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Objectives: Contractile function in the normally perfused infarct borderzone (BZ) is depressed. However, the impact of reduced BZ contractility on left ventricular (LV) pump function is unknown. As a consequence, there have been no therapies specifically d

The right ventricle (RV) and pulmonary arterial (PA) tree are inextricably linked, continually transferring energy back and forth in a process known as RV-PA coupling. Healthy organisms maintain this relationship in optimal balance by modulating RV contractility, pulmonary vascular resistance, and compliance to sustain RV-PA coupling through life's many physiologic challenges. Early in states of adaptation to cardiovascular disease-for example, in diastolic heart failure-RV-PA coupling is maintained via a multitude of cellular and mechanical transformations. However, with disease progression, these compensatory mechanisms fail and become maladaptive, leading to the often-fatal state of "uncoupling." Noninvasive imaging modalities, including echocardiography, magnetic resonance imaging, and computed tomography, allow us deeper insight into the state of coupling for an individual patient, providing for prognostication and potential intervention before uncoupling occurs. In this review, we discuss the physiologic foundations of RV-PA coupling, elaborate on the imaging techniques to qualify and quantify it, and correlate these fundamental principles with clinical scenarios in health and disease. © 2022 American Physiological Society. Compr Physiol 12: 1-26, 2022., (Copyright © 2022 American Physiological Society. All rights reserved.)

Introduction: Myriad disorders cause right ventricular (RV) dilation and lead to tricuspid regurgitation (TR). Because the thin-walled, flexible RV is mechanically coupled to the pulmonary circulation and the left ventricular septum, it distorts with any disturbance in the cardiopulmonary system. TR, therefore, can result from pulmonary hypertension, left heart failure, or intrinsic RV dysfunction; but once it occurs, TR initiates a cycle of worsening RV volume overload, potentially progressing to right heart failure. Characteristic three-dimensional RV shape-changes from this process, and changes particular to individual TR causes, have not been defined in detail. Methods: Cardiac MRI was obtained in 6 healthy volunteers, 41 patients with ≥ moderate TR, and 31 control patients with cardiac disease without TR. The mean shape of each group was constructed using a three-dimensional statistical shape model via the particle-based shape modeling approach. Changes in shape were examined across pulmonary hypertension and congestive heart failure subgroups using principal component analysis (PCA). A logistic regression approach based on these PCA modes identified patients with TR using RV shape alone. Results: Mean RV shape in patients with TR exhibited free wall bulging, narrowing of the base, and blunting of the RV apex compared to controls ( p < 0.05). Using four primary PCA modes, a logistic regression algorithm identified patients with TR correctly with 82% recall and 87% precision. In patients with pulmonary hypertension without TR, RV shape was narrower and more streamlined than in healthy volunteers. However, in RVs with TR and pulmonary hypertension, overall RV shape continued to demonstrate the free wall bulging characteristic of TR. In the subgroup of patients with congestive heart failure without TR, this intermediate state of RV muscular hypertrophy was not present. Conclusion: The multiple causes of TR examined in this study changed RV shape in similar ways. Logistic regression classification based on these shape changes reliably identified patients with TR regardless of etiology. Furthermore, pulmonary hypertension without TR had unique shape features, described here as the "well compensated" RV. These results suggest shape modeling as a promising tool for defining severity of RV disease and risk of decompensation, particularly in patients with pulmonary hypertension., Competing Interests: BS reports research support from AltaThera, Cardiva, Abbott, Sanofi, and Janssen; and consulting to AltaThera. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Orkild, Zenger, Iyer, Rupp, Ibrahim, Khashani, Perez, Foote, Bergquist, Morris, Kim, Steinberg, Selzman, Ratcliffe, MacLeod, Elhabian and Morgan.)

Purpose: Myocardial strain is increasingly used to assess left ventricular (LV) function. Incorporation of LV deformation into finite element (FE) modeling environment with subsequent strain calculation will allow analysis to reach its full potential. We describe a new kinematic model-based analysis framework (KMAF) to calculate strain from 3D cine-DENSE (displacement encoding with stimulated echoes) MRI., Methods: Cine-DENSE allows measurement of 3D myocardial displacement with high spatial accuracy. The KMAF framework uses cine cardiovascular magnetic resonance (CMR) to facilitate cine-DENSE segmentation, interpolates cine-DENSE displacement, and kinematically deforms an FE model to calculate strain. This framework was validated in an axially compressed gel phantom and applied in 10 healthy sheep and 5 sheep after myocardial infarction (MI)., Results: Excellent Bland-Altman agreement of peak circumferential (E cc ) and longitudinal (E ll ) strain (mean difference = 0.021 ± 0.04 and -0.006 ± 0.03, respectively), was found between KMAF estimates and idealized FE simulation. E rr had a mean difference of -0.014 but larger variation (±0.12). Cine-DENSE estimated end-systolic (ES) E cc , E ll and E rr exhibited significant spatial variation for healthy sheep. Displacement magnitude was reduced on average by 27%, 42%, and 56% after MI in the remote, adjacent and MI regions, respectively., Conclusions: The KMAF framework allows accurate calculation of 3D LV E cc and E ll from cine-DENSE., (© 2021 International Society for Magnetic Resonance in Medicine. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Introduction: Finite element (FE) mechanics models of the heart are becoming more sophisticated. However, there is lack of consensus about optimal element type and coupling of FE models to the circulation. We describe biventricular (left (LV) and right (RV) ventricles) FE mechanics model creation using hexahedral elements, airbags and a functional mockup interface (FMI) to lumped-parameter models of the circulation., Methods: Cardiac MRI (CMR) was performed in two healthy volunteers and a single patient with ischemic heart disease (IHD). CMR images were segmented and surfaced, meshing with hexahedral elements was performed with a "thin butterfly with septum" topology. LV and RV inflow and outflow airbags were coupled to lumped-parameter circulation models with an FMI interface. Pulmonary constriction (PAC) and vena cava occlusion (VCO) were simulated and end-systolic pressure-volume relations (ESPVR) were calculated., Results: Mesh construction was prompt with representative contouring and mesh adjustment requiring 32 and 26 min Respectively. The numbers of elements ranged from 4104 to 5184 with a representative Jacobian of 1.0026 ± 0.4531. Agreement between CMR-based surfaces and mesh was excellent with root-mean-squared error of 0.589 ± 0.321 mm. The LV ESPVR slope was 3.37 ± 0.09 in volunteers but 2.74 in the IHD patient. The effect of PAC and VCO on LV ESPVR was consistent with ventricular interaction (p = 0.0286)., Conclusion: Successful co-simulation using a biventricular FE mechanics model with hexahedral elements, airbags and an FMI interface to lumped-parameter model of the circulation was demonstrated. Future studies will include comparison of element type and study of cardiovascular pathologies and device therapies., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: Left ventricular (LV) diastolic dysfunction (DD) is common after myocardial infarction (MI). Whereas current clinical assessment of DD relies on indirect markers including LV filling, finite element (FE) -based computational modeling directly measures regional diastolic stiffness. We hypothesized that an inverse deformation gradient (DG) method calculation of diastolic strain (IDGDS) allows the FE model-based calculation of regional diastolic stiffness (material parameters; MP) in post-MI patients with DD., Methods: Cardiac magnetic resonance (CMR) with tags (CSPAMM) and late gadolinium enhancement (LGE) was performed in 10 patients with post-MI DD and 10 healthy volunteers. The 3-dimensional (3D) LV DG from end-diastole (ED) to early diastolic filling (EDF; DG ED→EDF ) was calculated from CSPAMM. Diastolic strain was calculated from DG EDF→ED by inverting the DG ED→EDF . FE models were created with MI and non-MI (remote; RM) regions determined by LGE. Guccione MPs C, and exponential fiber, b f , and transverse, b t , terms were optimized with IDGDS strain., Results: 3D circumferential and longitudinal diastolic strain (E cc ;E ll ) calculated using IDGDS in CSPAMM obtained in volunteers and MI patients were [Formula: see text]  = 0.27 ± 0.01, [Formula: see text]  = 0.24 ± 0.03 and [Formula: see text]  = 0.21 ± 0.02, and [Formula: see text]  = 0.15 ± 0.02, respectively. MPs in the volunteer group were C H  = 0.013 [0.001, 0.235] kPa, [Formula: see text]  = 20.280 ± 4.994, and [Formula: see text]  = 7.460 ± 2.171 and C RM  = 0.0105 [0.010, 0.011] kPa, [Formula: see text]  = 50.786 ± 13.511 (p = 0.0846), and [Formula: see text]  = 17.355 ± 2.743 (p = 0.0208) in the remote myocardium of post-MI patients., Conclusion: Diastolic strain, calculated from CSPAMM with IDGDS, enables calculation of FE model-based regional diastolic material parameters. Transverse stiffness of the remote myocardium, , may be a valuable new metric for determination of DD in patients after MI., (Published by Elsevier Ltd.)

Tricuspid regurgitation (TR) is a failure in right-sided AV valve function which, if left untreated, leads to marked cardiac shape changes and heart failure. However, the specific right ventricular shape changes resulting from TR are unknown. The goal of this study is to characterize the RV shape changes of patients with severe TR. RVs were segmented from CINE MRI images. Using particle-based shape modeling (PSM), a dense set of homologous landmarks were placed with geometric consistency on the endocardial surface of each RV, via an entropy-based optimization of the information content of the shape model. Principal component analysis (PCA) identified the significant modes of shape variation across the population. These modes were used to create a patient-prediction model. 32 patients and 6 healthy controls were studied. The mean RV shape of TR patients demonstrated increased sphericity relative to controls, with the three most dominant modes of variation showing significant widening of the short axis of the heart, narrowing of the base at the RV outflow tract (RVOT), and blunting of the RV apex. By PCA, shape changes based on the first three modes of variation correctly identified patient vs. control hearts 86.5% of the time. The shape variation may further illuminate the mechanics of TR-induced RV failure and recovery, providing potential targets for therapies including novel devices and surgical interventions.

The decrease in contractility in myocardium adjacent (border zone; BZ) to a myocardial infarction (MI) is correlated with an increase in reactive oxygen species (ROS). We hypothesized that injection of a thermoresponsive hydrogel, with ROS scavenging properties, into the MI would decrease ROS and improve BZ function. Fourteen sheep underwent antero-apical MI. Seven sheep had a comb-like copolymer synthesized from N-isopropyl acrylamide (NIPAAm) and 1500 MW methoxy poly(ethylene glycol) methacrylate, (NIPAAm-PEG1500), injected (20 × 0.5 mL) into the MI zone 40 min after MI (MI + NIPAAm-PEG1500) and seven sheep were MI controls. Cardiac MRI was performed 2 weeks before and 6 weeks after MI + NIPAAm-PEG1500. BZ wall thickness at end systole was significantly higher for MI + NIPAAm-PEG1500 (12.32 ± 0.51 mm/m 2 MI + NIPAAm-PEG1500 vs. 9.88 ± 0.30 MI; p = .023). Demembranated muscle force development for BZ myocardium 6 weeks after MI was significantly higher for MI + NIPAAm-PEG1500 (67.67 ± 2.61 mN/m 2 MI + NIPAAm-PEG1500 vs. 40.53 ± 1.04 MI; p < .0001) but not significantly different from remote myocardium or BZ or non-operated controls. Levels of ROS in BZ tissue were significantly lower in the MI + NIPAAm-PEG1500 treatment group (hydroxyl p = .0031; superoxide p = .0182). We conclude that infarct injection of the NIPAAm-PEG1500 hydrogel with ROS scavenging properties decreased ROS and improved contractile protein function in the border zone 6 weeks after MI., (© 2020 Wiley Periodicals, Inc.)

The left ventricular (LV) end-systolic (ES) pressure volume relationship (ESPVR) is the cornerstone of systolic LV function analysis. We describe a 2D real-time (RT) MRI-based method (RTPVR) with separate software tools for 1) semi-automatic level set-based shape prior method (LSSPM) of the LV, 2) generation of synchronized pressure area loops and 3) calculation of the ESPVR. We used the RTPVR method to measure ventricular geometry, ES pressure area relationship (ESPAR) and ESPVR during vena cava occlusion (VCO) in normal sheep. 14 adult sheep were anesthetized and underwent measurement of LV systolic function. Ten of the 14 sheep underwent RTMRI and eight of the 14 underwent measurement with conductance catheter; 4 had both RTMRI and conductance measurements. 2D cross sectional RTMRI were performed at apex, mid-ventricle and base levels during separate VCOs. The Dice similarity coefficient was used to compare LSSPM and manual image segmentation and thus determine LSSPM accuracy. LV cross-sectional area, major and minor axis length, axis ratio, major axis orientation angle and ESPAR were measured at each LV level. ESPVR was calculated with a trapezoidal rule. The Dice similarity coefficient between LSSPM and manual segmentation by two readers was 87.31±2.51% and 88.13±3.43%. All cross sections became more elliptical during VCO. The major axis orientation shifted during VCO but remained in the septo-lateral direction. LV chamber obliteration at the apical level occurred during VCO in 7 of 10 sheep that underwent RTMRI. ESPAR was non-linear at all levels. Finally, ESPVR was non-linear because of apical collapse. ESPVR measured by conductance catheter (EES,Index = 2.23±0.66 mmHg/ml/m2) and RT (EES,Index = 2.31±0.31 mmHg/ml/m2) was not significantly different. LSSPM segmentation of 2D RT MRI images is accurate and allows calculation of LV geometry, ESPAR and ESPVR during VCO. In the future, RTPVR will facilitate determination of regional systolic material parameters underlying ESPVR., Competing Interests: The authors have declared that no competing interests exist.

Background: Functional Mitral Regurgitation (FMR) associated with coronary artery disease affects nearly 3 million patients in the United States. Both myocardial infarction (MI) and ischemia contribute to FMR development but uncertainty as to which patients will respond to revascularization (REVASC) of ischemia alone prevents rational decision making about FMR therapy. The aim of this study was to create patient-specific cardiac MRI (CMR) informed finite element (FE) models of the left ventricle (LV), calculate regional LV systolic contractility and then use optimized systolic material properties to simulate the effect of revascularization (virtual REVASC)., Methods: We describe a novel FE method able to predict the effect of myocardial ischemia on regional LV function. CMR was obtained in five patients with multi-vessel coronary disease and FMR before and 3 months after percutaneous REVASC and a single healthy volunteer. Patient-specific FE models were created and divided into 17 sectors where the systolic contractility parameter, T m a x of each sector was a function of regional stress perfusion (SP-CMR) and myocardial infarction (LGE-CMR) scores. Sector-specific circumferential and longitudinal end-systolic strain and LV volume from CSPAMM were used in a formal optimization to determine the sector based myocardial contractility, T m a x and ischemia effect, α. Virtual REVASC was simulated by setting α to zero., Results: The FE optimization successfully converged with good agreement between calculated and experimental end-systolic strain and LV volumes. Specifically, the optimized T max for the healthy myocardium for five patients and the volunteer was 495.1, 336.8, 173.5, 227.9, 401.4, and 218.9 kPa. The optimized α was found to be 1.0, 0.44, and 0.08 for Patients 1, 2, and 3, and 0 for Patients 4 and 5. The calculated average of radial strain for Patients 1, 2, and 3 at baseline and after virtual REVASC was 0.23 and 0.25, respectively., Conclusion: We developed a novel computational method able to predict the effect of myocardial ischemia in patients with FMR. This method can be used to predict the effect of ischemia on the regional myocardium and promises to facilitate better understanding of FMR response to REVASC., (Copyright © 2020 Zhang, Wang, Morgan, Kim, Ge, Guccione, Weinsaft and Ratcliffe.)

Background: Echocardiography (echo) is widely used to guide therapeutic decision-making for patients being considered for MitraClip. Relative utility of two- (2D) and three-dimensional (3D) echo predictors of MitraClip response, and impact of MitraClip on mitral annular geometry, are uncertain., Methods: The study population comprised patients with advanced (> moderate) MR undergoing MitraClip. Mitral annular geometry was quantified on pre-procedural 2D transthoracic echocardiography (TTE) and intra-procedural 3D transesophageal echocardiography (TEE); 3D TEE was used to measure MitraClip induced changes in annular geometry. Optimal MitraClip response was defined as ≤mild MR on follow-up (mean 2.7 ± 2.5 months) post-procedure TTE., Results: Eighty patients with advanced MR underwent MitraClip; 41% had optimal response (≤mild MR). Responders had smaller pre-procedural global left ventricular (LV) end-diastolic size and mitral annular diameter on 2D TTE (both p ≤ 0.01), paralleling smaller annular area and circumference on 3D TEE (both p = 0.001). Mitral annular size yielded good diagnostic performance for optimal MitraClip response (AUC 0.72, p < 0.01). In multivariate analysis, sub-optimal MitraClip response was independently associated with larger pre-procedural mitral annular area on 3D TEE (OR 1.93 per cm 2 /m 2 [CI 1.19-3.13], p = 0.007) and global LV end-diastolic volume on 2D TTE (OR 1.29 per 10 ml/m 2 [CI 1.02-1.63], p = 0.03). Substitution of 2D TTE derived mitral annular diameter for 3D TEE data demonstrated a lesser association between pre-procedural annular size (OR 5.36 per cm/m 2 [CI 0.95-30.19], p = 0.06) and sub-optimal MitraClip response. Matched pre- and post-procedural TEE analyses demonstrated MitraClip to acutely decrease mitral annular area and circumference (all p < 0.001) as well as mitral tenting height, area, and volume (all p < 0.05): Magnitude of MitraClip induced reductions in mitral annular circumference on intra-procedural 3D TEE was greater among patients with, compared to those without, sub-optimal MitraClip response (>mild MR) on followup TTE (p = 0.017); greater magnitude of device-induced annular reduction remained associated with sub-optimal MitraClip response even when normalized for pre-procedure annular circumference (p = 0.028)., Conclusions: MitraClip alters mitral annular geometry as quantified by intra-procedural 3D TEE. Pre-procedural mitral annular dilation and magnitude of device-induced reduction in mitral annular size on 3D TEE are each associated with sub-optimal therapeutic response to MitraClip.

Purpose: MitraClip is the sole percutaneous device approved for functional mitral regurgitation (MR; FMR) but MR recurs in over one third of patients. As device-induced mechanical effects are a potential cause for MR recurrence, we tested the hypothesis that MitraClip increases leaflet stress and procedure-related strain in sub-valvular left ventricular (LV) myocardium in FMR associated with coronary disease (FMR-CAD)., Methods: Simulations were performed using finite element models of the LV + mitral valve based on MRI of 5 sheep with FMR-CAD. Models were modified to have a 20% increase in LV volume (↑LV&#95;VOLUME) and MitraClip was simulated with contracting beam elements (virtual sutures) placed between nodes in the center edge of the anterior (AL) and posterior (PL) mitral leaflets. Effects of MitraClip on leaflet stress in the peri-MitraClip region of AL and PL, septo-lateral annular diameter (SLAD), and procedure-related radial strain (Err) in the sub-valvular myocardium were calculated., Results: MitraClip increased peri-MitraClip leaflet stress at end-diastole (ED) by 22.3±7.1 kPa (p<0.0001) in AL and 14.8±1.2 kPa (p<0.0001) in PL. MitraClip decreased SLAD by 6.1±2.2 mm (p<0.0001) and increased Err in the sub-valvular lateral LV myocardium at ED by 0.09±0.04 (p<0.0001)). Furthermore, MitraClip in ↑LV&#95;VOLUME was associated with persistent effects at ED but also at end-systole where peri-MitraClip leaflet stress was increased in AL by 31.9±14.4 kPa (p = 0.0268) and in PL by 22.5±23.7 kPa (p = 0.0101)., Conclusions: MitraClip for FMR-CAD increases mitral leaflet stress and radial strain in LV sub-valvular myocardium. Mechanical effects of MitraClip are augmented by LV enlargement., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To assess impact of left ventricular (LV) chamber remodeling on MitraClip (MClp) response., Background: MitraClip is the sole percutaneous therapy approved for mitral regurgitation (MR) but response varies. LV dilation affects mitral coaptation; determinants of MClp response are uncertain., Methods: LV and mitral geometry were quantified on pre- and post-procedure two-dimensional (2D) transthoracic echocardiography (TTE) and intra-procedural three-dimensional (3D) transesophageal echocardiography (TEE). Optimal MClp response was defined as ≤mild MR at early (1-6 month) follow-up., Results: Sixty-seven degenerative MR patients underwent MClp: Whereas MR decreased ≥1 grade in 94%, 39% of patients had optimal response (≤mild MR). Responders had smaller pre-procedural LV end-diastolic volume (94 ± 24 vs. 109 ± 25 mL/m 2 , p = 0.02), paralleling smaller annular diameter (3.1 ± 0.4 vs. 3.5 ± 0.5 cm, p = 0.002), and inter-papillary distance (2.2 ± 0.7 vs. 2.5 ± 0.6 cm, p = 0.04). 3D TEE-derived annular area correlated with 2D TTE (r = 0.59, p < 0.001) and was smaller among optimal responders (12.8 ± 2.1 cm 2 vs. 16.8 ± 4.4 cm 2 , p = 0.001). Both 2D and 3D mitral annular size yielded good diagnostic performance for optimal MClp response (AUC 0.73-0.84, p < 0.01). In multivariate analysis, sub-optimal MClp response was associated with LV end-diastolic diameter (OR 3.10 per-cm [1.26-7.62], p = 0.01) independent of LA size (1.10 per-cm 2 [1.02-1.19], p = 0.01); substitution of mitral annular diameter for LV size yielded an independent association with MClp response (4.06 per-cm 2 [1.03-15.96], p = 0.045)., Conclusions: Among degenerative MR patients undergoing MClp, LV and mitral annular dilation augment risk for residual or recurrent MR, supporting the concept that MClp therapeutic response is linked to sub-valvular remodeling., (© 2019 Wiley Periodicals, Inc.)

Ischemic mitral regurgitation (iMR) augments risk for right ventricular dysfunction (RV DYS ). Right and left ventricular (LV) function are linked via common coronary perfusion, but data is lacking regarding impact of LV ischemia and infarct transmurality-as well as altered preload and afterload-on RV performance. In this prospective multimodality imaging study, stress CMR and 3-dimensional echo (3D-echo) were performed concomitantly in patients with iMR. CMR provided a reference for RV DYS (RVEF < 50%), as well as LV function/remodeling, ischemia and infarction. Echo was used to test multiple RV performance indices, including linear (TAPSE, S'), strain (GLS), and volumetric (3D-echo) approaches. 90 iMR patients were studied; 32% had RV DYS . RV DYS patients had greater iMR, lower LVEF, larger global ischemic burden and inferior infarct size (all p < 0.05). Regarding injury pattern, RV DYS was associated with LV inferior ischemia and infarction (both p < 0.05); 80% of affected patients had substantial viable myocardium (< 50% infarct thickness) in ischemic inferior segments. Regarding RV function, CMR RVEF similarly correlated with 3D-echo and GLS (r = 0.81-0.87): GLS yielded high overall performance for CMR-evidenced RV DYS (AUC: 0.94), nearly equivalent to that of 3D-echo (AUC: 0.95). In multivariable regression, GLS was independently associated with RV volumetric dilation on CMR (OR - 0.90 [CI - 1.19 to - 0.61], p < 0.001) and 3D echo (OR - 0.43 [CI - 0.84 to - 0.02], p = 0.04). Among patients with iMR, RV DYS is associated with potentially reversible processes, including LV inferior ischemic but predominantly viable myocardium and strongly impacted by volumetric loading conditions.

Background Mitral regurgitation ( MR ) has the potential to impede exercise capacity; it is uncertain whether this is because of regurgitation itself or the underlying cause of valvular insufficiency. Methods and Results The population comprised 3267 patients who underwent exercise treadmill myocardial perfusion imaging and transthoracic echocardiography within 6±8 days. MR was present in 28%, including 176 patients (5%) with moderate or greater MR . Left ventricular systolic function significantly decreased and chamber size increased in relation to MR , paralleling increments in stress and rest myocardial perfusion deficits (all P<0.001). Exercise tolerance (metabolic equivalents of task) decreased stepwise in relation to graded MR severity ( P<0.05). Workload was significantly lower with mild versus no MR (mean±SD, 9.8±3.0 versus 10.1±3.0; P=0.02); magnitude of workload reduction significantly increased among patients with advanced versus those with mild MR (mean±SD, 8.6±3.0 versus 9.8±3.0; P<0.001). MR -associated exercise impairment was accompanied by lower heart rate and blood pressure augmentation and greater dyspnea (all P<0.05). Both functional and nonfunctional MR subgroups demonstrated significantly decreased effort tolerance in relation to MR severity ( P≤0.01); impairment was greater with functional MR ( P=0.04) corresponding to more advanced left ventricular dysfunction and dilation (both P<0.001). Functional MR predicted reduced metabolic equivalent of task-based effort (B=-0.39 [95% CI, -0.62 to -0.17]; P=0.001) independent of MR severity. Among the overall cohort, advanced (moderate or greater) MR was associated with reduced effort tolerance (B=-1.36 [95% CI, -1.80 to -0.93]; P<0.001) and remained significant ( P=0.01) after controlling for age, clinical indexes, stress perfusion defects, and left ventricular dysfunction. Conclusions MR impairs exercise tolerance independent of left ventricular ischemia, dysfunction, and clinical indexes. Magnitude of exercise impairment parallels severity of MR .

Background: Therapy for moderate ischemic mitral regurgitation remains unclear. Determination of myocardial viability, a necessary prerequisite for an improvement in regional contractility, is a likely key factor in determining response to revascularization alone. Myocardial strain has been proposed as a viability measure but has not been compared with late gadolinium enhancement (LGE) cardiac magnetic resonance imaging. We hypothesized that abnormal strain overestimates nonviable left ventricular (LV) segments measured with LGE and that ischemia and mechanical tethering by adjacent transmural myocardial infarction (TMI) also decreases strain in viable segments., Methods: Sixteen patients with mild or greater ischemic mitral regurgitation and 7 healthy volunteers underwent cardiac magnetic resonance imaging with noninvasive tags (complementary spatial modulation of magnetization [CSPAMM]), LGE, and stress perfusion. CSPAMM images were post-processed with harmonic phase and circumferential and longitudinal strains were calculated. Viability was defined as the absence of TMI on LGE (hyperenhancement >50% of wall thickness). The borderzone was defined as any segment bordering TMI. Abnormal strain thresholds (±1 to 2.5 SDs from normal mean) were compared with TMI, ischemia, and borderzone., Results: 7.4% of LV segments had TMI on LGE, and more than 14.5% of LV segments were nonviable by strain thresholds (p < 0.005). In viable segments, ischemia impaired longitudinal strain (least perfused one-third of LV segments: -0.18 ± 0.08 versus most perfused: -0.22 ± 0.1, p = 0.01) and circumferential strain (-0.12 ± 0.1 versus -0.16 ± 0.08, p < 0.05). In addition, infarct proximity impaired longitudinal strain (-0.16 ± 0.11 borderzone versus -0.18 ± 0.09 remote, p = 0.05)., Conclusions: Impaired LV strain overestimates nonviable myocardium compared with TMI on LGE. Ischemia and infarct proximity also decrease strain in viable segments., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Decreased contractility in the non-ischemic border zone surrounding a MI is in part due to degradation of cardiomyocyte sarcomeric components by intracellular matrix metalloproteinase-2 (MMP-2). We recently reported that MMP-2 levels were increased in the border zone after a MI and that treatment with doxycycline for two weeks after MI was associated with normalization of MMP-2 levels and improvement in ex-vivo contractile protein developed force in the myocardial border zone. The purpose of the current study was to determine if there is a sustained effect of short term treatment with doxycycline (Dox) on border zone function in a large animal model of antero-apical myocardial infarction (MI). Antero-apical MI was created in 14 sheep. Seven sheep received doxycycline 0.8 mg/kg/hr IV for two weeks. Cardiac MRI was performed two weeks before, and then two and six weeks after MI. Two sheep died prior to MRI at six weeks from surgical/anesthesia-related causes. The remaining 12 sheep completed the protocol. Doxycycline induced a sustained reduction in intracellular MMP-2 by Western blot (3649±643 MI+Dox vs 9236±114 MI relative intensity; p = 0.0009), an improvement in ex-vivo contractility (65.3±2.0 MI+Dox vs 39.7±0.8 MI mN/mm2; p<0.0001) and an increase in ventricular wall thickness at end-systole 1.0 cm from the infarct edge (12.4±0.6 MI+Dox vs 10.0±0.5 MI mm; p = 0.0095). Administration of doxycycline for a limited two week period is associated with a sustained improvement in ex-vivo contractility and an increase in wall thickness at end-systole in the border zone six weeks after MI. These findings were associated with a reduction in intracellular MMP-2 activity.

Background: Myocardial strain provides a novel means of quantifying subtle alterations in contractile function; incremental utility post-MI is unknown., Objectives: To test longitudinal-quantified by postprocessing routine echo-for assessment of MI size measured by cardiac magnetic resonance (CMR) and conventional methods, and assess regional and global strain (GLS) as markers of LV thrombus., Methods: The population comprised of patients with anterior ST-segment MI who underwent echo and CMR prospectively. Preexisting echoes were retrieved, re-analyzed for strain, and compared to conventional MI markers as well as CMR-evidenced MI, function, and thrombus., Results: Seventy-four patients underwent echo and CMR 4 ± 1 weeks post-MI; 72% had abnormal GLS. CMR-quantified MI size was 2.5-fold larger and EF lower among patients with abnormal GLS, paralleling 2.6-3.1 fold differences in Q-wave size and CPK (all P ≤ .002). GLS correlated with CMR-quantified MI (r = .66), CPK (r = .52) and Q-wave area (r = .44; all P ≤ .001): Regional strain was lower in the base, mid, and apical LV among patients with CMR-defined transmural MI in each territory (P < .05) and correlated with cine-CMR regional EF (r = .53-.71; P < .001) and echo wall motion (r = .45-.71; P < .001). GLS and apical strain were ~2-fold lower among patients with LV thrombus (P ≤ .002): Apical strain yielded higher diagnostic performance for thrombus (AUC: 0.83 [0.72-0.93], P = .001) than wall motion (0.73 [0.58-0.88], P = .02), as did global strain (0.78 [0.65-0.90], P = .005) compared to LVEF (0.58 [0.45-0.72], P = .41)., Conclusions: Echo-quantified longitudinal strain provides a marker of MI size and improves stratification for post-MI LV thrombus beyond conventional indices., (© 2017, Wiley Periodicals, Inc.)

Background: Ischemic mitral regurgitation (iMR) predisposes to right ventricular (RV) pressure and volume overload, providing a nidus for RV dysfunction (RVDYS) and non-ischemic fibrosis (NIF). Echocardiography (echo) is widely used to assess iMR, but performance of different indices as markers of RVDYS and NIF is unknown., Methods: iMR patients prospectively underwent echo and cardiac magnetic resonance (CMR) within 72 hours. Echo quantified iMR, assessed conventional RV indices (TAPSE, RV-S', fractional area change [FAC]), and strain via speckle tracking in apical 4-chamber (global longitudinal strain [RV-GLS]) and parasternal long axis orientation (transverse strain). CMR volumetrically quantified RVEF, and assessed ischemic pattern myocardial infarction (MI) and septal NIF., Results: 73 iMR patients were studied; 36% had RVDYS (EF<50%) on CMR among whom LVEF was lower, PA systolic pressure higher, and MI size larger (all p<0.05). CMR RVEF was paralleled by echo results; correlations were highest for RV-GLS (r = 0.73) and lowest for RV-S' (r = 0.43; all p<0.001). RVDYS patients more often had CMR-evidenced NIF (54% vs. 7%; p<0.001). Whereas all RV indices were lower among NIF-affected patients (all p≤0.006), percent change was largest for transverse strain (48.3%). CMR RVEF was independently associated with RV-GLS (partial r = 0.57, p<0.001) and transverse strain (r = 0.38, p = 0.002) (R = 0.78, p<0.001). Overall diagnostic performance of RV-GLS and transverse strain were similar (AUC = 0.93[0.87-0.99]|0.91[0.84-0.99], both p<0.001), and yielded near equivalent sensitivity and specificity (85%|83% and 80%|79% respectively)., Conclusion: Compared to conventional echo indices, RV strain parameters yield stronger correlation with CMR-defined RVEF and potentially constitute better markers of CMR-evidenced NIF in iMR.

Background: Recurrence of mitral regurgitation (MR) after undersized mitral annuloplasty (MA) for ischemic MR is as high as 60%, with the recurrence rate likely due to continued dilation of the left ventricle (LV). To better understand the causes of recurrent MR, we studied the effect of undersized MA on strain in the LV wall. We hypothesize that the acute change in ventricular shape induced by MA will cause increased strain in regions nearest the mitral valve., Methods: Finite element models were previously reported, based on cardiac magnetic resonance images of 5 sheep with mild to moderate ischemic MR. A 24-mm saddle-shaped rigid annuloplasty ring was modeled and used to simulate virtual MA. Longitudinal and myofiber strains were calculated at end-diastole and end-systole, with preoperative early diastolic geometry as the reference state., Results: The undersized MA significantly increased longitudinal strain at end-diastole in the lateral LV wall. The effect was greatest in the proximal-lateral endocardial surface, where longitudinal strain after MA was approximately triple the preoperative strain (11.17% ± 2.15% vs 3.45% ± 0.92%, p = 0.0057). In contrast, postoperative end-diastolic fiber strain decreased in this same region (2.53% ± 2.14% vs 7.72% ± 1.79%, p = 0.0060). There were no significant changes in either strain type at end-systole., Conclusions: Undersized MA increased longitudinal strain in the proximal lateral LV wall at end-diastole. This procedure-related strain at the proximal-lateral LV wall may foster continued LV enlargement and subsequent recurrence of mitral regurgitation., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Right ventricular (RV) and left ventricular (LV) function are closely linked due to a variety of factors, including common coronary blood supply. Altered LV perfusion holds the potential to affect the RV, but links between LV ischemia and RV performance, and independent impact of RV dysfunction on effort tolerance, are unknown., Methods and Results: The population comprised 2051 patients who underwent exercise stress myocardial perfusion imaging and echo (5.5±7.9 days), among whom 6% had echo-evidenced RV dysfunction. Global summed stress scores were ≈3-fold higher among patients with RV dysfunction, attributable to increments in inducible and fixed LV perfusion defects (all P≤0.001). Regional inferior and lateral wall ischemia was greater among patients with RV dysfunction (both P<0.01), without difference in corresponding anterior defects (P=0.13). In multivariable analysis, inducible inferior and lateral wall perfusion defects increased the likelihood of RV dysfunction (both P<0.05) independent of LV function, fixed perfusion defects, and pulmonary artery pressure. Patients with RV dysfunction demonstrated lesser effort tolerance whether measured by exercise duration (6.7±2.8 versus 7.9±2.9 minutes; P<0.001) or peak treadmill stage (2.6±0.9 versus 3.1±1.0; P<0.001), paralleling results among patients with LV dysfunction (7.0±2.9 versus 8.0±2.9; P<0.001|2.7±1.0 versus 3.1±1.0; P<0.001 respectively). Exercise time decreased stepwise in relation to both RV and LV dysfunction (P<0.001) and was associated with each parameter independent of age or medication regimen., Conclusions: Among patients with known or suspected coronary artery disease, regional LV ischemia involving the inferior and lateral walls confers increased likelihood of RV dysfunction. RV dysfunction impairs exercise tolerance independent of LV dysfunction., (© 2016 American Heart Association, Inc.)

Background: Recurrent mitral regurgitation after mitral valve repair is common, occurring in nearly 50% of patients within 10 years of surgery. Durability of repair is partly related to stress distribution over the mitral leaflets. We hypothesized that repair with neochords (NCs) results in lower stress than leaflet resection (LR)., Materials and Methods: Magnetic resonance imaging and 3D echocardiography were performed before surgical repair of P2 prolapse in a single patient. A finite element model of the left ventricle and mitral valve was created previously, and the modeling program LS-DYNA was used to calculate leaflet stress for the following repairs: Triangular LR; LR with ring annuloplasty (LR + RA); One NC; Two NCs; and 2NC + RA., Results: (1) NC placement resulted in stable posterior leaflet stress: Baseline versus 2 NC at end diastole (ED), 12.1 versus 12.0 kPa, at end systole (ES) 20.3 versus 21.7 kPa. (2) In contrast, LR increased posterior leaflet stress: Baseline versus LR at ED 12.1 versus 40.8 kPa, at ES 20.3 versus 46.1 kPa. (3) All repair types reduced anterior leaflet stress: Baseline versus 2 NC versus LR 34.2 versus 25.8 versus 20.6 kPa at ED and 80.8 versus 76.8 versus 67.8 kPa at ES. (4) The addition of RA reduced leaflet stress relative to repair without RA., Conclusions: Neochord repair restored normal leaflet coaptation without creating excessive leaflet stress, whereas leaflet resection more than doubled stress across the posterior leaflet. The excess stress created by leaflet resection was partially, but not completely, mitigated by ring annuloplasty., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of severe aortic stenosis in intermediate, high-risk, and inoperable patients. TAVR has multiple access routes, including transfemoral (TF), transapical (TA), direct aortic (DA), axillary, transcarotid, and transcaval. The most commonly applied algorithm is a TF-first approach, where only when patients are unsuitable for TF are alternatives such as TA considered. An infrequent - but dreaded - risk is left ventricular (LV) apical bleeding from tearing or rupture with the TA approach. With burgeoning transcatheter mitral technology that requires a TA approach, the study aim was to develop a mathematical model to determine suture forces for TA closure., Methods: Preoperative cine-cardiac magnetic resonance imaging (MRI) was used to acquire three-dimensional (3D) LV geometry at end-systole and end-diastole. Endocardial and epicardial boundaries were manually contoured using MeVisLab, a surface reconstruction software. 3D surfaces of endocardium and epicardium were reconstructed, and surfaces at end-systole were used to create a 3D LV finite element (FE) mesh. TA access was mimicked by developing a 10-mm defect within the LV FE model. The LV apex was closed using a virtual suture technique in FE analysis with the application of two virtual sutures. After virtual closure, a FE analysis was performed of LV model diastolic filling and systolic contraction., Results: Proof of concept was achieved to develop an LV transapical access site and perform FE analysis to achieve closure. The FE method of virtual suture technique successfully approximated the LV apical defect. The peak axial forces on virtual sutures at end-diastole and end-systole were 0.445N and 0.736N, respectively., Conclusions: A LV TA access model was mathematically developed that could be used to evaluate the suture tension of the TA closure process. Further development of this approach may be useful to risk-stratify patients in the future for LV apical tearing. Video 1: Cine cardiac magnetic resonance imaging of the left ventricle. Video 2: Slow motion animation of left ventricular baseline simulation. Video 3: Animation of the virtual suturing process.

Background: Chronic ischemic mitral regurgitation (CIMR) is associated with poor outcome. Left ventricular (LV) strain after posterolateral myocardial infarction (MI) may drive LV remodeling. Although moderate CIMR has been previously shown to affect LV remodeling, the effect of CIMR on LV strain after posterolateral MI remains unknown. We tested the hypothesis that moderate CIMR alters LV strain after posterolateral MI., Methods: Posterolateral MI was created in 10 sheep. Cardiac magnetic resonance imaging with tags was performed 2 weeks before and 2, 8, and 16 weeks after MI. The left and right ventricular volumes were measured, and regurgitant volume indexed to body surface area (regurgitant volume index) was calculated as the difference between left ventricle and right ventricle stroke volumes divided by body surface area. Three-dimensional strain was calculated., Results: Circumferential strain (Ecc) and longitudinal strain (Ell) were reduced in the infarct proper, MI borderzone, and remote myocardium 16 weeks after MI. In addition, radial circumferential (Erc) and radial longitudinal (Erl) shear strains were reduced in remote myocardium but increased in the infarct and borderzone 16 weeks after MI. Of all strain components, however, only Erc was affected by regurgitant volume index (p = 0.0005). There was no statistically significant effect of regurgitant volume index on Ecc, Ell, Erl, or circumferential longitudinal shear strain (Ecl)., Conclusions: Moderate CIMR alters radial circumferential shear strain after posterolateral MI in sheep. Further studies are needed to determine the effect of shear strain on myocyte hypertrophy and the effect of mitral repair on myocardial strain., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Surgical ventricular restoration (Dor procedure) is generally thought to reduce left ventricular (LV) myofiber stress (FS) but to adversely affect pump function. However, the underlying mechanism is unclear. The goal of this study was to determine the effect of residual stress (RS) on LV FS and pump function after the Dor procedure., Methods: Previously described finite element models of the LV based on magnetic resonance imaging data obtained in 5 sheep 16 weeks after anteroapical myocardial infarction were used. Simulated polyethylene terephthalate fiber (Dacron) patches that were elliptical and 25% of the infarct opening area were implanted using a virtual suture technique (VIRTUAL-DOR). In each case, diastole and systole were simulated, and RS, FS, LV volumes, systolic and diastolic function, and pump (Starling) function were calculated., Results: VIRTUAL-DOR was associated with significant RS that was tensile (2.89 ± 1.31 kPa) in the remote myocardium and compressive (234.15 ± 65.53 kPa) in the border zone. VIRTUAL-DOR+RS (compared with VIRTUAL-DOR-NO-RS) was associated with further reduction in regional diastolic and systolic FS, with the greatest change in the border zone (43.5-fold and 7.1-fold, respectively; p < 0.0001). VIRTUAL-DOR+RS was also associated with further reduction in systolic and diastolic volumes (7.9%; p = 0.0606, and 10.6%; p = 0.0630, respectively). The resultant effect was a further reduction in pump function after VIRTUAL-DOR+RS., Conclusions: Residual stress that occurs after the Dor procedure is positive (tensile) in the remote myocardium and negative (compressive) in the border zone and associated with reductions in FS and LV volumes. The resultant effect is a further reduction in LV pump (Starling) function., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Ischemic mitral regurgitation (MR) is common, but its response to percutaneous coronary intervention (PCI) is poorly understood. This study tested the utility of myocardial perfusion imaging (MPI) for the stratification of MR response to PCI., Methods: MPI and transthoracic echocardiography (echo) were performed among patients undergoing PCI. MPI was used to assess stress/rest myocardial perfusion. MR was assessed via echo (performed before and after PCI)., Results: A total of 317 patients with abnormal myocardial perfusion on MPI underwent echo 25±39 days before PCI. MR was present in 52%, among whom 24% had advanced (≥moderate) MR. MR was found to be associated with left ventricular (LV) chamber dilation on MPI and echo (both P<0.001). The magnitude of global LV perfusion deficits increased in relation to MR severity (P<0.01). Perfusion differences were greatest for global summed rest scores, which were 1.6-fold higher among patients with advanced MR versus those with mild MR (P=0.004), and 2.4-fold higher versus those without MR (P<0.001). In multivariate analysis, advanced MR was found to be associated with a fixed perfusion defect size on MPI [odds ratio 1.16 per segment (confidence interval 1.002-1.34), P=0.046], independent of LV volume [odds ratio 1.10 per 10 ml (confidence interval 1.04-1.17), P=0.002]. Follow-up via echo (1.0±0.6 years) demonstrated MR to decrease (≥1 grade) in 31% of patients and increase in 12% of patients. Patients with increased MR after PCI had more severe inferior perfusion defects on baseline MPI (P=0.028), whereas defects in other distributions and LV volumes were similar (P=NS)., Conclusion: The extent and distribution of single-photon emission computed tomography-evidenced myocardial perfusion defects impact MR response to revascularization. An increased magnitude of inferior fixed perfusion defects predicts post-PCI progression of MR.

Background and Aim of the Study: Mitral annuloplasty (MA) devices are available in different shapes and sizes, but the preferred shape and size are unclear., Methods: A previously described and validated finite element (FE) model of the left ventricle (LV) with mitral valve (MV) based on magnetic resonance imaging and three-dimensional echocardiography images from a patient with posterior leaflet (PL; P2) prolapse was used in this study. FE models of MA devices with different shapes (flat partial, shallow saddle, pronounced saddle) and sizes (36-30) were created. Virtual leaflet resection + MA with each shape and size were simulated. Leaflet geometry, stresses in the leaflets and base of the LV, and forces in the chordae and MA sutures were calculated., Results: All MA shapes increased the mitral coaptation length, reduced the elevated PL stress at end-diastole (ED) and end-systole (ES) that occurred after leaflet resection, and reduced anterior leaflet (AL) stress at ES. MA devices of all shapes and sizes modestly reduced myofiber stress at the LV base in ED and ES. In general, saddle-shaped devices had the greatest effect., Conclusion: All MA shapes increased coaptation length and reduced mitral leaflet stress and myofiber stress in the base of the LV. an additional reduction in MA size further increased coaptation length and reduced leaflet and myofiber stress. In general, saddle-shaped devices had the greatest effect.

After myocardial infarction, a poorly contracting nonischemic border zone forms adjacent to the infarct. The cause of border zone dysfunction is unclear. The goal of this study was to determine the myofilament mechanisms involved in postinfarction border zone dysfunction. Two weeks after anteroapical infarction of sheep hearts, we studied in vitro isometric and isotonic contractions of demembranated myocardium from the infarct border zone and a zone remote from the infarct. Maximal force development (Fmax) of the border zone myocardium was reduced by 31 ± 2% versus the remote zone myocardium (n = 6/group, P < 0.0001). Decreased border zone Fmax was not due to a reduced content of contractile material, as assessed histologically, and from myosin content. Furthermore, decreased border zone Fmax did not involve altered cross-bridge kinetics, as assessed by muscle shortening velocity and force development kinetics. Decreased border zone Fmax was associated with decreased cross-bridge formation, as assessed from muscle stiffness in the absence of ATP where cross-bridge formation should be maximized (rigor stiffness was reduced 34 ± 6%, n = 5, P = 0.011 vs. the remote zone). Furthermore, the border zone myocardium had significantly reduced phosphorylation of myosin essential light chain (ELC; 41 ± 10%, n = 4, P < 0.05). However, for animals treated with doxycycline, an inhibitor of matrix metalloproteinases, rigor stiffness and ELC phosphorylation were not reduced in the border zone myocardium, suggesting that doxycycline had a protective effect. In conclusion, myofilament dysfunction contributes to postinfarction border zone dysfunction, myofilament dysfunction involves impaired cross-bridge formation and decreased ELC phosphorylation, and matrix metalloproteinase inhibition may be beneficial for limiting postinfarct border zone dysfunction.

Background: The role of posterior papillary muscle anchoring (PPMA) in the management of chronic ischemic mitral regurgitation (CIMR) is controversial. We studied the effect of anchoring point direction and relocation displacement on left ventricular (LV) regional myofiber stress and pump function., Methods: Previously described finite element models of sheep 16 weeks after posterolateral myocardial infarction (MI) were used. True-sized mitral annuloplasty (MA) ring insertion plus different PPM anchoring techniques were simulated. Anchoring points tested included both commissures and the central anterior mitral annulus; relocation displacement varied from 10% to 40% of baseline diastolic distance from the PPM to the anchor points on the annulus. For each reconstruction scenario, myofiber stress in the MI, border zone, and remote myocardium as well as pump function were calculated., Results: PPMA caused reductions in myofiber stress at end-diastole and end-systole in all regions of the left ventricle that were proportional to the relocation displacement. Although stress reduction was greatest in the MI region, it also occurred in the remote region. The maximum 40% displacement caused a slight reduction in LV pump function. However, with the correction of regurgitation by MA plus PPMA, there was an overall increase in forward stroke volume. Finally, anchoring point direction had no effect on myofiber stress or pump function., Conclusions: PPMA reduces remote myofiber stress, which is proportional to the absolute distance of relocation and independent of anchoring point. Aggressive use of PPMA techniques to reduce remote myofiber stress may accelerate reverse LV remodeling without impairing LV function., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The full-length isoform of matrixmetalloproteinase-2 (FL-MMP-2) plays a role in turnover of the cardiac extracellular matrix. FL-MMP-2 is also present intracellularly in association with sarcomeres and, in the setting of oxidative stress, cleaves myofilament proteins with resultant impaired contractility. Recently, a novel N-terminal truncated MMP-2 isoform (NTT-MMP-2) generated during oxidative stress was identified and shown to induce severe systolic failure; however, the injury mechanisms remained unclear. In this study, cardiac-specific NTT-MMP-2 transgenic mice were used to determine the physiological effects of NTT-MMP-2 on: force development of intact myocardium; the function of cardiac myofilaments in demembranated myocardium; and on intracellular Ca(2+) transients in isolated myocytes. We related the contractile defects arising from NTT-MMP-2 expression to the known intracellular locations of NTT-MMP-2 determined using immunohistochemistry. Comparison was made with the pathophysiology arising from cardiac-specific FL-MMP-2 transgenic mice. Consistent with previous studies, FL-MMP-2 was localized to myofilaments, while NTT-MMP-2 was concentrated within subsarcolemmal mitochondria and to sites in register with the Z-line. NTT-MMP-2 expression caused a 50% reduction of force development by intact myocardium. However, NTT-MMP-2 expression did not reduce myofilament force development, consistent with the lack of NTT-MMP-2 localization to myofilaments. NTT-MMP-2 expression caused a 50% reduction in the amplitude of Ca(2+) transients, indicating impaired activation., Conclusions: Unlike FL-MMP-2, NTT-MMP-2 does not mediate myofilament damage. Instead, NTT-MMP-2 causes impaired myocyte activation, which may involve effects due to localization in mitochondria and/or to transverse tubules affecting Ca(2+) transients. Thus, FL-MMP-2 and NTT-MMP-2 have discrete intracellular locations and mediate different intracellular damage to cardiac myocytes.

The Parachute(®) (Cardiokinetix, Inc., Menlo Park, California) is a catheter-based device intended to reverse left ventricular (LV) remodeling after antero-apical myocardial infarction. When deployed, the device partitions the LV into upper and lower chambers. To simulate its mechanical effects, we created a finite element LV model based on computed tomography (CT) images from a patient before and 6 months after Parachute(®) implantation. Acute mechanical effects were determined by in silico device implantation (VIRTUAL-Parachute). Chronic effects of the device were determined by adjusting the diastolic and systolic material parameters to better match the 6-month post-implantation CT data and LV pressure data at end-diastole (ED) (POST-OP). Regional myofiber stress and pump function were calculated in each case. The principal finding is that VIRTUAL-Parachute was associated with a 61.2 % reduction in the lower chamber myofiber stress at ED. The POST-OP model was associated with a decrease in LV diastolic stiffness and a larger reduction in myofiber stress at the upper (27.1%) and lower chamber (78.4%) at ED. Myofiber stress at end-systole and stroke volume was little changed in the POST-OP case. These results suggest that the primary mechanism of Parachute(®) is a reduction in ED myofiber stress, which may reverse eccentric post-infarct LV hypertrophy.

Although computational modeling is common in many areas of science and engineering, only recently have advances in experimental techniques and medical imaging allowed this tool to be applied in cardiac surgery. Despite its infancy in cardiac surgery, computational modeling has been useful in calculating the effects of clinical devices and surgical procedures. In this review, we present several examples that demonstrate the capabilities of computational cardiac modeling in cardiac surgery. Specifically, we demonstrate its ability to simulate surgery, predict myofiber stress and pump function, and quantify changes to regional myocardial material properties. In addition, issues that would need to be resolved in order for computational modeling to play a greater role in cardiac surgery are discussed., (© 2014 Wiley Periodicals, Inc.)

Background: Recurrent mitral regurgitation after mitral valve (MV) repair for degenerative disease occurs at a rate of 2.6% per year and reoperation rate progressively reaches 20% at 19.5 years. We believe that MV repair durability is related to initial postoperative leaflet and annular geometry with subsequent leaflet remodeling due to stress. We tested the hypothesis that MV leaflet and annular stress is increased after MV repair., Methods: Magnetic resonance imaging was performed before and intraoperative three-dimensional (3D) transesophageal echocardiography was performed before and after repair of posterior leaflet prolapse in a single patient. The repair consisted of triangular resection and annuloplasty band placement. Images of the heart were manually co-registered. The left ventricle and MV were contoured, surfaced, and a 3D finite element (FE) model was created. Elements of the posterior leaflet region were removed to model leaflet resection and virtual sutures were used to repair the leaflet defect and attach the annuloplasty ring., Results: The principal findings of the current study are the following: (1) FE simulation of MV repair is able to accurately predict changes in MV geometry including changes in annular dimensions and leaflet coaptation; (2) average posterior leaflet stress is increased; and (3) average anterior leaflet and annular stress are reduced after triangular resection and mitral annuloplasty., Conclusions: We successfully conducted virtual mitral valve prolapse repair using FE modeling methods. Future studies will examine the effects of leaflet resection type as well as annuloplasty ring size and shape., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Surgical ventricular restoration (SVR) is a procedure designed to treat heart failure by surgically excluding infarcted tissues from the dilated failing left ventricle. To elucidate and predict the effects of geometrical changes from SVR on cardiac function, we created patient-specific mathematical (finite-element) left ventricular models before and after surgery using untagged magnetic resonance images. Our results predict that the postsurgical improvement in systolic function was compromised by a decrease in diastolic distensibility in patients. These two conflicting effects typically manifested as a more depressed Starling relationship (stroke volume vs. end-diastolic pressure) after surgery. By simulating a restoration of the left ventricle back to its measured baseline sphericity, we show that both diastolic and systolic function improved. This result confirms that the increase in left ventricular sphericity commonly observed after SVR (endoventricular circular patch plasty) has a negative impact and contributes partly to the depressed Starling relationship. On the other hand, peak myofiber stress was reduced substantially (by 50%) after SVR, and the resultant left ventricular myofiber stress distribution became more uniform. This significant reduction in myofiber stress after SVR may help reduce adverse remodeling of the left ventricle. These results are consistent with the speculation proposed in the Surgical Treatment for Ischemic Heart Failure trial (20) for the neutral outcome, that "the lack of benefit seen with surgical ventricular reconstruction is that benefits anticipated from surgical reduction of left ventricular volume (reduced wall stress and improvement in systolic function) are counter-balanced by a reduction in diastolic distensibility."

Background: The Acorn CorCap Cardiac Support Device (CSD; Acorn Cardiovascular Inc, St. Paul, MN) is a woven polyester jacket that is placed around the heart and designed to reverse the progressive remodeling associated with dilated cardiomyopathy. However, the effects of the Acorn CSD on myofiber stress and ventricular function remain unknown. We tested the hypothesis that the Acorn CSD reduces end-diastolic (ED) myofiber stress., Methods: A previously described weakly coupled biventricular finite element (FE) model and circulatory model based on magnetic resonance images of a dog with dilated cardiomyopathy was used. Virtual applications of the CSD alone (Acorn), CSD with rotated fabric fiber orientation (rotated), CSD with 5% prestretch (tight), and CSD wrapped only around the left ventricle (LV; LV-only) were performed, and the effect on myofiber stress at ED and pump function was calculated., Results: The Acorn CSD has a large effect on ED myofiber stress in the LV free wall, with reductions of 55%, 79%, 92%, and 40% in the Acorn, rotated, tight, and LV-only cases, respectively. However, there is a tradeoff in which the Acorn CSD reduces stroke volume at LV end-diastolic pressure of 8 mm Hg by 23%, 25%, 30%, and 7%, respectively, in the Acorn, rotated, tight, and LV-only cases., Conclusions: The Acorn CSD significantly reduces ED myofiber stress. However, CSD wrapped only around the LV was the only case with minimal negative effect on pump function. Findings suggest that LV-only CSD and Acorn fabric orientation should be optimized to allow maximal myofiber stress reduction with minimal reduction in pump function., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Contractility in the borderzone (BZ) after anteroapical myocardial infarction (MI) is depressed. We tested the hypothesis that BZ contractility is also decreased after posterolateral MI., Methods: Five sheep underwent posterolateral MI. Magnetic resonance imaging (MRI) was performed 2 weeks before and 16 weeks after MI, and left ventricular (LV) volume and regional strain were measured. Finite element (FE) models were constructed, and the systolic material parameter, Tmax, was calculated in the BZ and remote myocardium by minimizing the difference between experimentally measured and calculated LV strain and volume. Sheep were sacrificed 17 weeks after MI, and myocardial muscle fibers were taken from the BZ and remote myocardium. Fibers were chemically demembranated, and isometric developed force, Fmax, was measured at supramaximal [Ca(2+)]. Routine light microscopy was also performed., Results: There was no difference in Tmax in the remote myocardium before and 16 weeks after MI. However, there was a large decrease (63.3%, p = 0.005) in Tmax in the BZ when compared with the remote myocardium 16 weeks after MI. In addition, there was a significant reduction of BZ Fmax for all samples (18.9%, p = 0.0067). Myocyte cross-sectional area increased by 61% (p = 0.021) in the BZ, but there was no increase in fibrosis., Conclusions: Contractility in the BZ is significantly depressed relative to the remote myocardium after posterolateral MI. The reduction in contractility is due at least in part to a decrease in contractile protein function., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Cardiac imaging using magnetic resonance requires a gating signal in order to compensate for motion. Human patients are routinely scanned using an electrocardiogram (ECG) as a gating signal during imaging. However, we found that in sheep the ECG is not a reliable method for gating. We developed a software based method that allowed us to use the left ventricular pressure (LVP) as a reliable gating signal. By taking the time derivative of the LVP (dP/dt), we were able to start imaging at both end-diastole for systolic phase images, and end-systole for diastolic phase images. We also used MR tissue tagging to calculate 3D strain information during diastole. Using the LVP in combination with our digital circuit provided a reliable and time efficient method for ovine cardiac imaging. Unlike the ECG signal the left ventricular pressure was a clean signal and allowed for accurate, nondelay based triggering during systole and diastole.

Background: Myocardial function deteriorates during ventricular remodeling in patients with congestive heart failure (HF). Ventricular restraint therapy using a cardiac support device (CSD) is designed to reduce the amount of stress inside the dilated ventricles, which in turn halts remodeling. However, as an open mesh surrounding the heart, it is unknown what the mechanical properties of the CSD are in different fiber orientations., Methods: Composite specimens of CorCap (Acorn Cardiovascular, Inc, St. Paul, MN) CSD fabric and silicone were constructed in different fiber orientations and tested on a custom-built biaxial stretcher. Silicone controls were made and stretched to detect the parameters of the matrix. CSD coefficients were calculated using the composite and silicone matrix stress-strain data. Stiffness in different fiber orientations was determined., Results: Silicone specimens exerted a linear behavior, with stiffness of 2.57 MPa. For the composites with 1 fiber set aligned with respect to the stretch axes, stiffness in the direction of the aligned fiber set was higher than that in the cross-fiber direction (14.39 MPa versus 5.66 MPa), indicating greater compliance in the cross-fiber direction. When the orientation of the fiber sets in the composite were matched to the expected clinical orientation of the implanted CorCap, the stiffness in the circumferential axis (with respect to the heart) was greater than in the longitudinal axis (10.55 MPa versus 9.70 MPa)., Conclusions: The mechanical properties of the CorCap demonstrate directionality with greater stiffness circumferentially than longitudinally. Implantation of the CorCap clinically should take into account the directionality of the biomechanics to optimize ventricular restraint., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Numerical modelling of the cardiovascular system is becoming an important tool for assessing the influence of heart disease and treatment therapies. In the current study, we present an approach for modelling the interaction between the heart and the circulatory system. This was accomplished by creating animal-specific biventricular finite element (FE) models, which characterise the mechanical response of the heart, and by coupling them to a lumped-parameter model that represents the systemic and pulmonic circulatory system. In order to minimise computation time, the coupling was enforced in a weak (one-way) manner, where the ventricular pressure-volume relationships were generated by the FE models and then passed into the circulatory system model to ensure volume conservation and physiological pressure changes. The models were first validated by tuning the parameters, such that the output of the models matched experimentally measured pressures and volumes. Then the models were used to examine cardiac function and the myofibre stress in a healthy canine heart and a canine heart with dilated cardiomyopathy. The results showed good agreement with experimental measurements. The stress in the case of cardiomyopathy was found to increase significantly, while the pump function was decreased, compared to the healthy case. The total runtime of the simulations is lesser than that of many fully coupled models presented in the literature. This will allow for a much quicker evaluation of possible treatment strategies for combating the effects of heart failure, especially in optimisation schemes that require numerous FE simulations.

The current study presents a finite element model of mitral leaflet tissue, which incorporates the anisotropic material response and approximates the layered structure. First, continuum mechanics and the theory of layered composites are used to develop an analytical representation of membrane stress in the leaflet material. This is done with an existing anisotropic constitutive law from literature. Then, the concept is implemented in a finite element (FE) model by overlapping and merging two layers of transversely isotropic membrane elements in LS-DYNA, which homogenizes the response. The FE model is then used to simulate various biaxial extension tests and out-of-plane pressure loading. Both the analytical and FE model show good agreement with experimental biaxial extension data, and show good mutual agreement. This confirms that the layered composite approximation presented in the current study is able to capture the exponential stiffening seen in both the circumferential and radial directions of mitral leaflets.

Background: We sought to determine regional myofiber stress after Coapsys device (Myocor, Inc, Maple Grove, MN) implantation using a finite element model of the left ventricle (LV). Chronic ischemic mitral regurgitation is caused by LV remodeling after posterolateral myocardial infarction. The Coapsys device consists of a single trans-LV chord placed below the mitral valve such that when tensioned it alters LV shape and decreases chronic ischemic mitral regurgitation., Methods: Finite element models of the LV were based on magnetic resonance images obtained before (preoperatively) and after (postoperatively) coronary artery bypass grafting with Coapsys implantation in a single patient. To determine the effect of Coapsys and LV before stress, virtual Coapsys was performed on the preoperative model. Diastolic and systolic material variables in the preoperative, postoperative, and virtual Coapsys models were adjusted so that model LV volume agreed with magnetic resonance imaging data. Chronic ischemic mitral regurgitation was abolished in the postoperative models. In each case, myofiber stress and pump function were calculated., Results: Both postoperative and virtual Coapsys models shifted end-systolic and end-diastolic pressure-volume relationships to the left. As a consequence and because chronic ischemic mitral regurgitation was reduced after Coapsys, pump function was unchanged. Coapsys decreased myofiber stress at end-diastole and end-systole in both the remote and infarct regions of the myocardium. However, knowledge of Coapsys and LV prestress was necessary for accurate calculation of LV myofiber stress, especially in the remote zone., Conclusions: Coapsys decreases myofiber stress at end-diastole and end-systole. The improvement in myofiber stress may contribute to the long-term effect of Coapsys on LV remodeling., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Cardiac growth and remodeling in the form of chamber dilation and wall thinning are typical hallmarks of infarct-induced heart failure. Over time, the infarct region stiffens, the remaining muscle takes over function, and the chamber weakens and dilates. Current therapies seek to attenuate these effects by removing the infarct region or by providing structural support to the ventricular wall. However, the underlying mechanisms of these therapies are unclear, and the results remain suboptimal. Here we show that myocardial infarction induces pronounced regional and transmural variations in cardiac form. We introduce a mechanistic growth model capable of predicting structural alterations in response to mechanical overload. Under a uniform loading, this model predicts non-uniform growth. Using this model, we simulate growth in a patient-specific left ventricle. We compare two cases, growth in an infarcted heart, pre-operative, and growth in the same heart, after the infarct was surgically excluded, post-operative. Our results suggest that removing the infarct and creating a left ventricle with homogeneous mechanical properties does not necessarily reduce the driving forces for growth and remodeling. These preliminary findings agree conceptually with clinical observations.

Objectives: Contractile function in the normally perfused infarct borderzone (BZ) is depressed. However, the impact of reduced BZ contractility on left ventricular (LV) pump function is unknown. As a consequence, there have been no therapies specifically designed to improve BZ contractility. We tested the hypothesis that an improvement in borderzone contractility will improve LV pump function., Methods: From a previously reported study, magnetic resonance imaging (MRI) images with non-invasive tags were used to calculate 3D myocardial strain in five sheep 16 weeks after anteroapical myocardial infarction. Animal-specific finite element (FE) models were created using MRI data and LV pressure obtained at early diastolic filling. Analysis of borderzone function using those FE models has been previously reported. Chamber stiffness, pump function (Starling's law) and stress in the fiber, cross fiber, and circumferential directions were calculated. Animal-specific FE models were performed for three cases: (a) impaired BZ contractility (INJURED); (b) BZ-contractility fully restored (100% BZ IMPROVEMENT); or (c) BZ-contractility partially restored (50% BZ IMPROVEMENT)., Results: 100% BZ IMPROVEMENT and 50% BZ IMPROVEMENT both caused an upward shift in the Starling relationship, resulting in a large (36 and 26%) increase in stroke volume at LVP(ED) = 20 mmHg (8.0 ml, p < 0.001). Moreover, there were a leftward shift in the end-systolic pressure volume relationship, resulting in a 7 and 5% increase in LVP(ES) at 110 mmHg (7.7 ml, p < 0.005). It showed that even 50% BZ IMPROVEMENT was sufficient to drive much of the calculated increase in function., Conclusion: Improved borderzone contractility has a beneficial effect on LV pump function. Partial improvement of borderzone contractility was sufficient to drive much of the calculated increase in function. Therapies specifically designed to improve borderzone contractility should be developed.