uncertainties associated with experimental processes and physiological conditions.

Approach: We have used published data measured in different species including humans, dogs, and mice to investigate: (a) the effects of time delay and signal noise in the pressure-flow data, (b) uncertainties about the blood flow conditions, (c) periodicity of the cardiac cycle versus the breathing cycle, on the frequency and time domain estimates of Zc, and (d) if discrepancies observed under different hemodynamic conditions can be eliminated. Main results and Significance: We have shown that the frequency and time domain estimates are not equally sensitive to certain characteristics of hemodynamic signals including phase lag between pressure and flow, signal to noise ratio and the end of systole retrograde flow. The discrepancies between two types of estimates are inherent due to their intrinsically different mathematical expressions and therefore it is impossible to define a criterion to resolve such discrepancies. Considering the interpretation and role of Zc as an important hemodynamic parameter, we suggest that the frequency and time domain estimates should be further assessed as two different hemodynamic parameters in a future study.
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http://dx.doi.org/10.1088/1361-6579/aa9d60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828940PMC
January 2018

A novel single-beat approach to assess right ventricular systolic function.

J Appl Physiol (1985) 2018 02 12;124(2):283-290. Epub 2017 Oct 12.

Department of Biomedical Engineering, University of Wisconsin-Madison , Madison, Wisconsin.

Clinical assessment of right ventricular (RV) contractility in diseases such as pulmonary arterial hypertension (PAH) has been hindered by the lack of a robust methodology. Here, a novel, clinically viable, single-beat method was developed to assess end-systolic elastance (E), a measure of right ventricular (RV) contractility. We hypothesized that this novel approach reduces uncertainty and interobserver variability in the estimation of the maximum isovolumic pressure (P), the key step in single-beat methods. The new method was designed to include a larger portion of the RV pressure data and minimize subjective adjustments by the operator. Data were obtained from right heart catheterization of PAH patients in a multicenter prospective study ( data set 1) and a single-center retrospective study ( data set 2). To obtain P, three independent observers used an established single-beat method (based on the first derivative of the pressure waveform) and the novel method (based on the second derivative). Interobserver variability analysis included paired t-test, one-way ANOVA, interclass correlation (ICC) analysis, and a modified Bland-Altman analysis. The P values obtained from the two methods were linearly correlated for both data set 1 ( R = 0.74) and data set 2 ( R = 0.91). Compared with the established method, the novel method resulted in smaller interobserver variability ( P < 0.001), nonsignificant differences between observers, and a narrower confidence interval. By reducing uncertainty and interobserved variability, this novel approach may pave the way for more effective clinical management of PAH. NEW & NOTEWORTHY A novel methodology to assess right ventricular contractility from clinical data is demonstrated. This approach significantly reduces interobserver variability in the analysis of ventricular pressure data, as demonstrated in a relatively large population of subjects with pulmonary hypertension. This study may enable more accurate clinical monitoring of systolic function in subjects with pulmonary hypertension.
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http://dx.doi.org/10.1152/japplphysiol.00258.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867365PMC
February 2018

Right Ventricular-Pulmonary Vascular Interactions.

Physiology (Bethesda) 2017 09;32(5):346-356

Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, Wisconsin; and

Accurate and comprehensive evaluation of right ventricular (RV)-pulmonary vascular (PV) interactions is critical to the assessment of cardiopulmonary function, dysfunction, and failure. Here, we review methods of quantifying RV-PV interactions and experimental results from clinical trials as well as large- and small-animal models based on pressure-volume analysis. We conclude by outlining critical gaps in knowledge that should drive future studies.
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http://dx.doi.org/10.1152/physiol.00040.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625265PMC
September 2017

Dobutamine stress MRI in pulmonary hypertension: relationships between stress pulmonary artery relative area change, RV performance, and 10-year survival.

Pulm Circ 2017 Apr-Jun;7(2):465-475. Epub 2017 Mar 27.

2 Scottish Pulmonary Vascular Unit, Golden Jubilee National Hospital, Glasgow, UK.

In pulmonary hypertension (PH), right ventricular (RV) performance determines survival. Pulmonary artery (PA) stiffening is an important biomechanical event in PH and also predicts survival based on the PA relative area change (RAC) measured at rest using magnetic resonance imaging (MRI). In this exploratory study, we sought to generate novel hypotheses regarding the influence of stress RAC on PH prognosis and the interaction between PA stiffening, RV performance and survival. Fifteen PH patients underwent dobutamine stress-MRI (ds-MRI) and right heart catheterization. RAC, RAC, and ΔRAC (RAC - RAC ) were correlated against resting invasive hemodynamics and ds-MRI data regarding RV performance and RV-PA coupling efficiency (n' [RV stroke volume/RV end-systolic volume]). The impact of RAC, RV data, and n' on ten-year survival were determined using Kaplan-Meier analysis. PH patients with a low ΔRAC (<-2.6%) had a worse long-term survival (log-rank P = 0.045, HR for death = 4.46 [95% CI = 1.08-24.5]) than those with ΔRAC ≥ -2.6%. Given the small sample, these data should be interpreted with caution; however, low ΔRAC was associated with an increase in stress diastolic PA area indicating proximal PA stiffening. Associations of borderline significance were observed between low RAC and low n', Δη', and ΔRVEF. Further studies are required to validate the potential prognostic impact of ΔRAC and the biomechanics potentially connecting low ΔRAC to shorter survival. Such studies may facilitate development of novel PH therapies targeted to the proximal PA.
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http://dx.doi.org/10.1177/2045893217704838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467938PMC
March 2017

Estrogen maintains mitochondrial content and function in the right ventricle of rats with pulmonary hypertension.

Physiol Rep 2017 Mar;5(6)

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin

The typical cause of death in pulmonary hypertension (PH) is right ventricular (RV) failure, with females showing better survival rates than males. Recently, metabolic shift and mitochondrial dysfunction have been demonstrated in RV failure secondary to PH In light of evidence showing that estrogen protects mitochondrial function and biogenesis in noncardiovascular systems, we hypothesized that the mechanism by which estrogen preserves RV function is via protection of mitochondrial content and oxidative capacity in PH We used a well-established model of PH (Sugen+Hypoxia) in ovariectomized female rats with/without estrogen treatment. RV functional measures were derived from pressure-volume relationships measured via RV catheterization in live rats. Citrate synthase activity, a marker of mitochondrial density, was measured in both RV and LV tissues. Respiratory capacity of mitochondria isolated from RV was measured using oxygraphy. We found that RV ventricular-vascular coupling efficiency decreased in the placebo-treated SuHx rats (0.78 ± 0.10 vs. 1.50 ± 0.13 in control,  < 0.05), whereas estrogen restored it. Mitochondrial density decreased in placebo-treated SuHx rats (0.12 ± 0.01 vs. 0.15 ± 0.01 U citrate synthase/mg in control,  < 0.05), and estrogen attenuated the decrease. Mitochondrial quality and oxidative capacity tended to be lower in placebo-treated SuHx rats only. The changes in mitochondrial biogenesis and function paralleled the expression levels of PGC-1 in RV Our results suggest that estrogen protects RV function by preserving mitochondrial content and oxidative capacity. This provides a mechanism by which estrogen provides protection in female PH patients and paves the way to develop estrogen and its targets as a novel RV-specific therapy for PH.
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http://dx.doi.org/10.14814/phy2.13157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371553PMC
March 2017
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