Left Ventricular Relaxation Rate Research Articles

Sympathetic Activity and Diastolic Dysfunction in HFrEF: Muscle metaboreflex induced changes in left ventricle passive filling pressure

During exercise, activation of afferents within active skeletal muscle improves cardiovascular performance through reflex increases in cardiac output (CO), ventricular function, and central blood volume mobilization - termed the muscle metaboreflex. In heart failure (HF) ventricular function is depressed and muscle metaboreflex activation (MMA) does little to improve ventricular performance. In HF reflex characteristics shift to from cardio-centric mediated increases in mean arterial pressure via increases in ventricular function and central blood volume mobilization, to profound vasoconstriction of not only the peripheral circulation but also the myocardium which thereby further limits increases in contractility. Impaired increases in CO during MMA in HF are not a result of reductions in preload, but are primarily a result of reduced contractile function via pathology and enhanced negative reflex characteristics. In HF, there are attenuated improvements in the rate of left ventricular relaxation just after the cessation of contraction during MMA vs. that observed in healthy subjects. To what degree MMA also induces alterations in passive left ventricular filling is unknown. We sought to determine if rate of rise in left ventricular passive filling pressure (LVPFR) (an index of ventricular stiffness) during MMA in HF was significantly increased, thus suggesting not only pathological but sympathetically mediated ventricular stiffening. Using conscious, chronically instrumented canines who were observed before and after the induction of HF via rapid ventricular pacing we analyzed 10 ventricular beats in each experiment taken from steady state values at rest, during volitional exercise (3.2 km/hr), and during volitional exercise (3.2 km/hr) with MMA achieved via imposed reductions in hindlimb blood flow by ~ 50%. From these 10 beats the rate of ventricular filling pressure was assessed prior to the atrial kick. We observed in healthy subjects that neither exercise nor MMA significantly altered LVPFR. In HF the LVPFR was significantly increased from rest to exercise (312 ± 54 to 449 ± 76 mmHg/sec) and in response to MMA (449 ± 76 to 726 ± 111 mmHg/sec). The effect of heart failure on LVPFR at rest (217 ± 22 vs 312 ± 54 mmHg/sec P=0.051) and during exercise (288 ± 47 to 449 ± 76 mmHg/sec P=0.059) approached significance, but only reached significance during MMA (385 ± 58 to 726 ± 111 mmHg/sec P= 0.030) when compared to healthy controls. We conclude that in HF, MMA significantly increases the LVPFR thereby indicating reflex mediated increases in ventricular stiffness in addition to those induced as a result of HF. Increases in ventricular stiffness during MMA may be an additional mechanism that limits CO, reducing peripheral perfusion during exercise and potentially leading to sudden cardiac death. This project was funded by NHLBI grant HL-055473. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of myocardial function and systemic circulation on regional coronary perfusion.

Cardiac-coronary interaction and the effects of its pathophysiological variations on spatial heterogeneity of coronary perfusion and myocardial work are still poorly understood. This hypothesis-generating study predicts spatial heterogeneities in both regional cardiac work and perfusion that offer a new paradigm on the vulnerability of the subendocardium to ischemia, particularly at the apex. We propose a mathematical and computational modeling framework to simulate the interaction of left ventricular mechanics, systemic circulation, and coronary microcirculation. The computational simulations revealed that the relaxation rate of the myocardium has a significant effect whereas the contractility has a marginal effect on both the magnitude and transmural distribution of coronary perfusion. The ratio of subendocardial to subepicardial perfusion density (Qendo/Qepi) changed by -12 to +6% from a baseline value of 1.16 when myocardial contractility was varied by +25 and -10%, respectively; Qendo/Qepi changed by 37% when sarcomere relaxation rate, b, was faster and increased by 10% from the baseline value. The model predicts axial differences in regional myocardial work and perfusion density across the wall thickness. Regional myofiber work done at the apex is 30-50% lower than at the center region, whereas perfusion density in the apex is lower by only 18% compared with the center. There are large axial differences in coronary flow and myocardial work at the subendocardial locations, with the highest differences located at the apex region. A mismatch exists between perfusion density and regional work done at the subendocardium. This mismatch is speculated to be compensated by coronary autoregulation.NEW & NOTEWORTHY We present a model of left ventricle perfusion based on an anatomically realistic coronary tree structure that includes its interaction with the systemic circulation. Left ventricular relaxation rate has a significant effect on the regional distribution of coronary flow and myocardial work.

ATP‐sensitive K+ Channel Inhibition via Glibenclamide Impairs Maximal Aerobic Capacity and Critical Speed of Healthy Rats without Compromising Cardiac Function

Glibenclamide (GLI) enhances insulin release for Type II diabetes patients by inhibiting pancreatic ATP‐sensitive K+ (KATP) channels. However, systemic KATP channel inhibition decreases maximal aerobic capacity (V̇O2max) during treadmill running in rats; where V̇O2max is determined by cardiac output (Q̇) and O2 utilization within contracting skeletal muscle (arterial‐venous O2 difference). In vitro studies demonstrate that KATP channels enhance isolated cardiomyocyte and vascular smooth muscle relaxation. In vivo studies show that GLI induces vasoconstriction, decreases blood flow, and impairs O2 delivery‐utilization matching in contracting skeletal muscle. Whether high‐intensity exercise tolerance (i.e. the speed‐duration relationship with critical speed, CS, and distance covered above CS, D′) is dependent upon cardiac and/or peripheral (i.e., vascular) KATP channel function in vivo is unknown.PURPOSETo determine the role of KATP channels in establishing cardiac function (see below), maximal aerobic capacity (V̇O2max) and sustaining submaximal exercise tolerance (CS). We hypothesized that acute KATP channel inhibition via GLI would decrease V̇O2max and CS, but not decrease cardiac function.METHODSTen adult female Sprague‐Dawley rats were assessed during the proestrus cycle in randomized order with and without GLI. GLI (10 mg kg−1 in DMSO i.p.) was administered 30–60 min prior to resting Doppler echocardiography and exercise tests. Doppler echocardiography measured Q̇, heart rate (HR), stroke volume (SV), ejection fraction (EF), fractional shortening (FS) and rates of left ventricular contraction and relaxation. V̇O2max and CS tests utilized a motorized treadmill at a 5% incline. V̇O2max was measured via plexiglass metabolic chamber connected to an O2 analyzer with increasing treadmill speed (5–10 m min−1) every minute until V̇O2 plateaued with increases in treadmill speed. Multiple (i.e., ≥5) constant speed runs to exhaustion were used to resolve CS and D′.RESULTSAt rest GLI did not alter SV, EF, FS, nor rates of left ventricular contraction and relaxation compared to control (p>0.05 for all). However, GLI did reduce HR (321 ± 8 vs 300 ± 7 b min−1) and V̇ (217 ± 23 vs 192 ± 13 mL min−1; p<0.05 for both). Despite HR and Q̇ reductions at rest, neither were significantly correlated with decreases in V̇O2max or CS (p>0.05 for both). GLI significantly reduced V̇O2max (69 ± 2 vs 72 ± 1 mL O2 kg−1 min−1), CS (32 ± 1 vs 36 ± 1 m min−1; n=8), and D′ (100 ± 6 vs 86 ± 8 m; n=7) compared to control (all p<0.05).CONCLUSIONSConsistent with our hypothesis, KATP channels are vital in establishing maximal aerobic capacity (GLI decreased V̇O2max ~4%) and exercise tolerance (GLI decreased CS ~12%). Therefore, we speculate that HR regulation via KATP channel activity is overridden during exercise. These data support that vascular KATP channel function is important for matching O2 delivery to O2 requirements within skeletal muscles and this plays a pivotal role in determining exercise tolerance. Thus GLI treatment may potentiate the exercise intolerance of diabetic and other cardiovascular disease patients.Support or Funding InformationHL108328This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Reduction in Cardiac Function Precedes Structural Adaptations in Experimental Spinal Cord Injury

IntroductionChronic high‐thoracic spinal cord injury (SCI) is associated with systolic dysfunction, cardiomyocyte atrophy and the upregulation of major proteolytic pathways in the heart. How such dysfunction manifests with time is presently unknown.MethodsMale Wistar rats underwent complete SCI at the 3rd thoracic spinal level (T3‐SCI; n=10) or dorsal durotomy (SHAM; n=5). T3‐SCI rats were terminated at different time points: three days post‐SCI (3‐day SCI; n=5) or seven days post‐SCI (7‐day SCI; n=5). SHAM rats were terminated at seven days post‐durotomy. On termination day, prior to euthanasia, left‐ventricular (LV) catheterization was performed to assess cardiac function. Additionally, cardiac tissue was collected for histological analysis to quantify cardiomyocyte dimensions (standardized to femur length).ResultsRelative to SHAM, T3‐SCI rats at both 3‐day and 7‐day post‐SCI exhibited reduced stroke work (SW; p=0.036), load‐independent contractile function (inferred with end‐systolic pressure‐volume relationship, ESPVR; p=0.0013) and maximal rate of LV systolic pressure increment (dP/dtmax; p=0.0070). The maximal rate of LV relaxation (i.e. ‐dP/dtmin; p=0.019) was reduced at 3‐day and 7‐day post‐SCI vs. SHAM; however, tau (time constant of isovolumic relaxation) was not different (p=0.15). There were no differences for any functional indices between 3‐day vs. 7‐day SCI. Histological analysis of cardiomyocytes indicates no significant differences in length and width in SCI groups vs. SHAM (length p=0.20; width p=0.24).ConclusionSystolic cardiac function decreased significantly in both 3‐day and 7‐day SCI rats vs. SHAM. This indicates a rapid onset of cardiac dysfunction following T3‐SCI. Cardiomyocyte atrophy was not present in either 3‐day or 7‐day SCI rats, implying a reduction in cardiac function precedes structural remodeling.Support or Funding InformationHeart and Stroke Foundation of Canada (HSFC), International Collaboration on Repair Discoveries (ICORD) and Blusson Integrated Cure Partnership (BICP).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Linggui Zhugan Decoction (苓桂术甘汤) Inhibits Ventricular Remodeling after Acute Myocardial Infarction in Rats by Suppressing TGF-β1/Smad Signaling Pathway

To investigate the inhibitory effect of Linggui Zhugan Decoction (LZD, ) on the ventricular remodeling (VR) after acute myocardial infarction (AMI) and related mRNA and proteins expression in transforming growth factor-beta 1 (TGF-β1)/Smad signaling pathway, and explain its putative mechanism. A VR model was generated by ligation of coronary artery in mice. Two weeks after surgery, 60 mice were randomly divided into the model group, the sham-operation group (distilled water), the positive control group (2.4 mg/kg simvastatin), and the low-, medium- and high-dose LZD groups (2.1, 4.2, 8.4 g crude drug/kg, respectively) by a random number table, 10 mice in each group. Mice in each group was treated for 4 weeks. Changes of hemodynamics indices and cardiac weight index were detected by the PowerLab data acquisition and analysis recording instrument. Morphology changes of myocardial tissue were observed by hematoxylin-eosin and Masson staining. The expressions of TGF-β1, Smad2, Smad3, p-Smad2 and p-Smad3 in myocardial tissue were detected by Western blotting. The mRNA expressions of TGF-β1, Smad2 and Smad3 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expressions of matrix metalloprotein 2 (MMP2), MMP9, collagen I and collagen III were observed by immunohistochemical methods. VR mice showed significant dysfunction in hemodynamic indices and cardiac structure and function. Compared with the shamoperation group, myocardial tissue damage, interstitial fibrosis occurred in the model mice, left ventricular systolic pressure (LVSP), left ventricular pressure maximum contraction rate (+dp/dtmax) and left ventricular pressure maximum relaxation rate (-dp/dtmax) decreased significantly (all P<0.01), while left ventricular end-diastolic pressure (LVEDP), cardiac weight index and left ventricular weight index elevated significantly, meanwhile TGF-β1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen I, collagen III protein expressions in myocardial tissue and TGF-β1, Smad2 and Smad3 mRNA expressions increased significantly (all P<0.01). Compared with the model group, LZD could significantly improve the pathological changes of myocardial tissue, increase LVSP, +dp/dtmax and -dp/dtmax, lower LVEDP, reduce the whole heart weight index and left ventricular weight index and inhibit the over-expressions of TGF-β1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen I and collagen III proteins in myocardial tissue and mRNA expressions of TGF-β1, Smad2 and Smad3 (P<0.05 or P<0.01). LZD can significantly suppress VR induced by AMI, and its underlying mechanism may be associated with its inhibitory effect on the TGF-β1/Smad signaling pathway.

Sodium nitrate supplementation alters mitochondrial H2O2 emission but does not improve mitochondrial oxidative metabolism in the heart of healthy rats.

Supplementation with dietary inorganic nitrate ([Formula: see text]) is increasingly recognized to confer cardioprotective effects in both healthy and clinical populations. While the mechanism(s) remains ambiguous, in skeletal muscle oral consumption of NaNO3 has been shown to improve mitochondrial efficiency. Whether NaNO3 has similar effects on mitochondria within the heart is unknown. Therefore, we comprehensively investigated the effect of NaNO3 supplementation on in vivo left ventricular (LV) function and mitochondrial bioenergetics. Healthy male Sprague-Dawley rats were supplemented with NaNO3 (1 g/l) in their drinking water for 7 days. Echocardiography and invasive hemodynamics were used to assess LV morphology and function. Blood pressure (BP) was measured by tail-cuff and invasive hemodynamics. Mitochondrial bioenergetics were measured in LV isolated mitochondria and permeabilized muscle fibers by high-resolution respirometry and fluorometry. Nitrate decreased ( P < 0.05) BP, LV end-diastolic pressure, and maximal LV pressure. Rates of LV relaxation (when normalized to mean arterial pressure) tended ( P = 0.13) to be higher with nitrate supplementation. However, nitrate did not alter LV mitochondrial respiration, coupling efficiency, or oxygen affinity in isolated mitochondria or permeabilized muscle fibers. In contrast, nitrate increased ( P < 0.05) the propensity for mitochondrial H2O2 emission in the absence of changes in cellular redox state and decreased the sensitivity of mitochondria to ADP (apparent Km). These results add to the therapeutic potential of nitrate supplementation in cardiovascular diseases and suggest that nitrate may confer these beneficial effects via mitochondrial redox signaling.

Abstract P205: Short-term Western Diet Induced Hypertension in Female Rats is Associated With Vascular Epigenetic Modification

Over consumption of the western diet (WD) is a major contributor to the global epidemic of metabolic syndrome. Studies on the impact of WD on vascular complications related to hypertension have revealed contradictory results. Moreover, reports on the effect of WD on female cohorts is limited. Results from our lab have indicated that transient diabetic conditions increase vascular lysine acetylation levels, a post-translational epigenetic modification. Therefore, we hypothesized that short-term exposure to WD causes vascular endothelial dysfunction and hypertension in association with increased vascular lysine acetylation. Adult female Wistar rats were assigned either a control diet (13.4% fat, 56% carbohydrate, and 29.8% protein; n=4) or a WD (41% fat, 43% carbohydrates, and 17% protein; n=6) for 17 weeks. Results showed the WD group exhibited increased body weight (376 ± 49 vs 305 ± 41g, p&lt;0.05), periabdominal fat content (30 ±11 vs 11 ±2g, p&lt;0.01), % body fat (8.1 ±1.0 vs 3.6 ±0.4%, p&lt;0.01), and serum triglycerides levels (56 ± 13 vs 25 ± 4mg/dl, p&lt;0.01) compared to controls. Blood glucose and free fatty acid levels did not differ between groups. Vascular reactivity studies, using wire myography, showed WD aortas had impaired acetylcholine-induced endothelial-dependent relaxation (83.5 ±4.2 vs 93.1 ±3.0%, p&lt;0.001). Invasive left ventricular (LV) catheterization demonstrated that the WD group had increased systolic (147 ±12 vs 120 ±6mmHg, p&lt;0.01) and diastolic blood pressures (105 ±9 vs 87± 4mmHg, p&lt;0.01), and rate of LV relaxation (-dP/dt: 13.5 ±1.3 vs 9.4 ±2.4mmHg/ms, p&lt;0.01) compared to controls. Histological orcein staining and morphometric analysis showed that WD aortas displayed severe elastic fiber derangement and medial thickening (150.6 ±13.5 vs 110.5 ±20.2μm, p&lt;0.05). Lysine acetylation levels were significantly increased in WD vascular tissue (1.5-fold increase vs control, p&lt;0.05). Additionally, levels of KAT2B/HAT, an acetyltransferase protein, were elevated in aortas from WD (2.0-fold increase vs control, n=2). Our results support our hypothesis that endothelial dysfunction and hypertension induced by WD in female rats correlates with increased epigenetic markers in vascular tissue.

Early detection of abnormal left ventricular relaxation in acute myocardial ischemia with a quadratic model

AimsThe time constant of left ventricular (LV) relaxation derived from a monoexponential model is widely used as an index of LV relaxation rate, although this model does not reflect the non-uniformity of ventricular relaxation. This study investigates whether the relaxation curve can be better fitted with a “quadratic” model than with the “conventional” monoexponential model and if changes in the LV relaxation waveform due to acute myocardial ischemia could be better detected with the quadratic model. Methods and resultsIsovolumic relaxation was assessed with quadratic and conventional models during acute myocardial ischemia performed in 6 anesthetized pigs. Mathematical development indicates that one parameter (Tq) of the quadratic model reflects the rate of LV relaxation, while the second parameter (K) modifies the shape of the relaxation curve. Analysis of experimental data obtained in anesthetized pigs showed that the shape of LV relaxation consistently deviates from the conventional monoexponential decay. During the early phase of acute myocardial ischemia, the rate and non-uniformity of LV relaxation, assessed with the quadratic function, were significantly enhanced. Tq increased by 16% (p<0.001) and K increased by 12% (p<0.001) within 30 and 60min, respectively, after left anterior descending (LAD) coronary artery occlusion. However, no significant changes were observed with the conventional monoexponential decay within 60min of ischemia. ConclusionsThe quadratic model better fits LV isovolumic relaxation than the monoexponential model and can detect early changes in relaxation due to acute myocardial ischemia that are not detectable with conventional methods.

Oral treatment with Euterpe oleracea Mart. (açaí) extract improves cardiac dysfunction and exercise intolerance in rats subjected to myocardial infarction.

BackgroundThis study was designed to evaluate the cardioprotective effects of Euterpe oleracea Mart., popularly known as “açaí”, on rats subjected to myocardial infarction (MI).MethodsHydroalcoholic extracts of açaí were obtained from a decoction of the seeds. Two male Wistar rat groups were delineated: 1) the sham-operated group (control, n = 6), with no surgical amendment, and 2) the MI group (n = 12), in which the anterior descendent coronary artery was occluded during surgery. MI group was divided into two subgroups, in which rats were either treated with hydroalcoholic extract of Euterpe oleracea seeds (100 mg/kg/day p.o.) or received no treatment. Treatment began on the day of surgery, and lasted 4 weeks. Subsequently, rats were subject to an exercise test protocol, hemodynamic evaluation, and histological analysis of the left ventricle. Groups were compared using one-way analysis of variance (ANOVA), followed by Dunnett’s test.ResultsThe total running distance of sham rats was 1339.0 ± 276.6 m, MI rats was 177.6 ± 15.8 m (P < 0.05), and MI-açaí rats was 969.9 ± 362.2 m. Systolic arterial pressure was significantly decreased in MI rats (86.88 ± 4.62 mmHg) compared to sham rats (115.30 ± 7.24 mmHg; P < 0.05). Açaí treatment prevented a reduction in systolic arterial pressure (130.00 ± 8.16 mmHg) compared to MI rats (P < 0.05). Left ventricular (LV) end-diastolic pressure was significantly augmented in MI rats (17.62 ± 1.21 mmHg) compared to sham rats (4.15 ± 1.60 mmHg; P < 0.05), but was 3.69 ± 2.69 mmHg in açaí-treated rats (P < 0.05 vs. MI). The LV relaxation rate (-dp/dt) was reduced in MI rats compared to the sham group, whereas açaí treatment prevented this reduction. Açaí treatment prevented cardiac hypertrophy and LV fibrosis in MI rats.ConclusionsEuterpe oleracea treatment of MI rats prevented the development of exercise intolerance, cardiac hypertrophy, fibrosis, and dysfunction.

Photochemically Altered Air Pollution Mixtures and Contractile Parameters in Isolated Murine Hearts before and after Ischemia

Background: The cardiopulmonary effects of the individual criteria air pollutants have been well investigated, but little is known about the cardiopulmonary effects of inhaled multipollutant mixtures that more realistically represent environmental exposures.Objectives: We assessed the cardiopulmonary effects of exposure to photochemically altered particle-free multipollutant mixtures.Methods: We exposed mice to filtered air (FA), multipollutant mixtures, or ozone (O3) for 4 hr in a photochemical reaction chamber. Eight hours after exposure, we assessed cardiac responses using a Langendorff preparation in a protocol consisting of 20 min of global ischemia followed by 2 hr of reperfusion. Cardiac function was assessed by measuring the index of left-ventricular developed pressure (LVDP) and contractility (dP/dt) before ischemia. On reperfusion after ischemia, recovery of postischemic LVDP and size of infarct were examined. We used bronchoalveolar lavage (BAL) cell counts to assess lung inflammation.Results: Exposure to the multipollutant mixtures decreased LVDP, baseline rate of left ventricular contraction (dP/dtmaximum), and baseline rate of left ventricular relaxation (dP/dtminimum) compared with exposure to FA. Exposure to O3 also decreased heart rate and dP/dtminimum. Time to ischemic contracture was prolonged in the multipollutant-mixture group relative to that in the FA group. Mice in the multipollutant-mixture group had better recovery of postischemic LVDP and smaller infarct size. Exposure to multipollutant mixtures and to O3 exposure increased numbers of macrophages in the BAL fluid.Conclusions: Exposure to photochemically altered urban air pollution appears to affect cardiac mechanics in isolated perfused hearts. Inhalation of acute multipollutant mixtures decreases LVDP and cardiac contractility in isolated non-ischemic murine hearts, prolongs ischemic contracture, increases postischemic recovery of LVDP, and reduces infarct size.Citation: McIntosh-Kastrinsky R, Diaz-Sanchez D, Sexton KG, Jania CM, Zavala J, Tilley SL, Jaspers I, Gilmour MI, Devlin RB, Cascio WE, Tong H. 2013. Photochemically altered air pollution mixtures and contractile parameters in isolated murine hearts before and after ischemia. Environ Health Perspect 121:1344–1348; http://dx.doi.org/10.1289/ehp.1306609

Enhanced N-terminal degradation of troponin I blunts cardiac function responsiveness to isoproterenol in 4-week tail-suspended rats

The N-terminal extension of cardiac troponinI (cTnI) is important in regulating cardiac function. Although the normal rat myocardium shows some cTnI N-terminal degradation (cTnI-ND), exposure to 4weeks of tail-suspension markedly increased cTnI-ND. We hypothesized that the increased cTnI-ND in tail-suspended rats may affect cardiac function, particularly during β-adrenergic (β-A) stimulation. The increase in cardiac output with isoproterenol (ISO) treatment was smaller in tail-suspended rats compared with controls. Left ventricular end-diastolic pressure was elevated and increases in maximal rates of left ventricular pressure development and relaxation were lower during ISO treatment in tail-suspended rats. Response to ISO, forskolin, DB-cAMP and IBMX was also lower in cardiomyocytes from tail-suspended rats. The increase in shortening and re-lengthening the rates of cardiomyocytes at a maximal dose of ISO, forskolin, DB-cAMP and IBMX treatment was limited in tail-suspended rats. There was no difference in Ca2+ sensitivity of the isometric force between tail-suspended and control rats, although Ca2+ sensitivity was decreased less in tail-suspended rats versus control rats during PKA phosphorylation. There was no difference in PKA protein expression and activation during ISO stimulation between the twogroups. Due to the increase in cTnI-ND, ISO-induced phosphorylation of cTnI was reduced in tail-suspended rats. The total phospholamban expression and phosphorylation by ISO was unaltered in tail-suspended rat hearts. These data suggest that enhanced cTnI-ND following 4-week tail-suspension is a major component of the β-A receptor signaling pathway, depressing cardiac function under ISO stimulation.

Myocardial Relaxation, Restoring Forces, and Early-Diastolic Load Are Independent Determinants of Left Ventricular Untwisting Rate

Peak left ventricular (LV) untwisting rate (UTR) has been introduced as a clinical marker of diastolic function. This study investigates if early-diastolic load and restoring forces are determinants of UTR in addition to the rate of LV relaxation. In 10 anesthetized dogs we measured UTR by sonomicrometry and speckle tracking echocardiography at varying LV preloads, increased contractility, and myocardial ischemia. UTR was calculated as the time derivative of LV twist. Because preload modified end-diastolic twist, LV systolic twist was calculated in absolute terms with reference to the end-diastolic twist configuration at baseline. Relaxation rate was measured as the time constant (τ) of LV isovolumic pressure decay. Early-diastolic load was measured as LV pressure at the time of mitral valve opening. Circumferential-longitudinal shear strain was used as an index of restoring forces. In a multivariable mixed model analysis a strong association was observed between UTR and LV pressure at the time of mitral valve opening (parameter estimate [β]=6.9; P<0.0001), indicating an independent effect of early-diastolic load. Furthermore, the associations between UTR and circumferential-longitudinal shear strain (β=-11.3; P<0.0001) and τ (β=-1.6, P<0.003) were consistent with independent contributions from restoring forces and rate of relaxation. Maximal UTR before mitral valve opening, however, was determined only by relaxation rate and restoring forces. The present study indicates that early-diastolic load, restoring forces, and relaxation rate are independent determinants of peak UTR. However, only relaxation rate and restoring forces contributed to UTR during isovolumic relaxation.

Spatio-temporal attributes of left ventricular pressure decay rate during isovolumic relaxation

Global left ventricular (LV) isovolumic relaxation rate has been characterized: 1) via the time constant of isovolumic relaxation τ or 2) via the logistic time constant τ(L). An alternate kinematic method, characterizes isovolumic relaxation (IVR) in accordance with Newton's Second Law. The model's parameters, stiffness E(k), and damping/relaxation μ result from best fit of model-predicted pressure to in vivo data. All three models (exponential, logistic, and kinematic) characterize global relaxation in terms of pressure decay rates. However, IVR is inhomogeneous and anisotropic. Apical and basal LV wall segments untwist at different times and rates, and transmural strain and strain rates differ due to the helically variable pitch of myocytes and sheets. Accordingly, we hypothesized that the exponential model (τ) or kinematic model (μ and E(k)) parameters will elucidate the spatiotemporal variation of IVR rate. Left ventricular pressures in 20 subjects were recorded using a high-fidelity, multipressure transducer (3 cm apart) catheter. Simultaneous, dual-channel pressure data was plotted in the pressure phase-plane (dP/dt vs. P) and τ, μ, and E(k) were computed in 1631 beats (average: 82 beats per subject). Tau differed significantly between the two channels (P < 0.05) in 16 of 20 subjects, whereas μ and E(k) differed significantly (P < 0.05) in all 20 subjects. These results show that quantifying the relaxation rate from data recorded at a single location has limitations. Moreover, kinematic model based analysis allows characterization of restoring (recoil) forces and resistive (crossbridge uncoupling) forces during IVR and their spatio-temporal dependence, thereby elucidating the relative roles of stiffness vs. relaxation as IVR rate determinants.

Adipocyte-derived factors suppress heart contraction

Obesity is strongly associated with cardiovascular diseases including systemic hypertension, coronary artery disease and heart failure. Despite several investigations the pathophysiological mechanisms involved remain unclear. We have previously shown that adipose tissue exerts a highly potent activity with an acute depressant effect on cardiomyocytes, thus suggesting direct involvement of adipose tissue in the development of heart dysfunction. This study investigates the effects of adipocyte factors obtained from subcutaneous adipose tissue on the whole cardiac function by using isolated perfused rat hearts in a Langendorff mode. We recorded changes in coronary flow, developed isovolumetric left ventricular pressure, contraction rate and relaxation rate. We observed a significant decrease in heart contractility parameters as well as in coronary flow within a few seconds of incubation with adipocyte factors. The cardiodepressant effects could not be blocked by the nonselective cyclooxygenase-inhibitor indomethacin. Human adipocytes release tumor necrosis factor-α, interleukin-6 (IL-6) and IL-1β into extracellular medium. These cytokines were tested for their potential effect but were, however, not responsible for the cardiodepressant effect observed. These data indicate that human adipocytes secrete factors with a strong acute depressant effect on cardiac force generation and coronary flow due to contraction of the coronary vessels, thus suggesting a direct role of adipose tissue in the pathogenesis of cardiac dysfunction.

The Time Constant of Left Ventricular Relaxation

Left ventricular (LV) diastolic dysfunction induces the increase of LV diastolic pressure and subsequently of left atrial and pulmonary capillary pressures independent of systolic function, resulting in the onset of heart failure. In the early 1990s, several clinical studies demonstrated that diastolic dysfunction is an independent prognostic factor in patients with heart failure with reduced ejection fraction (EF).1,2 In the past decade, many clinical studies have clarified that heart failure with preserved EF (HFPEF) accounts for ≈40% of heart failure and that its prognosis is as poor as heart failure with reduced EF.3 With the growing interest in HFPEF, the important role of diastolic dysfunction in the pathogenesis of heart failure has been realized again, because it is plausible that LV diastolic dysfunction is one of the principal causes for this phenotype of heart failure.4 Article see p 268 Major determinants of LV diastolic function are relaxation and stiffness.5 Despite the clinical requisite for their evaluation in understanding the pathophysiology of each patient with heart failure, there are no established indices for the noninvasive assessment of these factors. An invasive measure of LV pressure is required for the evaluation of LV relaxation, and the simultaneous recording of LV pressure and geometry is necessary for the assessment of LV stiffness. LV relaxation abnormality is likely to precede LV stiffening or systolic dysfunction during the development of chronic heart failure and has been assigned as a sensitive sign of LV dysfunction. Peak negative value of the first derivative of LV pressure (peak−dP/dt) has been used as a quantitative index for LV relaxation, but it depends on many other hemodynamic and functional factors. Weiss et al6 showed that the time course of isovolumic pressure decrease subsequent to peak−dP/dt is exponential and proposed the time …

Characterization of an animal model of postmenopausal cardiac hypertrophy and novel mechanisms responsible for cardiac decompensation using ovariectomized pressure-overloaded rats

The development of animal models of cardiovascular disease are critical to define pathophysiological mechanisms and to advance diagnosis and therapy. The lack of a suitable animal model represents a failure to define the mechanisms responsible for postmenopausal myocardial hypertrophy in hypertension and adverse cardiac remodeling. In this review, we presented a rat model of postmenopausal myocardial hypertrophy, with particular focus on the similarities between the animal model and postmenopausal women regarding myocardial function as well as molecular and subcellular mechanisms. To elucidate the molecular mechanism of left ventricular (LV) hypertrophy and remodeling in postmenopausal women, we analyzed myocardial hypertrophy as well as cardiac function and hypertrophy-related protein expression in ovariectomized (OVX) and pressure overloaded (PO) rats. The model is characterized by depletion of serum estrogen and increased heart-to-body weight and lung-to-body weight ratios. Moreover, the OVX-PO rats also show increased mean arterial blood pressure, LV end-diastolic pressure, LV developed pressure, and maximal rates of LV contraction and relaxation compared with the OVX group. Importantly, Akt activity was largely attenuated, and both endothelial nitric oxide synthase expression and activity were markedly reduced in the OVX-PO group. Finally, significant increased mortality was observed in the OVX-PO group after chronic isoproterenol administration. Our results demonstrate that rats subject to OVX are unable to compensate for hypertrophy partly due to impaired Akt-endothelial nitric oxide synthase signaling along with deteriorated heart function and demonstrated increased mortality. In this review, we discussed the mechanisms of cardiac injury, which could play a critical role in postmenopausal hypertrophy, as well as the characteristics of the OVX-PO female rats as a model to test cardioprotective drugs in postmenopausal women.

Left ventricular function of isoproterenol-induced hypertrophied rat hearts perfused with blood: mechanical work and energetics

We investigated left ventricular (LV) mechanical work and energetics in the cross-circulated (blood-perfused) isoproterenol [Iso 1.2 mg x kg(-1).day(-1) for 3 days (Iso3) or 7 days (Iso7)]-induced hypertrophied rat heart preparation under isovolumic contraction-relaxation. We evaluated pressure-time curves per beat, end-systolic pressure-volume and end-diastolic pressure-volume relations, and myocardial O(2) consumption per beat (Vo(2))-systolic pressure-volume area (PVA; a total mechanical energy per beat) linear relations at 240 beats/min, because Iso-induced hypertrophied hearts failed to completely relax at 300 beats/min. The LV relaxation rate at 240 beats/min in Iso-induced hypertrophied hearts was significantly slower than that in control hearts [saline 24 microl/day for 3 and 7 days (Sa)] with unchanged contraction rate. The Vo(2)-intercepts (composed of basal metabolism and Ca(2+) cycling energy consumption in excitation-contraction coupling) of Vo(2)-PVA linear relations were unchanged associated with their unchanged slopes in Sa, Iso3, and Iso7 groups. The oxygen costs of LV contractility were also unchanged in all three groups. The amounts of expression of sarcoplasmic reticulum Ca(2+)-ATPase, phospholamban (PLB), phosphorylated-Ser(16) PLB, phospholemman, and Na(+)-K(+)-ATPase are significantly decreased in Iso3 and Iso7 groups, although the amount of expression of NCX1 is unchanged in all three groups. Furthermore, the marked collagen production (types I and III) was observed in Iso3 and Iso7 groups. These results suggested the possibility that lowering the heart rate was beneficial to improve mechanical work and energetics in isoproterenol-induced hypertrophied rat hearts, although LV relaxation rate was slower than in normal hearts.

Determinants of Left Ventricular Early-Diastolic Lengthening Velocity

Peak early-diastolic mitral annulus velocity (e') by tissue Doppler imaging has been introduced as a clinical marker of diastolic function. This study investigates whether lengthening load (early-diastolic load) and restoring forces are determinants of e' in addition to rate of left ventricular (LV) relaxation. In 10 anesthetized dogs, we measured e' by sonomicrometry and tissue Doppler imaging during baseline, volume loading, caval constriction, dobutamine infusion, and occlusion of the left anterior descending coronary artery. Relaxation was measured as the time constant (tau) of LV pressure decay by micromanometer. Lengthening load was measured as LV transmural pressure at mitral valve opening (LVP(MVO)). Restoring forces were quantified by 2 different indices: (1) As the difference between minimum and unstressed LV diameter (Lmin-L0) and (2) as the estimated fully relaxed LV transmural pressure (FRP(Est)) at minimum diameter. In the overall analysis, a strong association was observed between e' and LVP(MVO) (beta=0.49; P<0.001), which indicates an independent effect of lengthening load, as well as between e' and Lmin-L0 (beta=-0.38; P<0.002) and between e' and FRP(Est) (beta=-0.31; P<0.002), consistent with an independent contribution of restoring forces. A direct effect of rate of relaxation on e' was observed in a separate analysis of baseline, dobutamine, and ischemia when postextrasystolic beats were included (beta=-0.06, P<0.01). The present study indicates that in the nonfailing ventricle, in addition to LV relaxation, restoring forces and lengthening load are important determinants of early-diastolic lengthening velocity.

Role of Oxidative Stress in the Development of Cardiac Depression in Severe Isolated Brain Injury (Experimental Study)

Objective: to study the role of oxidative stress in the development of cardiac structural and metabolic disorders in severe isolated brain injury (BI). Materials and methods. The impact of BI on the parameters of serum chemilu-minescence and the contractility of isolated rat hearts were studied in experiments on 66 outbred male albino rats, as described by E. T. Fallen et al. Lipid peroxidation processes were inhibited, by intraperitoneally injecting the antioxidant carnosine (100 mg/kg) 1 and 24 hours before or just after BI. Results. The rate of free radical processes rose an hour after severe isolated BI, which was associated with the indirect signs of cardiomyocitic membrane damages, depressed rat heart contractility, and their diminished resistance to hypoxia, reoxygenation, and exercise by high rhythm. Administration of carnosine to the animals favored the normalization of chemluminescent values with the high overall antioxidative capacity of serum. The effect of the agent depended on the time of its use and it was high when carnosine was injected 1 and 24 hours before injury. At the stage of reoxygenation after the hypoxic test, there was a significant increase in evolving pressure, the rate of left ventricular myocardial contraction and relaxation, and a reduction in AsAT activity in all coronary duct tests, as compared with the controls. A negative correlation was found between the burst amplitude and the myocardial relaxation rate in the animals receiving the agent. Conclusion. Improved cardiac contractility and increased capacities of the mechanisms responsible for Ca2+ transport due to the use of the antioxidant carnosine allow one to state that oxidative stress is one of the pathogenetic factors of cardiac depression in severe isolated BI. Key words: brain injury, heart, oxidative stress, carnosine.

Monitoring dynamic alterations in calcium homeostasis by T1‐weighted and T1‐mapping cardiac manganese‐enhanced MRI in a murine myocardial infarction model

Manganese has been used as a T(1)-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn(2+)) enter viable myocardial cells via voltage-gated Ca(2+) channels, manganese-enhanced MRI is sensitive to the viability and inotropic state of the heart. In spite of the established importance of Ca(2+) regulation in the heart both before and after myocardial injury, monitoring strategies to assess Ca(2+) homeostasis in affected cardiac tissues are limited. This study implements a T(1)-mapping method to obtain quantitative information both dynamically and over a range of MnCl(2) infusion doses. To optimize the current Mn(2+) infusion protocols, we performed both dose-dependent and temporal washout studies. A non-linear relationship between infused MnCl(2) solution dose and increase in left ventricular wall relaxation rate (DeltaR(1)) was observed. Control mice also exhibited significant Mn(2+) clearance over time, with a decrease in DeltaR(1) of approximately 50% occurring in just 2.5 h. The complicated efflux time dependence possibly suggests multiple efflux mechanisms. With the use of the measured relationship between infused Mn(2+) dose, DeltaR(1), and inductively coupled plasma mass spectrometry data analysis provided a means of estimating the absolute heart Mn concentration in vivo. We show that this technique has the sensitivity to observe or monitor potential alterations in Ca(2+) handling in vivo because of the physiological remodeling after myocardial infarction. Left ventricular free wall DeltaR(1) values were significantly lower (P = 0.005) in the adjacent zone, surrounding the injured myocardial tissue, than in healthy tissue. This inferred reduction in Mn concentration can be used to estimate potentially salvageable myocardium in vivo for future treatment or evaluation of disease progression.