Myocardial Mechanical Function Research Articles

Effects evaluation of different exercises on subclinical left ventricular dysfunction in obese rats by speckle-tracking echocardiography

ObjectiveTo identify subclinical left ventricle dysfunction (LVD) in obese rats by speckle-tracking echocardiography, and to evaluate the effects of 12-week Moderate-Intensity Continuous Training (MICT) or High-Intensity Interval Training (HIIT) on LV geometry, histology and function in obese rats. MethodsEighteen male standard or obese Sprague-Dawley rats were randomly divided into the Control group, the MICT group, and the HIIT group. Exercise interventions were conducted for 12 weeks, with equal total load and increased intensity gradient. Using dual-energy X-ray, two-dimensional speckle-tracking echocardiography, pulse Doppler, and HE staining to evalucate body shape, LV morphology, structure, and myocardial mechanics function. Results(1) Both MICT and HIIT have good weight loss shaping effect. (2) The LV of obese rats underwent pathological remodeling, with decreased longitudinal contractility and synchrony, and increased circumferential contractility and synchrony. (3) Exercise can inhibit LV pathological remodeling, improve myocardial mechanical function. HIIT is superior to MICT. (4) The global longitudinal strain of obese rats in the HIIT group showed a significant correlation with Fat% and Lean%. ConclusionObesity can induce LV pathological remodeling and subclinical dysfunction. Compared with MICT, 12-week HIIT can effectively inhibit the pathological remodeling of LV and promote the benign development of myocardial mechanical function in obese rats.

Integrated Functions of Cardiac Energetics, Mechanics, and Purine Nucleotide Metabolism.

Purine nucleotides play central roles in energy metabolism in the heart. Most fundamentally, the free energy of hydrolysis of the adenine nucleotide adenosine triphosphate (ATP) provides the thermodynamic driving force for numerous cellular processes including the actin-myosin crossbridge cycle. Perturbations to ATP supply and/or demand in the myocardium lead to changes in the homeostatic balance between purine nucleotide synthesis, degradation, and salvage, potentially affecting myocardial energetics and, consequently, myocardial mechanics. Indeed, both acute myocardial ischemia and decompensatory remodeling of the myocardium in heart failure are associated with depletion of myocardial adenine nucleotides and with impaired myocardial mechanical function. Yet there remain gaps in the understanding of mechanistic links between adenine nucleotide degradation and contractile dysfunction in heart disease. The scope of this article is to: (i) review current knowledge of the pathways of purine nucleotide depletion and salvage in acute ischemia and in chronic heart disease; (ii) review hypothesized mechanisms linking myocardial mechanics and energetics with myocardial adenine nucleotide regulation; and (iii) highlight potential targets for treating myocardial metabolic and mechanical dysfunction associated with these pathways. It is hypothesized that an imbalance in the degradation, salvage, and synthesis of adenine nucleotides leads to a net loss of adenine nucleotides in both acute ischemia and under chronic high-demand conditions associated with the development of heart failure. This reduction in adenine nucleotide levels results in reduced myocardial ATP and increased myocardial inorganic phosphate. Both of these changes have the potential to directly impact tension development and mechanical work at the cellular level. © 2024 American Physiological Society. Compr Physiol 14:5345-5369, 2024.

Comorbidities and cardiac symptoms can modify myocardial function regardless of ischemia: a cross-sectional study with PET/CT.

Associating comorbidities and cardiac symptoms that alter myocardial mechanical function could help clinicians to correctly identify at-risk population. We conducted a functional open population cross-sectional study of patients referred to a positron emission computed tomography/computed tomography unit in Mexico City for evaluation of myocardial function, perfusion, and coronary circulation. Ischemia was defined as a sum difference score (SDS) > 2. Association between comorbidities and cardiac symptoms was tested using logistic regression models and trend analysis. We performed an interaction analysis to evaluate the addition of any accompanying symptoms to comorbid conditions on impairment of myocardial function. One thousand two hundred and seventy-three patients were enrolled, 66.1% male, with a mean age of 62.4 (± 12.7) years, 360 (28.7%) with ischemia, 925 (72.7%) with at least one comorbidity, and 676 (53.1%) had at least one associated cardiac symptom. Patients without ischemia, type 2 diabetes, arterial hypertension, and adverse cardiac symptoms were associated with adverse function, perfusion, and coronary flow parameters. We observed a trend of a cumulative number of comorbidities and cardiac symptoms with increased ischemia and decreased coronary flow. Only in decreased LVEF, we demonstrated an interaction effect between increased comorbidities and adverse symptoms. The high burden of comorbidities and symptoms in our population alter myocardial function regardless of the level of ischemia.

Effects of septal myectomy on left atrial and left ventricular function in obstructive hypertrophic cardiomyopathy.

Mechanical function of the left atrium (LA) and the left ventricle (LV) has been demonstrated to be a prognostic factor in patients with hypertrophic cardiomyopathy (HCM). We explore whether myocardial mechanical function can be improved by septal reduction therapy in symptomatic obstructive HCM. Among 65 patients who underwent septal myectomy for symptomatic obstructive HCM from 2006 to 2022, 44 were analysed after excluding those who underwent simultaneous valve repair or replacement or maze operation. LA and LV functional variables including LA strain and LV global longitudinal strain were evaluated by two-dimensional and speckle-tracking echocardiography and compared before and 1year after surgery. After septal myectomy, LA volume index (58.1±18.3 vs. 45.3±14.6mL/m2 , P=0.001) decreased significantly. As LV end-systolic dimension increased after surgery, the LV ejection fraction decreased (73.8±6.7 vs. 62.9±8.3%, P<0.001). LA strain (24.4±9.3 vs. 30.5±13.6%, P=0.004) improved after septal myectomy, but LV global longitudinal strain deteriorated (-12.6±3.6 vs. -11.6±4.3%, P=0.033), mainly related to worsening non-septal longitudinal strain (-14.4±4.3 vs. -10.9±8.4%, P=0.005). As haemodynamic loads due to LV outflow tract obstruction was relieved through surgical septal reduction therapy in patients with symptomatic obstructive HCM, there was a significant reduction in LA volume and restoration of LA mechanical dysfunction. However, LV mechanical dysfunction deteriorated even after surgical septal reduction therapy.

Regional contributions to impaired myocardial mechanical function in heart failure with preserved ejection fraction.

Hypertensive heart disease (HHD) is recognized as a key clinical precursor to heart failure with preserved ejection fraction (HFPEF). However, pathophysiological transition from HHD to HFPEF is not well understood. We sought determine whether regional differences in impaired myocardial function may underlie the greater mechanical dysfunction seen in HFPEF compared to HHD. We used standardized echocardiography to assess regional myocardial deformation in a cohort of n = 327 adults with preserved left ventricular (LV) ejection fraction (≥45%), including: n = 129 with HFPEF, n = 158 with HHD and no heart failure, and n = 40 normotensive controls. From detailed measurements of LV systolic strain performed in multiple views, we derived and then compared regional measures of basal, mid-ventricular, and apical longitudinal strains. In models adjusting for clinical covariates, basal and mid-ventricular LV myocardial deformation was more impaired in HHD than in controls (P ≤ 0.003), whereas apical deformation was more impaired in HFPEF than in HHD (P = 0.005). In multivariable-adjusted analyses, only apical strain remained independently associated with HFPEF vs. HHD status [odds ratio 1.18 (1.02-1.37), P = 0.030 per 1% decrease in apical strain]. Compared to other regional strains, apical longitudinal strain optimally differentiated HFPEF from HHD (area under the receiver operating curve: apical longitudinal strain = 0.67; mid-ventricular longitudinal strain = 0.59; basal longitudinal strain = 0.60). We found that while apical mechanical function is preserved in HHD, it was impaired in HFPEF and may contribute to the transition from an asymptomatic heart disease to a symptomatic heart disease.

Left ventricular assist device mode: Co-pulse left ventricular unloading in a working mode of ex vivo heart perfusion

For normothermic ex vivo heart perfusion (EVHP), a resting mode and working mode have been proposed. We newly developed a left ventricular assist device (LVAD) mode that supports heart contraction by co-pulse synchronized LVAD. Following resting mode during time 0 to 1 hour, pig hearts (n=18) were perfused in either resting, working, or LVAD mode during time 1 to 5 hour, and then myocardial function was evaluated in working mode at 6 hour. The preservation ratio was defined as the myocardial mechanical function at 330 minute divided by the function at 75 minute. In LVAD mode, LVAD unloaded the pressure and the volume in the left ventricle in the systolic phase. The LVAD group was significantly associated with higher preservation ratios in cardiac output (resting, 33 ± 3; working, 35 ± 5; LVAD, 76% ± 5%; p < 0.001), stroke work, dP/dt maximum, and dP/dt minimum compared with the other groups. Glucose consumption was significantly reduced in the resting group. The LVAD group was significantly associated with higher myocardial oxygen consumption (resting, 2.2 ± 0.3; working; 4.6 ± 0.5; LVAD, 6.1 ± 0.5 mL O2/min/100 g, p < 0.001) and higher adenosine triphosphate (ATP) levels (resting, 1.1 ± 0.1; working, 0.7 ± 0.1; LVAD, 1.6 ± 0.2 μmol/g, p=0.001) compared with the others. These data suggest that myocardial mechanical function was better preserved in LVAD mode than in resting and working modes. Although our data suggested similar glycolysis activity in the LVAD and working groups, the higher final ATP in the LVAD group might be explained by reduced external work in LVAD.

Abstract 13614: Why the Pulmonary Veins: Linking Atrial 4D Flow MRI Derived Biomechanics and Pulmonary Vein Electrical Remodeling

Introduction: Pulmonary veins (PV) often trigger atrial fibrillation (AF). However, the underlying mechanism is not completely understood and predicting who benefits from PV isolation (PVI) is imprecise. We propose that arrhythmogenic PV remodeling may be related to myocardial mechanical function. Flow-encoded cardiac magnetic resonance imaging (4D Flow MRI) based computational modeling enables assessment of left atrial (LA) hemodynamics and biomechanics. In this pilot study, 4D Flow MRI derived parameters were compared to invasive electroanatomic mapping (EAM) and hemodynamics to explore potential non-invasive evaluation of PV remodeling and arrhythmogenicity. Methods: Patients (5 female, 4 male, age 64±6.7 years) with paroxysmal or early persistent AF scheduled for PVI were enrolled. All patients underwent 4D Flow MRI prior to ablation (in sinus rhythm) and intraprocedural EAM (Carto) with atrial pacing under baseline conditions and after increasing LA pressure with a fluid bolus. Non-invasive measures included peak and average velocity (m/s) and net flow (ml/cycle) in each vein (n=36) and averaged for each patient. Apparent conduction velocities in the proximal, mid and distal portions of each vein were calculated under baseline and stretch conditions from EAM. Change in LA pressure per volume bolus, a measure of atrial stiffness, was compared to non-invasive parameters. Results: In patients with LA stiffness greater than median, peak velocities (0.77±0.12 vs. 0.62±0.24 m/s, p=0.26) and net flows were higher (17±2.0 vs. 14.0±2.4 ml/cycle, p=0.06). Patients with paroxysms of spontaneous arrhythmias during mapping had higher LA stiffness (11.5±5.7 vs. 7.6±5.3 mmHg/L, p=0.30). There was a significant correlation between non-invasive average velocity and apparent conduction velocity in the proximal portion of the vein (R=-0.36, p=0.03) and the suggestion of a correlation between increasing peak flow velocity and decreased apparent conduction velocity under stretch conditions compared to baseline (R=-0.24, p=0.16). Conclusions: Our findings may indicate a link between atrial hemodynamics, electrical remodeling and PV arrhythmogenicity. Additional studies are warranted to confirm and better define these findings.

Beneficial Effects of RNS60 in Cardiac Ischemic Injury.

RNS60 is a physically modified saline solution hypothesized to contain oxygen nanobubbles. It has been reported to reduce ischemia/reperfusion injury in a pig model of acute myocardial infarction. We investigated the effects of RNS60 during cardiac hypoxia in mice and as an additive to cardioplegic solution in rat hearts. ApoE−/−LDLr−/− mice were treated by intravenous injection of RNS60 or saline as a control while monitoring the ECG and post-hypoxic serum release of troponin T and creatine kinase activity. Hearts infused with Custodiol containing 10% RNS60 or saline as the control were subjected to 4 h of 4 °C preservation, followed by an assessment of myocardial metabolites, purine release, and mechanical function. RNS60 attenuated changes in the ECG STU area during hypoxia, while the troponin T concentration and creatine kinase activity were significantly higher in the serum of the controls. During reperfusion after 4 h of cold ischemia, the Custodiol/RNS60-treated hearts had about 30% lower LVEDP and better dp/dtmax and dp/dtmin together with a decreased release of purine catabolites vs. the controls. The myocardial ATP, total adenine nucleotides, and phosphocreatine concentrations were higher in the RNS60-treated hearts. This study indicates that RNS60 enhances cardioprotection in experimental myocardial hypoxia and under conditions of cardioplegic arrest. Improved cardiac energetics are involved in the protective effect, but complete elucidation of the mechanism requires further study.

Clinical research progress of myocardial work in assessment and prediction of coronary artery disease in noninvasive pressure-strain loop technique.

Early identification and treatment of high-risk coronary artery disease (CAD) is the main goal of current cardiovascular disease treatments. Speckle-tracking ultrasound technology can quantify myocardial work using pressure-strain loops. Because myocardial work takes into account the effect of the left ventricular systolic function afterload, it can more objectively reflect left ventricular myocardial mechanical function than the overall left ventricular longitudinal strain. Therefore, this technique is more widely used in diseases caused by CAD. This article reviews the evaluation and prediction of different CAD types using a variety of myocardial work parameters and provides a new method for clinical research to assess myocardial function, which is expected to become a new prediction method for CAD.

Abstract 11241: Longitudinal Myocardial Mechanics in Covid-19 Survivors with Normal Left Ventricular Ejection Fraction, a Single Center Study

Introduction: Subclinical cardiovascular involvement in COVID-19 patients has not been well described. 2D-Speckle Tracking Echocardiography derived global longitudinal strain (GLS) and systolic and early diastolic strain rate (SRs, SRe) measurements are more sensitive than standard echocardiographic parameters to diagnose subclinical mechanical dysfunction in patients with normal Left Ventricle Ejection Fraction (LVEF). Hypothesis: Evaluate subclinical myocardial mechanical function and reserve in active COVID-19 systemic disease patients with normal LVEF vs controls and between survivors and non survivors of COVID-19 in the longitudinal domain of contractility. Methods &amp; Results: 166 adult patients with active COVID 19 having normal LVEF were included and compared to 89 healthy volunteers. Baseline parameters were recorded. Peak GLS, SRs and SRe, were measured offline. Mean age was 62.53 ± 18.96 years and 87 (52%) were males and Mean LVEF was 62±5%. COVID-19 patients had higher GLS compared to controls (-20.93%±0.30 vs. -18.48%±0.40; p value &lt;0.0001), SRs was similar (-0.97 s -1 ±0.10 vs. -0.98 s -1 ±0.02, p value 0.2528) and SRe was lower (0.85 s -1 ±0.0 vs. 1.05 s -1 ±0.02; p value &lt;0.0001) respectively. After adjusting for age and sex, GLS, SRs and SRe was significant (p&lt;0.001). GLS, SRs and SRe were similar in survivors vs. non survivors (p NS), both groups had elevated biomarkers (cardiac troponin, NT-pro BNP, CRP), but non survivors had higher levels (3.22±0.18 vs 3.62±0.28, p = 0.2371, 5.86±0.19 vs 7.15±0.27, p = 0.0004, 3.75±0.14 vs 4.31±0.21, p = 0.0422, 7.64±0.17 vs 8.26±0.25, p=0.0487 respectively) (Table 1). Conclusions: In our cohort, COVID-19 patients had better systolic reserve and abnormal relaxation compared to controls. There was no significant difference in strain (GLS) and strain rate (SRs &amp; SRe) amongst survivors and non survivors in the longitudinal domain of contractility despite of higher inflammatory biomarkers in non-survivors.

Microvascular and mechanical improvements following bariatric surgery in the obese; mechanistic insights from advanced &amp; automated quantitative perfusion cardiac MRI

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Guy"s and St Thomas" Charity University College London Hospital Biomedical Research Centre Background In people with obesity, bariatric surgery reduces mortality, heart failure and coronary disease, improving metabolic (blood sugar, lipid profile, inflammation) and cardiovascular (diastolic/systolic function, filling pressure, cardiac remodelling) parameters. Myocardial microvascular function is a candidate causal link of metabolic to structural cardiac abnormalities. Purpose We hypothesised that bariatric surgery could improve myocardial microvascular and mechanical function in both those with and without diabetes. Methods Before and six months after bariatric surgery, 24 subjects with obesity were assessed with haematology, biochemistry and advanced CMR (cines, vasodilator adenosine stress and rest fully-automated quantitative perfusion mapping, tissue-tracking (CVI42, post processing). Results. Mean age was 49± 12 years, 35%(8) were male, 63%(15), had hypertension, 17 (71%) had diabetes. Surgery resulted in decreases in BMI (44 ± 7 to 34 ± 6 kg/m2 p = 0.0001) and HbA1c (57 ± 16 to 42 ± 9mmol/mol p = 0.0001). EF% and absolute LV end-diastolic volumes remained unchanged, but mass regressed and myocardial contraction fraction (ratio of stroke volume and LV volume) increased (see Table). There were also strain improvements (radial 35 ± 8.8 to 37.3 ± 8.7 %p = 0.029) (circumferential -19.8 ± 2.3 vs -20.7 ± 3% p = 0.017), although longitudinal did not improve (-16.3 ± 3.2 to -15.9 ± 3% p = 0.25). Myocardial perfusion significantly improved (stress myocardial blood flow, MBF 2.35 ± 0.71 to 2.80 ± 0.98 ml/g/min p = 0.008; myocardial perfusion reserve MPR 2.47 ± 0.78 to 2.97 ± 0.95 p = 0.005). Improvement in stress MBF and MPR from pre-operative to post-operative was higher in the non-diabetics (n = 7 (29%)) than the diabetics (n = 17 (71%)) (stress MBF: 1.15 ± 1.00 vs 0.16 ± 0.39ml/g/min p = 0.002) MPR: (1.09 ± 0.73 vs 0.25 ± 0.66 p = 0.011). Conclusion At 6 months, bariatric surgery results in beneficial myocardial remodelling and substantial improvements in myocardial microvascular function. These improvements occur most in those without diabetes suggesting that there may be reversible and irreversible components to microvascular dysfunction. Perfusion and strain variables Variable Pre-op (n = 24) Post-op (n = 24) p-value LVEDV (ml) 163 ± 28 161 ± 29 0.64 EF (%) 70 ± 8 70 ± 7 0.78 Stroke volume (ml) 113 ± 19 111 ± 21 0.6 LV Mass (g) 117 ± 25 103 ± 21 0.001 Myocardial contraction fraction 94 ± 14 105 ± 14 0.001 LVEDV - left ventricular end-diastolic volume, EF - ejection fraction Abstract Figure.

Abstract 13078: Evaluation of Ventricular Function in Fetus With Transposition of Great Arteries by Velocity Vector Imaging

Background: The aim of this study was to test the hypotheses that (1) fetuses with complete transposition of the great arteries (D-TGA) and Taussig-Bing anomaly (TBA) has decreased the left ventricular (LV) and right ventricular(RV) mechanical function compared with normal fetuses, and (2)the decreased myocardial mechanical function in fetal D-TGA and TBA was associated with the degree of transposition of the great arteries, pulmonary stenosis(PS) and ventricular septal defect(VSD). Methods: We retrospectively identified 49 cases of fetal D-TGA and 29 cases of fetal TBA and compared findings to 49 controls of comparable gestational age. Postprocessing analysis of the left ventricle and right ventricle were done using syngo Velocity Vector Imaging version 2.3. Global and regional longitudinal systolic peak velocity, strain and strain rate were generated. Results: (1) Comparing with control group, the global and regional longitudinal systolic peak velocity (GLV), strain (GLS) and strain rate (GLSR) of the LV and RV were decreased in the group of D-TGA and TBA (P&lt;0.05). (2) In the group of D-TGA and TBA, the multivariate linear regression analysis, the VSD was the independent determinant of LVGLS and RVGLS (β = 0.270, P=0.014 and β = 0.465, P&lt; 0.001). The PS was the independent determinant of RVGLSR (β = 0.090, P=0.009). Conclusion: The ventricular function of fetal D-TGA and TBA were decreased compared with control group. The PS and VSD were the independent determinant factors of the decreased LVGLS, RVGLS and RVGLSR in the fetal D-TGA and TBA.

Evaluating diastolic and systolic reserve by strain imaging during resistance exercise training in heart failure with preserved ejection fraction

Abstract Background Exercise intolerance is the cardinal manifestation of heart failure (HF), yet its underlying mechanism(s) remain poorly understood. Measures of ventricular function such as ejection fraction often have no relationship with exercise capacity in HF. 2D-STE has proved to be more reliable method to evaluate myocardial mechanical function. Our hypothesis is Resistance exercise training (Resist-HFpEF) will improve exercise tolerance and exertional symptoms in patients with HFpEF. Purpose The study aims to evaluate myocardial mechanical function by strain imaging during resistance exercise training in Heart Failure patients with Preserved Ejection Fraction (HFpEF) Methods This is a single centre prospective pilot study. 24 HFpEF patients were enrolled and their baseline comorbidities were recorded. Baseline 2D-STE imaging was performed at rest and during exercise (Visit 1). Patients were then randomized to either a novel resistance exercise training program for 36 sessions (3 sessions per week for 12 weeks) or a standard of care control group. 2D STE imaging was then repeated at follow-up (Visit 2). Peak Global Longitudinal strain (GLS), systolic strain rate (SSR), early diastolic strain rate (SRe) were measured offline. Results Mean age of the Rehab cohort was 68.57±10.52 years and the control cohort was 68.1±6.47 years. 23 study subjects were male (96%). 17% of the study subjects were hypertensive, 63% were diabetic, 42% had NYHA I, 46% had NYHA II and 13% had NYHA III of heart failure. The mean LV ejection fraction in the control and Rehab group after the training program at rest was 61.88±2.26% &amp; 54.74±2.07% (p-value 0.04) and during exercise was 59.90±2.05% and 53.13±2.05% (p-value 0.04). The peak GLS was −18.80±4.29% and −17.7±2.21% in controls during rest and exercise at Visit 1 (p-value 0.27) while the rehab cohort had −18.71±4.7% and −20.82±2.4% respectively (p-value 0.0268). The peak GLS was −17.40±3.05% and −17.96±2.65% in controls during rest and exercise at Visit 2 (p-value 0.3430) while rehab cohort had −17.97±6.21% and −16.57±3.82% respectively (p-value 0.67). (Figure 1a and 1b shows GLS, SRS, SRe at Baseline and after exercise program respectively) Conclusion This pilot study suggest systolic and diastolic reserve can be measured reliably during low grade exercise. These results could reflect improvement in clinical status and exercise tolerance. Figure 1. Comparison of peak GLS, SSR, SRe amongst HFpEF patients at rest and during exercise before and after the rehab training program. Funding Acknowledgement Type of funding source: None

Measuring the link between cardiac mechanical function and metabolism during hyperpolarized 13C-pyruvate magnetic resonance experiments

PurposeThe goal of this study was to develop a methodology to investigate the relationship between contractile function and hyperpolarized (HP) [1-13C]pyruvate metabolism in a small animal model. To achieve sufficient signal from HP 13C compounds, HP 13C MRS/MRSI has required relatively large infusion volumes relative to the total blood volume in small animal models, which may affect cardiac function. MethodsEight female Sprague Dawley rats were imaged on a 4.7T scanner with a dual tuned 1H/13C volume coil. ECG and respiratory gated k-t spiral MRSI and an IDEAL based reconstruction to determine [1-13C]pyruvate metabolism in the myocardium. This was coupled with 1H cine MRI to determine ventricular volumes and mechanical function pre- and post-infusion of [1-13C]pyruvate. For comparison to the [1-13C]pyruvate experiments, three female Sprague Dawley rats were imaged with 1H cine MRI to determine myocardial function pre- and post-saline infusion. ResultsWe demonstrated significant changes in cardiac contractile function between pre- and post-infusion of [1-13C]pyruvate. Specifically, there was an increase in end-diastolic volume (EDV), stroke volume (SV), and ejection fraction (EF). Additionally, the ventricular vascular coupling ratio (VVCR) showed an improvement after [1-13C]pyruvate infusion, indicating increased systolic performance due to an increased arterial load. There was a moderate to strong relationship between the downstream metabolic conversion of pyruvate to bicarbonate and a strong relationship between the conversion of pyruvate to lactate and the cardiac mechanical function response. ConclusionThe infusion of [1-13C]pyruvate resulted in demonstrable increases in contractile function which was related to pyruvate conversion to bicarbonate and lactate. The combined effects of the infusion volume and inotropic effects of pyruvate metabolism likely explains the augmentation in myocardial mechanical function seen in these experiments. Given the relationship between pyruvate metabolism and contractile function observed in this study, this methodological approach may be utilized to better understand cardiac metabolic and functional remodeling in heart disease.

Effects of Collagen Heterogeneity on Myocardial Infarct Mechanics in a Multiscale Fiber Network Model.

The scar that forms after a myocardial infarction is often characterized by a highly disordered architecture but generally exhibits some degree of collagen fiber orientation, with a resulting mechanical anisotropy. When viewed in finer detail, however, the heterogeneity of the sample is clear, with different subregions exhibiting different fiber orientations. In this work, we used a multiscale finite element model to explore the consequences of the heterogeneity in terms of mechanical behavior. To do so, we used previously obtained fiber alignment maps of rat myocardial scar slices (n = 15) to generate scar-specific finite element meshes that were populated with fiber models based on the local alignment state. These models were then compared to isotropic models with the same sample shape and fiber density, and to homogeneous models with the same sample shape, fiber density, and average fiber alignment as the scar-specific models. All simulations involved equibiaxial extension of the sample with free motion in the third dimension. We found that heterogeneity led to a lower degree of mechanical anisotropy and a higher level of local stress concentration than the corresponding homogeneous model, and also that fibers failed in the heterogeneous model at much lower macroscopic strains than in the isotropic and homogeneous models. Taken together, these results suggest that scar heterogeneity may impair myocardial mechanical function both in terms of anisotropy and strength, and that individual variations in scar heterogeneity could be an important consideration for understanding scar remodeling and designing therapeutic interventions for patients after myocardial infarction.

Remodeling of substrate consumption in the murine sTAC model of heart failure

BackgroundEnergy metabolism and substrate selection are key aspects of correct myocardial mechanical function. Myocardial preference for oxidizable substrates changes in both hypertrophy and in overt failure. Previous work has shown that glucose oxidation is upregulated in overpressure hypertrophy, but its fate in overt failure is less clear. Anaplerotic flux of pyruvate into the tricarboxylic acid cycle (TCA) has been posited as a secondary fate of glycolysis, aside from pyruvate oxidation or lactate production. Methods and resultsA model of heart failure that emulates both valvular and hypertensive heart disease, the severe transaortic constriction (sTAC) mouse, was assayed for changes in substrate preference using metabolomic and carbon-13 flux measurements. Quantitative measures of O2 consumption in the Langendorff perfused mouse heart were paired with 13C isotopomer analysis to assess TCA cycle turnover. Since the heart accommodates oxidation of all physiological energy sources, the utilization of carbohydrates, fatty acids, and ketones were measured simultaneously using a triple-tracer NMR method. The fractional contribution of glucose to acetyl-CoA production was upregulated in heart failure, while other sources were not significantly different. A model that includes both pyruvate carboxylation and anaplerosis through succinyl-CoA produced superior fits to the data compared to a model using only pyruvate carboxylation. In the sTAC heart, anaplerosis through succinyl-CoA is elevated, while pyruvate carboxylation was not. Metabolomic data showed depleted TCA cycle intermediate pool sizes versus the control, in agreement with previous results. ConclusionIn the sTAC heart failure model, the glucose contribution to acetyl-CoA production was significantly higher, with compensatory changes in fatty acid and ketone oxidation not reaching a significant level. Anaplerosis through succinyl-CoA is also upregulated, and is likely used to preserve TCA cycle intermediate pool sizes. The triple tracer method used here is new, and can be used to assess sources of acetyl-CoA production in any oxidative tissue.

Linking cross-bridge cycling kinetics to response to cardiac resynchronization therapy: a multiscale modelling study.

Cardiac resynchronization therapy (CRT) is currently the most widely used treatment for heart failure patients with left bundle branch block (LBBB). In recent years, the presence of septal rebound stretch (SRS) has been found to be a positive indicator for CRT response although the mechanism is unknown. In an attempt to understand the relation between cellular mechanics and global pump function in CRT patients, we utilize the CircAdapt closed-loop cardiovascular system model in combination with the MechChem model of cardiac sarcomere contraction. Left bundle branch block has been simulated with increasing delay in left ventricular free wall and septal wall activation. In addition to the electrical dyssynchrony, myocardial mechanical function was diminished by decreasing the cross-bridge cycling rate. Our results have shown that a decrease in the cross-bridge cycling rate in addition to LBBB resulted in a decrease in SRS with a concomitant decreased response to resynchronization. The results of our multiscale modelling study suggest that, while greater SRS during systole clearly indicates electrical dyssynchrony, it also predicts mechanical viability and healthy cross-bridge cycling rates in the myocardium. Hence, SRS positively indicates response to CRT.

P852Linking myocardial mechanical function to exercise performance: a cardiopulmonary stress echo study in first time London marathon participants

P852Linking myocardial mechanical function to exercise performance: a cardiopulmonary stress echo study in first time London marathon participants

Effects of Paclitaxel and Carboplatin combination on mechanical myocardial and microvascular functions: a transthoracic Doppler echocardiography and two-dimensional strain imaging study.

Paclitaxel and carboplatin are frequently used chemotherapy drugs in the treatment of gynecologic malignancies. Little is known about their effects on left ventricular mechanical and coronary microvascular functions. Thirty consecutive patients were prospectively enrolled. Patients underwent transthoracic echocardiography (TTE) before and after chemotherapy, to evaluate left ventricular mechanical functions and coronary flow reserve (CFR). A comprehensive TTE, tissue Doppler and two-dimensional (2D) strain imaging were performed and coronary flow velocity was measured at baseline and after dipyridamole infusion. CFR was calculated as the ratio of hyperemic to baseline diastolic peak flow velocities. Mitral annular velocities by tissue Doppler, peak strain, and systolic strain rate by velocity vector imaging (VVI) were measured. Baseline measurements were compared with healthy controls (n = 26). No patient developed heart failure (HF) symptoms, no significant change occurred in left ventricular ejection fraction or cardiac output and no significant difference was observed in CFR after chemotherapy. Baseline mean longitudinal peak strain and systolic stain rate were similar between patients and controls: -17.5 ± 2.6% versus -17.6 ± 2.2% (P = NS) and -1.04 ± 0.14/sec versus -1.05 ± 0.12/sec (P = NS). Peak strain and systolic strain rate decreased significantly after chemotherapy (from -17.5 ± 2.6% to -16.2 ± 2.5%, P < 0.02; and from -1.05 ± 0.12/sec to -0.96 ± 0.11/sec, P = 0.01, respectively). However, mean longitudinal velocity did not change significantly. Paclitaxel and carboplatin combination did not impair CFR; however, this chemotherapy combination could induce subtle impairment in myocardial mechanical function which can be detected by advanced deformation imaging techniques rather than by tissue Doppler imaging or conventional 2D and Doppler echocardiography.

The importance of non-uniformities in mechano-electric coupling for ventricular arrhythmias

Cardiac mechanical and electrical activities are tightly linked through an intra-cardiac regulatory loop (mechano-electric coupling). This connection is essential for normal heart function and auto-regulation. In diseases associated with altered myocardial mechanical properties or function, however, feedback from the mechanical environment to the origin and spread of excitation can result in deadly cardiac arrhythmias. Ventricular tachyarrhythmias, especially, are encountered in cardiac diseases associated with volume and pressure overload or changes in tissue mechanics. Little is known about the influence of changes in mechano-electric coupling on cardiac rhythm in these settings or the potential therapeutic benefit of its manipulation. Improved understanding may be central to explaining the origin of arrhythmias that occur with these pathologies and to the development of novel mechanics-based therapies. The present review explores the potential role of mechano-electric coupling in ventricular arrhythmogenesis, with a focus on the importance of non-uniformity in mechanical function for the induction and sustenance of ventricular tachyarrhythmias.