Skeletal Muscle SIRT3 Deficiency Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling. METHODS: Using skeletal muscle-specific Sirt3 knockout mice (Sirt3skm-/-) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF. RESULTS: Sirt3skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF.

Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS: Plasma proteomics identified high protein abundance levels of B2M (ß2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

The Lung Allocation Score Remains Inequitable for Patients with Pulmonary Arterial Hypertension, Even after the 2015 Revision.

Rationale: The lung allocation score (LAS) was revised in 2015 to improve waiting list mortality and rate of transplant for patients with pulmonary arterial hypertension (PAH). Objectives: We sought to determine if the 2015 revision achieved its intended goals. Methods: Using the Standard Transplant Analysis and Research file, we assessed the impact of the 2015 LAS revision by comparing the pre- and postrevision eras. Registrants were divided into the LAS diagnostic categories: group A-chronic obstructive pulmonary disease; group B-pulmonary arterial hypertension; group C-cystic fibrosis; and group D-interstitial lung disease. Competing risk regressions were used to assess the two mutually exclusive competing risks of waiting list death and transplant. Cumulative incidence plots were created to visually inspect risks. Measurements and Main Results: The LAS at organ matching increased by 14.2 points for registrants with PAH after the 2015 LAS revision, the greatest increase among diagnostic categories (other LAS categories: Δ, -0.9 to +2.8 points). Before the revision, registrants with PAH had the highest risk of death and lowest likelihood of transplant. After the 2015 revision, registrants with PAH still had the highest risk of death, now similar to those with interstitial lung disease, and the lowest rate of transplant, now similar to those with chronic obstructive pulmonary disease. Conclusions: Although the 2015 LAS revision improved access to transplant and reduced the risk of waitlist death for patients with PAH, it did not go far enough. Significant differences in waitlist mortality and likelihood of transplant persist.

Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial Hypertension?

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Role of Internal Jugular Venous Ultrasound in suspected or confirmed Heart Failure: A Systematic Review.

BACKGROUND: Few data are available on the use of internal jugular vein (IJV) ultrasound parameters to assess central venous pressure and clinical outcomes among patients with suspected or confirmed heart failure (HF). METHODS: We performed electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through January 9, 2021, to identify studies evaluating the accuracy and reliability of the IJV ultrasound parameters and exploring its correlation with central venous pressure and clinical outcomes in adult patients with suspected or confirmed acutely decompensated HF. The studies' report quality was assessed by Quality Assessment of Diagnostic Accuracy Studies-2 scale. RESULTS: A total of 11 studies were eligible for final analysis (n = 1481 patients with HF). The studies were segregated into 3 groups: (1) the evaluation of patients presenting to the emergency department with dyspnea, (2) the evaluation of patients presenting to the HF clinic for follow-up, and (3) the evaluation of hospitalized patients with acutely decompensated HF or undergoing right heart catheterization. US parameters included IJV height, IJV diameter, IJV diameter ratio, IJV cross-sectional area, respiratory compressibility index, and compression compressibility index. CONCLUSIONS: The findings of this systematic review suggest a significant role for ultrasound interrogation of the IJV in evaluation of patients in the emergency department presenting with dyspnea, in the outpatient clinic for poor clinical outcomes in HF, and in determining the timing of discharge for patients admitted with acutely decompensated HF. Further studies are warranted for testing the reliability of the reported ultrasound indices.

Right Ventricular Shape Feature Quantification for Evaluation of Pulmonary Hypertension: Feasibility and Preliminary Associations With Clinical Outcome Submitted for Publication.

This study aimed to demonstrate feasibility of statistical shape analysis techniques to identify distinguishing features of right ventricle (RV) shape as related to hemodynamic variables and outcome data in pulmonary hypertension (PH). Cardiovascular magnetic resonance images were acquired from 50 patients (33 PH, 17 non-PH). Contemporaneous right heart catheterization data were collected for all individuals. Outcome was defined by all-cause mortality and hospitalization for heart failure. RV endocardial borders were manually segmented, and three-dimensional surfaces reconstructed at end diastole and end systole. Registration and harmonic mapping were then used to create a quantitative correspondence between all RV surfaces. Proper orthogonal decomposition was performed to generate modes describing RV shape features. The first 15 modes captured over 98% of the total modal energy. Two shape modes, 8 (free wall expansion) and 13 (septal flattening), stood out as relating to PH state (mode 13: r = 0.424, p = 0.002; mode 8: r = 0.429, p = 0.002). Mode 13 was significantly correlated with outcome (r = 0.438, p = 0.001), more so than any hemodynamic variable. Shape analysis techniques can derive unique RV shape descriptors corresponding to specific, anatomically meaningful features. The modes quantify shape features that had been previously only qualitatively related to PH progression. Modes describing relevant RV features are shown to correlate with clinical measures of RV status, as well as outcomes. These new shape descriptors lay the groundwork for a noninvasive strategy for identification of failing RVs, beyond what is currently available to clinicians.

PROVIDE-HF primary results: Patient-Reported Outcomes inVestigation following Initiation of Drug therapy with Entresto (sacubitril/valsartan) in heart failure.

BACKGROUND: In PARADIGM-HF, sacubitril/valsartan improved quality of life (QOL) versus enalapril in heart failure with reduced ejection fraction (HFrEF), yet limited data are available regarding QOL changes after sacubitril/valsartan initiation in routine practice. METHODS: PROVIDE-HF was a prospective study within a national research network (Patient-Centered Outcomes Research Network) of HFrEF outpatients recently initiated on sacubitril/valsartan versus controls with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change. The primary end point was mean Kansas City Cardiomyopathy Questionnaire (KCCQ) change through 12 weeks. Other end points included responder analyses: ≥5-point and ≥20-point KCCQ increase. Adjusted QOL change was estimated after propensity score weighting. RESULTS: Overall, 270 patients had both baseline and 12-week KCCQ data (151 sacubitril/valsartan; 119 control). The groups had similar demographics and HF details: median EF 28% and N-terminal pro-brain natriuretic peptide 1083 pg/mL. Sacubitril/valsartan patients had larger improvements in KCCQ (mean difference +4.76; P = .027) and were more likely to have a ≥5-point and ≥20-point response (all P < .05). Adjusted comparisons demonstrated similar numerical improvements in the change in KCCQ (+4.55; 95% CI -0.89 to 9.99; P = .101) and likelihood of ≥5-point increase (odds ratio 1.55; 95% CI: 0.84-2.86; P = .16); ≥20-point increase remained statistically significant (odds ratio 3.79; 95% CI 1.47-9.73; P = .006). CONCLUSIONS: In this prospective HFrEF study of sacubitril/valsartan initiation compared with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change, the between-group difference in the primary end point, mean KCCQ change at 12 weeks was not statistically significant following adjustment, but sacubitril/valsartan initiation was associated with early improvements in QOL and a higher likelihood of ≥20-point improvement in KCCQ at 12 weeks. These data add additional real-world evidence related to patient-reported outcomes following the initiation of sacubitril/valsartan in routine clinical practice.

Current and Future Considerations in the Use of Mechanical Circulatory Support Devices: An Update, 2008-2018.

Our review in the 2008 volume of this journal detailed the use of mechanical circulatory support (MCS) for treatment of heart failure (HF). MCS initially utilized bladder-based blood pumps generating pulsatile flow; these pulsatile flow pumps have been supplanted by rotary blood pumps, in which cardiac support is generated via the high-speed rotation of computationally designed blading. Different rotary pump designs have been evaluated for their safety, performance, and efficacy in clinical trials both in the United States and internationally. The reduced size of the rotary pump designs has prompted research and development toward the design of MCS suitable for infants and children. The past decade has witnessed efforts focused on tissue engineering-based therapies for the treatment of HF. This review explores the current state and future opportunities of cardiac support therapies within our larger understanding of the treatment options for HF.

The Effects of Inhaled Sodium Nitrite on Pulmonary Vascular Impedance in Patients With Pulmonary Hypertension Associated with Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The severity of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance, which is a steady-state measurement and ignores the pulsatile load encountered by the right ventricle (RV). Pulmonary vascular impedance (PVZ) can depict both steady-state and pulsatile forces, and thus may better predict clinical outcomes. We sought to calculate PVZ in patients with PH associated with heart failure with preserved ejection fraction who were administered inhaled sodium nitrite to better understand the acute effects on afterload. METHODS AND RESULTS: Fourteen patients with PH associated with heart failure with preserved ejection fraction underwent right heart catherization and were administered inhaled sodium nitrite. A Fourier transform was used to calculate PVZ for both before and after nitrite for comparison. Inhaled sodium nitrite decreased characteristic impedance (inversely related to proximal pulmonary artery compliance) and total work performed by the RV. RV efficiency improved, defined by a reduction in the total work divided by cardiac output. There was a mild decrease in pulmonary steady-state resistance after the administration of inhaled sodium nitrite, but this effect was not significant. CONCLUSIONS: PVZ analysis showed administration of inhaled sodium nitrite was associated with an improvement in pulmonary vascular compliance via a decrease in characteristic impedance, more so than pulmonary steady-state resistance. This effect was associated with improved RV efficiency and total work.

Nationwide variability in the use of induction immunosuppression for adult heart transplantation.

BACKGROUND: Institutional factors have been shown to impact outcomes following orthotopic heart transplantation (OHT). This study evaluated center variability in the utilization of induction therapy for OHT and its implications on clinical outcomes. METHODS: Adult OHT patients between 2010 and 2018 were identified from the United Network for Organ Sharing registry. Transplant centers were stratified based on their rates of induction therapy utilization. Mixed-effects logistic regression models were created with drug-treated rejection within 1 year as primary endpoint and individual centers as a random parameter. Risk-adjusted Cox regression was used to evaluate patient-level mortality outcomes. RESULTS: In 17,524 OHTs performed at 100 centers, induction therapy was utilized in 48.6% (n = 8411) with substantial variability between centers (interquartile range, 21.4%-79.1%). There were 36, 30, and 34 centers in the low (<29%), intermediate (29%-66%), and high (>67%) induction utilization terciles groups, respectively. Induction therapy did not account for the observed variability in the treated rejection rate at 1 year among centers after adjusting for donor and recipient factors (p = .20). No differences were observed in postoperative outcomes among induction utilization centers groups (all, p > .05). Furthermore, there was a weak correlation between the percentage of induction therapy utilization at the center-level and recipients found to have moderate (r = .03) or high (r = .04) baseline risks for acute rejection at 1 year. CONCLUSIONS: This analysis demonstrates that there is substantial variability in the use of induction therapy among OHT centers. In addition, there was a minimal correlation with baseline recipient risk or 1-year rejection rates, suggesting a need for better-standardized practices for induction therapy use in OHT.

Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission.

AIMS: Diabetes may promote myocardial extracellular matrix (ECM) expansion that increases vulnerability. We hypothesized that: (i) type 2 diabetes would be associated with quantitative cardiovascular magnetic resonance (CMR) measures of myocardial ECM expansion, i.e. extracellular volume fraction (ECV); (ii) medications blocking the renin-angiotensin-aldosterone system (RAAS) would be associated with lower ECV; and (iii) ECV in diabetic individuals would be associated with mortality and/or incident hospitalization for heart failure. METHODS AND RESULTS: We enrolled 1176 consecutive patients referred for CMR without amyloidosis and computed ECV from measures of the haematocrit and myocardial and blood T1 pre- and post-contrast. Linear regression modelled ECV; Cox regression modelled mortality and/or hospitalization for heart failure. Diabetic individuals (n = 231) had higher median ECV than those without diabetes (n = 945): 30.2% (IQR: 26.9-32.7) vs. 28.1% (IQR: 25.9-31.0), respectively, P < 0.001). Diabetes remained associated with higher ECV in models adjusting for demographics, comorbidities, and medications (P < 0.001). Renin-angiotensin-aldosterone system blockade was associated with lower ECV (P = 0.028) in multivariable linear models. Over a median of 1.3 years (IQR: 0.8-1.9), 38 diabetic individuals had events (21 incident hospitalizations for heart failure; 24 deaths), and ECV was associated with these events (HR: 1.52, 95% CI: 1.21-1.89 per 3% ECV increase) in multivariable Cox regression models. CONCLUSION: Diabetes is associated with increased ECV. Extracellular volume fraction detects amelioration of ECM expansion associated with RAAS blockade, and is associated with mortality and/or incident hospitalization for heart failure in diabetic individuals. Extracellular matrix expansion may be an important intermediate phenotype in diabetic individuals that is detectable and treatable.

Isolated right ventricular dysfunction in patients with human immunodeficiency virus.

BACKGROUND: HIV-infected individuals are at increased risk for pulmonary hypertension and cardiomyopathy, portending a poor prognosis. Right ventricular (RV) dysfunction is associated with worse outcomes in these conditions, yet its prevalence is poorly defined in HIV. We sought to determine the prevalence of RV dysfunction in an outpatient HIV cohort. METHODS: Echocardiograms were evaluated from 104 HIV-infected adults. Measurements included estimated pulmonary arterial systolic pressure (PASP) and several measures of RV function, including tricuspid annular plane systolic excursion (TAPSE), RV longitudinal myocardial strain (RVLMS), RV fractional area change (RVFAC), and myocardial performance index (MPI). RESULTS: Sixteen subjects (15%) had PASP >35 mm Hg, yet RV function did not differ significantly from those with normal estimated PASP. RV dysfunction defined by RVFAC <35% occurred in 11%. RVLMS had a median value of -27.3%, and individuals below the median had lower TAPSE but no differences in left ventricular ejection fraction (LVEF), PASP, or other measures. Dyspnea was associated with the lowest quintile of RVLMS (≥-21.05%). There were 6 subjects with LVEF <50%, and these individuals had lower TAPSE but no differences in PASP or other RV functional measures. CONCLUSIONS: RV dysfunction was common as estimated PASP >35 mm Hg and LV dysfunction, but these findings did not cosegregate. RV dysfunction in HIV-infected individuals may be a separate entity from LV/global cardiomyopathy or pulmonary hypertension and deserves further study.

Beta blockers are associated with lower all-cause mortality among HFpEF patients.

BACKGROUND: The evidence regarding beta blocker (BB) benefit in heart failure with preserved ejection fraction (HFpEF) remains inconclusive, leading to consideration of BB withdrawal in this population. OBJECTIVES: In this study, we retrospectively analyzed the association of BB on all-cause mortality in HFpEF patients. METHODS: This is a single-center retrospective cohort study of 20,206 patients with left ventricular ejection fraction (EF) ≥ 50% who were hospitalized with decompensated HF between January 2011 and March 2020. Survival is reported at 30 days, 1 year, and 3 years. A secondary analysis comparing mortality for patients on BB with additional indications including hypertension (HTN), coronary artery disease (CAD), and atrial fibrillation (AF) was completed. Mortality was compared between patients on BB and additional therapies of spironolactone or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs). RESULTS: BB showed lower all-cause mortality at 30 days, 1 year, and 3 years (p < 0.0001). This association with lower all-cause mortality was validated by a supplementary propensity score-matched analysis. At 3 years, there was significant mortality reduction with addition of BB to either spironolactone (p = 0.0359) or ACEi/ARBs (p < 0.0001). CONCLUSION: In a large single-center retrospective registry, BB use was associated with lower mortality in HFpEF patients with a recent decompensated HF hospitalization. The mortality benefit persisted in those treated with spironolactone or ACEi/ARBs, and in those with AF. This provocative data further highlights the uncertainty of the benefit of BB use in this cohort and calls for re-consideration of BB withdrawal, especially in those tolerating it well, without conclusive, large, and randomized trials showing lack of benefit or harm.

Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality.

BACKGROUND: Extracellular matrix expansion may be a fundamental feature of adverse myocardial remodeling, it appears to be treatable, and its measurement may improve risk stratification. Yet, the relationship between mortality and extracellular matrix is not clear because of difficulties with its measurement. To assess its relationship with outcomes, we used novel, validated cardiovascular magnetic resonance techniques to quantify the full spectrum of extracellular matrix expansion not readily detectable by conventional cardiovascular magnetic resonance. METHODS AND RESULTS: We recruited 793 consecutive patients at the time of cardiovascular magnetic resonance without amyloidosis or hypertrophic cardiomyopathy as well as 9 healthy volunteers (ages 20-50 years). We measured the extracellular volume fraction (ECV) to quantify the extracellular matrix expansion in myocardium without myocardial infarction. ECV uses gadolinium contrast as an extracellular space marker based on T1 measures of blood and myocardium pre- and post-gadolinium contrast and hematocrit measurement. In volunteers, ECV ranged from 21.7% to 26.2%, but in patients it ranged from 21.0% to 45.8%, indicating considerable burden. There were 39 deaths over a median follow-up of 0.8 years (interquartile range 0.5-1.2 years), and 43 individuals who experienced the composite end point of death/cardiac transplant/left ventricular assist device implantation. In Cox regression models, ECV related to all-cause mortality and the composite end point (hazard ratio, 1.55; 95% confidence interval, 1.27-1.88 and hazard ratio, 1.48; 95% confidence interval, 1.23-1.78, respectively, for every 3% increase in ECV), adjusting for age, left ventricular ejection fraction, and myocardial infarction size. CONCLUSIONS: ECV measures of extracellular matrix expansion may predict mortality as well as other composite end points (death/cardiac transplant/left ventricular assist device implantation).

Effectiveness of late gadolinium enhancement to improve outcomes prediction in patients referred for cardiovascular magnetic resonance after echocardiography.

BACKGROUND: Echocardiography (echo) is a first line test to assess cardiac structure and function. It is not known if cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) ordered during routine clinical practice in selected patients can add additional prognostic information after routine echo. We assessed whether CMR improves outcomes prediction after contemporaneous echo, which may have implications for efforts to optimize processes of care, assess effectiveness, and allocate limited health care resources. METHODS AND RESULTS: We prospectively enrolled 1044 consecutive patients referred for CMR. There were 38 deaths and 3 cardiac transplants over a median follow-up of 1.0 years (IQR 0.4-1.5). We first reproduced previous survival curve strata (presence of LGE and ejection fraction (EF) < 50%) for transplant free survival, to support generalizability of any findings. Then, in a subset (n = 444) with contemporaneous echo (median 3 days apart, IQR 1-9), EF by echo (assessed visually) or CMR were modestly correlated (R(2) = 0.66, p < 0.001), and 30 deaths and 3 transplants occurred over a median follow-up of 0.83 years (IQR 0.29-1.40). CMR EF predicted mortality better than echo EF in univariable Cox models (Integrated Discrimination Improvement (IDI) 0.018, 95% CI 0.008-0.034; Net Reclassification Improvement (NRI) 0.51, 95% CI 0.11-0.85). Finally, LGE further improved prediction beyond EF as determined by hazard ratios, NRI, and IDI in all Cox models predicting mortality or transplant free survival, adjusting for age, gender, wall motion, and EF. CONCLUSIONS: Among those referred for CMR after echocardiography, CMR with LGE further improves risk stratification of individuals at risk for death or death/cardiac transplant.

Backscatter tensor imaging and 3D speckle tracking for simultaneous ex vivo structure and deformation measurement of myocardium.

OBJECTIVE: Biaxial mechanical testing is a common method for elucidation of mechanical properties of excised ventricular myocardium, especially in the context of structural remodeling that accompanies heart disease. Current imaging strategies in biaxial testing are based on optical camera imaging of the tissue surface, thus providing no information about the tissue microstructure and limiting strain measurements to two dimensions. Here, these limitations are overcome by replacing the camera with ultrasound imaging in order to measure both transmural fiber orientation and 3D tissue deformation during biaxial testing. METHODS: Quasi-static biaxial mechanical testing is applied to four samples of excised porcine ventricular myocardium (two left- and two right-ventricular tissues). During testing, a rotational scan of an ultrasound linear array provides data for both backscatter tensor imaging and 3D speckle tracking, from which transmural fiber orientation and tissue deformation are computed, respectively. Ultrasound-derived fiber orientation and tissue strain are validated against histology and camera surface imaging, respectively. DISCUSSION: Ultrasound-derived fiber angle and tissue strain exhibit good accuracy, with root-mean-square errors of 9.9° and 1.2% strain, respectively. Further investigation into the optimization of backscatter tensor imaging is warranted. Replacing the rotational scan of a linear array with volume imaging with a matrix array will improve the technique. CONCLUSION: Ultrasound imaging can replace the optical camera measurement during biaxial mechanical testing of ventricular myocardium in order to accurately provide measurements of transmural fiber orientation and tissue strain. In situ knowledge of transmural fiber structure and tissue deformation can enhance the inverse problem used to determine tissue mechanical properties from biaxial testing.

Pulmonary artery compliance in different forms of pulmonary hypertension.

OBJECTIVE: Pulmonary artery compliance (PAC), estimated as stroke volume (SV) divided by pulmonary artery pulse pressure (PP), may be a predictor of survival in pulmonary arterial hypertension (PAH). Resistance-compliance (RC) time, the product of PAC and pulmonary vascular resistance, is reported to be a physiological constant. We investigated if differences in PAC and RC time exist between pulmonary hypertension (PH) subgroups and examined whether PAC is an independent predictor of transplant-free survival in PAH. METHODS: This was a retrospective analysis of adult PAH (n=532) and chronic thromboembolic PH (CTEPH, n=84) patients enrolled in the US Pulmonary Hypertension Association Registry from 2015 to 2019. PAC and RC time were compared between PH subgroups (connective tissue disease-PAH (CTD-PAH), idiopathic/heritable-PAH (i/h-PAH), drug/toxin-PAH (d/t-PAH)). Cox proportional hazards models were constructed for transplant-free survival, adjusting for REVEAL 2.0 risk score. RESULTS: There were no differences in estimated PAC between PAH subgroups, nor between PAH and CTEPH. RC time was shorter in CTEPH compared with PAH (median 0.55 (IQR 0.45-0.64) vs 0.62 (0.52-0.73) s, p<0.0001). RC time was shortest in CTD-PAH when compared with i/h-PAH and d/t-PAH ((0.59±0.18) vs (0.65±0.20) vs (0.73±0.25) s, p=0.0001). PAC was associated with transplant-free survival (HR 0.72, 95% CI 0.55 to 0.94, p=0.02) but was not an independent predictor of outcome after adjustment for REVEAL 2.0 score. CONCLUSION: PAC was similar between PH groups and was not an independent predictor of transplant-free survival in PAH. RC time was different between PH subgroups, challenging RC time constancy. TRIAL REGISTRATION NUMBER: NCT04071327.