Oxidative stress adaptation improves postischemic ventricular recovery

Adaptation to various forms of stress has been found to be associated with increased cellular tolerance to myocardial ischemia. In this study, the effects of myocardial adaptation to oxidative stress was examined by injecting rats with endotoxin (0.5 mg/kg) and its non-toxic derivative, lipid A (0.5 mg/kg). Both compounds exerted oxidative stress within 1 h of treatment as evidenced by enhanced malonaldehyde formation. The oxidative stress disappeared steadily and progressively with time in concert with the appearance of the induction of glutathione and antioxidative enzymes that included superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. After 24 h of endotoxin or lipid A treatment, the amount of oxidative stress and antioxidant enzyme levels were significantly lower and higher, respectively, compared to those at the baseline levels. Corroborating these results, both endotoxin and lipid A provided protection against myocardial ischemia and reperfusion injury as evidenced by significantly improved postischemic recovery of left ventricular functions. The data presented here demonstrates that a controlled amount of oxidative stress induces the expression of intracellular antioxidants that can result in enhanced myocardial tolerance to ischemia. This suggests that myocardial adaptation to oxidative stress may be a potential tool for reduction of ischemic/reperfusion injury.     

Noninvasive radiodiagnosis of left ventricular diastolic dysfunction in hypertensive patients

To define the informative value of Doppler studies in the early diagnosis of left ventricular (LV) diastolic dysfunction in patients with hypertensive disease (HD), the authors examined 74 patients with grade 1-2 HD, including 65 men and 9 women aged 43 to 63 years. All the patients underwent echocardiography (echoCG), Doppler echoCG (DechoCG), tissue DechoCG (TDechoCG), and treadmill. According to the echoCG LV mass index (LVMI), all the patients were divided into 2 groups: 1) 33 patients with increased LVMI and 2) 41 with normal LVMI. A control group consisted of 20 apparently healthy patients. Groups 1 and 2 showed a preponderance of patients with concentric LV hypertrophy (CLVH) and those with concentric LV remodeling, respectively. In accordance with DechoCG, the signs of primary LV diastolic dysfunction ((E/A = 0.8+/-0.1; IVRT = 103+/-15) were found only in Group 1 patients. TDechoCG displayed the signs of primary LV diastolic dysfunction in both groups (e' or =10 ratio, suggests elevated LV filling pressure as an early stage of diastolic dysfunction.     

Acute hypothyroidism slows the rate of left ventricular diastolic relaxation

The effect of acute thyroid hormone deficiency on left ventricular diastolic filling was studied by radionuclide ventriculography with simultaneous right heart catheterization in nine athyreotic patients without cardiovascular disease. The patients were studied when they were hypothyroid and when they were euthyroid on replacement therapy. Peak filling rate and the time to peak filling were used to characterize diastolic function. The time to peak filling was defined as the interval from end-systole on the radionuclide time-volume curve to the time of occurrence of peak filling. The peak filling rate was determined in absolute terms from the normalized radionuclide peak filling rate and from the end-diastolic volume, which was derived from the radionuclide ejection fraction and from the thermodilution stroke volume. In all patients, the values for peak filling rate were lower in the hypothyroid than in the euthyroid state (287 +/- 91 mL/s vs. 400 +/- 118 mL/s, delta = 41 +/- 13%, p less than 0.01). Peak filling always occurred during the first half of the diastolic interval. The time to peak filling was not significantly affected by the thyroid state (170 +/- 10 ms vs. 159 +/- 21 ms, delta = 7 +/- 10%). Left ventricular filling pressure as reflected by the pulmonary capillary wedge pressure and end-systolic volume were similar in both thyroid states (6 +/- 2 mmHg vs. 8 +/- 2 mmHg (1 mmHg = 133.32 Pa) and 32 +/- 11 mL vs. 32 +/- 7 mL, respectively). The data suggest that the rate of active diastolic relaxation is decreased in short-duration hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modeling left ventricular diastolic dysfunction: classification and key indicators

Background

Mathematical modeling can be employed to overcome the practical difficulty of isolating the mechanisms responsible for clinical heart failure in the setting of normal left ventricular ejection fraction (HFNEF). In a human cardiovascular respiratory system (H-CRS) model we introduce three cases of left ventricular diastolic dysfunction (LVDD): (1) impaired left ventricular active relaxation (IR-type); (2) increased passive stiffness (restrictive or R-type); and (3) the combination of both (pseudo-normal or PN-type), to produce HFNEF. The effects of increasing systolic contractility are also considered. Model results showing ensuing heart failure and mechanisms involved are reported.

Methods

We employ our previously described H-CRS model with modified pulmonary compliances to better mimic normal pulmonary blood distribution. IR-type is modeled by changing the activation function of the left ventricle (LV), and R-type by increasing diastolic stiffness of the LV wall and septum. A 5^th-order Cash-Karp Runge-Kutta numerical integration method solves the model differential equations.

Results

IR-type and R-type decrease LV stroke volume, cardiac output, ejection fraction (EF), and mean systemic arterial pressure. Heart rate, pulmonary pressures, pulmonary volumes, and pulmonary and systemic arterial-venous O₂ and CO₂ differences increase. IR-type decreases, but R-type increases the mitral E/A ratio. PN-type produces the well-described, pseudo-normal mitral inflow pattern. All three types of LVDD reduce right ventricular (RV) and LV EF, but the latter remains normal or near normal. Simulations show reduced EF is partly restored by an accompanying increase in systolic stiffness, a compensatory mechanism that may lead clinicians to miss the presence of HF if they only consider LVEF and other indices of LV function. Simulations using the H-CRS model indicate that changes in RV function might well be diagnostic. This study also highlights the importance of septal mechanics in LVDD.

Conclusion

The model demonstrates that abnormal LV diastolic performance alone can result in decreased LV and RV systolic performance, not previously appreciated, and contribute to the clinical syndrome of HF. Furthermore, alterations of RV diastolic performance are present and may be a hallmark of LV diastolic parameter changes that can be used for better clinical recognition of LV diastolic heart disease.     

Sprint training improves contractility in postinfarction rat myocytes: role of Na+/Ca2+ exchange.

Previous studies in adult myocytes isolated from rat hearts 3-9 wk after myocardial infarction (MI) demonstrated abnormal contractility and decreased Na(+)/Ca(2+) exchanger (NCX1) activity. In addition, a program of high-intensity sprint training (HIST) instituted shortly after MI restored both contractility and NCX1 activity toward normal. The present study examined the hypotheses that reduced NCX1 activity caused abnormal contractility in myocytes isolated from sedentary (Sed) rat hearts 9-11 wk after coronary artery ligation and that HIST ameliorated contractile dysfunction in post-MI myocytes by increasing NCX1 activity. The approach was to upregulate NCX1 in MI-sedentary (MISed) myocytes and downregulate NCX1 in MI-exercised (MIHIST) myocytes by adenovirus-mediated gene transfer. Overexpression of NCX1 in MISed myocytes did not affect sarco(endo)plasmic reticulum Ca(2+)-ATPase and calsequestrin levels but rescued contractile abnormalities observed in MISed myocytes. That is, at 5 mM extracellular Ca(2+) concentration, the subnormal contraction amplitude in MISed myocytes (compared with Sham myocytes) was increased toward normal by NCX1 overexpression, whereas at 0.6 mM extracellular Ca(2+) concentration the supernormal contraction amplitude in MISed myocytes was lowered. Conversely, NCX1 downregulation by antisense in MIHIST myocytes abolished the beneficial effects of HIST on contraction amplitudes in MI myocytes. We suggest that decreased NCX1 activity may play an important role in contractile abnormalities in post-MI myocytes and that HIST ameliorated contractile dysfunction in post-MI myocytes partly by enhancing NCX1 activity.     

Assessment of left ventricular diastolic suction in dogs using wave-intensity analysis

Two apparently different types of mechanisms have emerged to explain diastolic suction (DS), that property of the left ventricle (LV) that tends to cause it to refill itself during early diastole independent of any force from the left atrium (LA). By means of the first mechanism, DS depends on decreased elastance [e.g., the relaxation time constant (tau)] and, by the second, end-systolic volume (V(LVES)). We used wave-intensity analysis (WIA) to measure the total energy transported by the backward expansion wave (I(W-)) during LV relaxation in an attempt to reconcile these mechanisms. In six anesthetized, open-chest dogs, we measured aortic, LV (P(LV)), LA (P(LA)), and pericardial pressures and LV volume by orthogonal ultrasonic crystals. Mitral velocity was measured by Doppler echocardiography, and aortic velocity was measured by an ultrasonic flow probe. Heart rate was controlled by pacing, V(LVES) by volume loading, and tau by isoproterenol or esmolol administration. I(W-) was found to be inversely related to tau and V(LVES). Our measure of DS, the energy remaining after mitral valve opening, I(W-DS), was also found to be inversely related to tau and V(LVES) and was approximately 10% of the total "aspirating" energy generated by LV relaxation (i.e., I(W-)). The size of the Doppler (early filling) E wave depended on I(W-DS) in addition to I(W+), the energy associated with LA decompression. We conclude that the energy of the backward-going wave generated by the LV during relaxation depends on both the rate at which elastance decreases (i.e., tau) and V(LVES). WIA provides a new approach for assessing DS and reconciles those two previously proposed mechanisms. The E wave depends on DS in addition to LA decompression.     

Effect of healthy aging on left ventricular relaxation and diastolic suction

Doppler ultrasound measures of left ventricular (LV) active relaxation and diastolic suction are slowed with healthy aging. It is unclear to what extent these changes are related to alterations in intrinsic LV properties and/or cardiovascular loading conditions. Seventy carefully screened individuals (38 female, 32 male) aged 21-77 were recruited into four age groups (young: <35; early middle age: 35-49; late middle age: 50-64 and seniors: ≥65 yr). Pulmonary capillary wedge pressure (PCWP), stroke volume, LV end-diastolic volume, and Doppler measures of LV diastolic filling were collected at multiple loading conditions, including supine baseline, lower body negative pressure to reduce LV filling, and saline infusion to increase LV filling. LV mass, supine PCWP, and heart rate were not affected significantly by aging. Measures of LV relaxation, including isovolumic relaxation time and the time constant of isovolumic pressure decay increased progressively, whereas peak early mitral annular longitudinal velocity decreased with advancing age (P < 0.001). The propagation velocity of early mitral inflow, a noninvasive measure of LV suction, decreased with aging with the greatest reduction in seniors (P < 0.001). Age-related differences in LV relaxation and diastolic suction were not attenuated significantly when PCWP was increased in older subjects or reduced in the younger subjects. There is an early slowing of LV relaxation and diastolic suction beginning in early middle age, with the greatest reduction observed in seniors. Because age-related differences in LV dynamic diastolic filling parameters were not diminished significantly with significant changes in LV loading conditions, a decline in ventricular relaxation is likely responsible for the alterations in LV diastolic filling with senescence.     

Assessment of left ventricular diastolic function by early diastolic mitral annulus peak acceleration rate: experimental studies and clinical application.

We sought to examine the hemodynamic determinants and clinical application of the peak acceleration rate of early (Ea) diastolic velocity of the mitral annulus by tissue Doppler. Simultaneous left atrial and left ventricular (LV) catheterization and Doppler echocardiography were performed in 10 dogs. Preload was altered using volume infusion and caval occlusion, whereas myocardial lusitropic state was altered with dobutamine and esmolol. The clinical application was examined in 190 consecutive patients (55 control, 41 impaired relaxation, 46 pseudonormal, and 48 restrictive LV filling). In addition, in 60 consecutive patients, we examined the relation between it and mean wedge pressure with simultaneous Doppler echocardiography and right heart catheterization. In canine studies, a significant positive relation was present between peak acceleration rate of Ea and transmitral pressure gradient only in the stages with normal or enhanced LV relaxation, but with no relation in the stages where the time constant of LV relaxation (tau) was > or =50 ms. Its hemodynamic determinants were tau, LV minimal pressure, and transmitral pressure gradient. In clinical studies, peak acceleration rate of Ea was significantly lower in patients with impaired LV relaxation irrespective of filling pressures (P < 0.001) and with similar accuracy to peak Ea velocity (area under the curve for septal and lateral peak acceleration rates: both 0.78) in identifying these patients. No significant relation was observed between peak acceleration rate and mean wedge pressure. Peak acceleration rate of Ea appears to be a useful index of LV relaxation but not of filling pressures and can be applied to identify patients with impaired LV relaxation irrespective of their filling pressures.     

T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice

Aberrant concentrations of cardiac extracellular matrix (ECM) fibrillar collagen cross-linking have been proposed to be an underlying cause of cardiac diastolic dysfunction however the role of the adaptive immune system in this process has yet to be investigated. Fibrillar collagen cross-linking is a product of the enzymatic activities of lysyl oxidase (LOX and LOXL-3) released by the cardiac fibroblast and possibly cardiac myocytes. Our hypothesis is that stimulation of the TH1 lymphocytes activates lysyl oxidase mediated ECM cross-linking and thereby alters left ventricular function. Three-month old C57BL/J female mice were treated with selective TH1 lymphocyte inducers — T-cell receptor Vβ peptides (TCR). After 6 weeks, candidate gene expression, tissue enzymatic activity, ECM composition, and left ventricular mechanics were quantified. Lymphocyte gene expression and cytokine assay revealed TH1 immune polarization with TCR administration which was associated with a 2.6-fold and 3.1-fold increase of LOX and LOXL3 gene expression, respectively, and a 55% increase in cardiac LOX enzymatic activity. The ECM cross-linked fibrillar collagen increased by 95% when compared with the control. Concurrently, there was a 33% increased ventricular stiffness, decreased cardiac output, and normal ejection fraction. These data implicate the TH1 lymphocyte in the pathogenesis of diastolic dysfunction which has potential clinical application in the pathogenesis of diastolic heart failure.     

Mechanics of left ventricular relaxation, early diastolic lengthening, and suction investigated in a mathematical model

We investigated the determinants of ventricular early diastolic lengthening and mechanics of suction using a mathematical model of the left ventricle (LV). The model was based on a force balance between the force represented by LV pressure (LVP) and active and passive myocardial forces. The predicted lengthening velocity (e') from the model agreed well with measurements from 10 dogs during 5 different interventions (R = 0.69, P < 0.001). The model showed that e' was increased when relaxation rate and systolic shortening increased, when passive stiffness was decreased, and when the rate of fall of LVP during early filling was decreased relative to the rate of fall of active stress. We first defined suction as the work the myocardium performed to pull blood into the ventricle. This occurred when contractile active forces decayed below and became weaker than restoring forces, producing a negative LVP. An alternative definition of suction is filling during falling pressure, commonly believed to be caused by release of restoring forces. However, the model showed that this phenomenon also occurred when there had been no systolic compression below unstressed length and therefore in the absence of restoring forces. In conclusion, relaxation rate, LVP, systolic shortening, and passive stiffness were all independent determinants of e'. The model generated a suction effect seen as lengthening occurring during falling pressure. However, this was not equivalent with the myocardium performing pulling work on the blood, which was performed only when restoring forces were higher than remaining active fiber force, corresponding to a negative transmural pressure.     

Computational modeling of left heart diastolic function: examination of ventricular dysfunction

A computational model that accounts for blood-tissue interaction under physiological flow conditions was developed and applied to a thin-walled model of the left heart. This model consisted of the left ventricle, left atrium, and pulmonary vein flow. The input functions for the model included the pulmonary vein driving pressure and time-dependent relationship for changes in chamber tissue properties during the simulation. The Immersed Boundary Method was used for the interaction of the tissue and blood in response to fluid forces and changes in tissue pathophysiology, and the fluid mass and momentum conservation equations were solved using Patankar's Semi-Implicit Method for Pressure Linked Equations (SIMPLE). This model was used to examine the flow fields in the left heart under abnormal diastolic conditions of delayed ventricular relaxation, delayed ventricular relaxation with increased ventricular stiffness, and delayed ventricular relaxation with an increased atrial contraction. The results obtained from the left heart model were compared to clinically observed diastolic flow conditions, and to the results from simulations of normal diastolic function in this model [1]. Cases involving impairment of diastolic function were modeled with changes to the input functions for fiber relaxation/contraction of the chambers. The three cases of diastolic dysfunction investigated agreed with the changes in diastolic flow fields seen clinically. The effect of delayed relaxation was to decrease the early filling magnitude, and this decrease was larger when the stiffness of the ventricle was increased. Also, increasing the contraction of the atrium during atrial systole resulted in a higher late filling velocity and atrial pressure. The results show that dysfunction can be modeled by changing the relationships for fiber resting-length and/or stiffness. This provides confidence in future modeling of disease, especially changes to chamber properties to examine the effect of local dysfunction on global flow fields.     

Frequency-dependent left ventricular performance in women and men

We aimed to determine whether sex differences in humans extend to the dynamic response of the left ventricular (LV) chamber to changes in heart rate (HR). Several observations suggest sex influences LV structure and function in health; moreover, this physiology is also affected in a sex-specific manner by aging. Eight postmenopausal women and eight similarly aged men underwent a cardiac catheterization-based study for force-interval relationships of the LV. HR was controlled by right atrial (RA) pacing, and LV +dP/dt(max) and volume were assessed by micromanometer-tipped catheter and Doppler echocardiography, respectively. Analysis of approximated LV pressure-volume relationships was performed using a time-varying model of elastance. External stroke work was also calculated. The relationship between HR and LV +dP/dt(max) was expressed as LV +dP/dt(max) = b + mHR. The slope (m) of the relationship was steeper in women compared with men (11.8 ± 4.0 vs. 6.1 ± 4.1 mmHg·s(-1)·beats(-1)·min(-1), P = 0.01). The greater increase in contractility in women was reproducibly observed after normalizing LV +dP/dt(max) to LV end-diastolic volume (LVVed) or by measuring end-systolic elastance. LVVed and stroke volume decreased more in women. Thus, despite greater increases in contractility, HR was associated with a lesser rise in cardiac output and a steeper fall in external stroke work in women. Compared with men, women exhibit greater inotropic responses to incremental RA pacing, which occurs at the same time as a steeper decline in external stroke work. In older adults, we observed sexual dimorphism in determinants of LV mechanical performance.     

Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits

Background

There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits.

Methods

A total of 30 rabbits were randomized into control group (CON, n?=?10), alloxan-induced diabetic group (DM, n?=?10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n?=?10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-β1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting.

Results

DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e′ ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (??dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway.

Conclusions

The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.

     

Sub-clinical left ventricular diastolic dysfunction in early stage of chronic obstructive pulmonary disease

Sub-clinical cardiac dysfunction may be significantly associated with chronic obstructive pulmonary disease (COPD) with a different degree of severity. In a cross-sectional design we aimed to evaluate the frequency of left ventricular diastolic dysfunction (LVdd) and its correlation with lung function, pulmonary arterial pressure and systemic inflammation in a selected population of COPD at an early stage of their disease. Fifty-five COPD patients with no clinical signs of cardiovascular dysfunction were recruited and compared to 40 matched healthy controls. All the subjects underwent pulmonary function testing, doppler echocardiography, and interleukin-6 blood sampling. Presence of LVdd was defined according to the significant change in both the ratio between early and late diastolic transmitral flow velocity (E/A ratio), isovolumetric relaxation time (IVRT), and deceleration time (DT). The frequency of LVdd was higher in the COPD group (70.9 percent) compared to controls (27.5 percent). In these patients decreased E/A ratio, and prolonged IVRT and DT clearly pointed to left ventricular filling impairment, a condition we found to be especially severe in those patients suffering from lung static hyperinflation as expressed by inspiratory-to-total lung capacity ratio (IC/TLC) <0.25. Circulating levels of interleukin-6 were also higher among COPD patients compared to controls. The results of the present study suggest that subclinical left ventricular filling impairment is frequently found in COPD patients at the earlier stage of the disease even in the absence of any other cardiovascular dysfunction. Doppler echocardiography may help the early identification of LVdd in COPD patients.     

Combining explosive and high-resistance training improves performance in competitive cyclists

In several recent studies, athletes experienced substantial gains in sprint and endurance performance when explosive training or high-intensity interval training was added in the noncompetitive phase of a season. Here we report the effect of combining these 2 types of training on performance in the competitive phase. We randomized 18 road cyclists to an experimental (n = 9) or control (n = 9) group for 4-5 weeks of training. The experimental group replaced part of their usual training with twelve 30-minute sessions consisting of 3 sets of explosive single-leg jumps (20 for each leg) alternating with 3 sets of high-resistance cycling sprints (5 x 30 seconds at 60-70 min(-1) with 30-second recoveries between repetitions). Performance measures, obtained over 2-3 days on a cycle ergometer before and after the intervention, were mean power in a 1- and 4-km time trial, peak power in an incremental test, and lactate-profile power and oxygen cost determined from 2 fixed submaximal workloads. The control group showed little mean change in performance. Power output sampled in the training sprints of the experimental group indicated a plateau in the training effect after 8-12 sessions. Relative to the control group, the mean changes (+/-90% confidence limits) in the experimental group were: 1-km power, 8.7% (+/-2.5%); 4-km power, 8.1% (+/-4.1%); peak power, 6.8% (+/-3.6); lactate-profile power, 3.7% (+/-4.8%); and oxygen cost, -3.0% (+/-2.6%). Individual responses to the training were apparent only for 4-km and lactate-profile power (standard deviations of 2.5% and 2.8%, respectively). The addition of explosive training and high-resistance interval training to the programs of already well-trained cyclists produces major gains in sprint and endurance performance, partly through improvements in exercise efficiency and anaerobic threshold.     

Neuromuscular training improves performance and lower-extremity biomechanics in female athletes

The purpose of this study was to examine the effects of a comprehensive neuromuscular training program on measures of performance and lower-extremity movement biomechanics in female athletes. The hypothesis was that significant improvements in measures of performance would be demonstrated concomitant with improved biomechanical measures related to anterior cruciate ligament injury risk. Forty-one female basketball, soccer, and volleyball players (age, 15.3 +/- 0.9 years; weight, 64.8 +/- 9.96 kg; height, 171.2 +/- 7.21 cm) underwent 6 weeks of training that included 4 main components (plyometric and movement, core strengthening and balance, resistance training, and speed training). Twelve age-, height-, and weight-matched controls underwent the same testing protocol twice 6 weeks apart. Trained athletes demonstrated increased predicted 1 repetition maximum squat (92%) and bench press (20%). Right and left single-leg hop distance increased 10.39 cm and 8.53 cm, respectively, and vertical jump also increased from 39.9 +/- 0.9 cm to 43.2 +/- 1.1 cm with training. Speed in a 9.1-m sprint improved from 1.80 +/- 0.02 seconds to 1.73 +/- 0.01 seconds. Pre- and posttest 3-dimensional motion analysis demonstrated increased knee flexion-extension range of motion during the landing phase of a vertical jump (right, 71.9 +/- 1.4 degrees to 76.9 +/- 1.4 degrees ; left, 71.3 +/- 1.5 degrees to 77.3 +/- 1.4 degrees ). Training decreased knee valgus (28%) and varus (38%) torques. Control subjects did not demonstrate significant alterations during the 6-week interval. The results of this study support the hypothesis that the combination of multiple-injury prevention-training components into a comprehensive program improves measures of performance and movement biomechanics.     

Stiffness- and relaxation-based quantitation of radial left ventricular oscillations: elucidation of regional diastolic function mechanisms.

Traditionally, global and longitudinal (i.e., regional) left ventricular (LV) diastolic function (DF) assessment has utilized features of transmitral Doppler E and A waves or Doppler tissue imaging (DTI)-derived mitral annular E' and A' waves, respectively. Quantitation of regional DF has included M-mode echocardiography-based approaches and strain and strain rate imaging (in selected imaging planes), while analysis of mitral annular "oscillations" has recently provided a new window into longitudinal (long-axis) function. The remaining major spatial degree of kinematic freedom during diastole, radial (short-axis) motion, has not been fully characterized, nor has it been exploited for its potential to provide radial LV stiffness (k'(rad)) and relaxation/damping (c'(rad)) indexes. Prior characterization of regional (longitudinal) DF used only annular E'- and A'-wave peak velocities or, alternatively, myocardial strain and strain rate. By kinematically modeling short-axis tissue motion as damped radial oscillation, we present a novel method of estimating k'(rad) and c'(rad) during early filling. As required by the (near) constant-volume property of the heart and tissue/blood incompressibility, in subjects (n = 10) with normal DF, we show that oscillation duration-determined longitudinal (k'(long) and c'(long)) and radial (k'(long) and c'(rad)) parameters are highly correlated (R = 0.69 and 0.92, respectively). Selected examples of diabetic and LV hypertrophic subjects yield radial (k'(long) and c'(rad)) parameters that differ substantially from controls. Results underscore the utility of the incompressibility-based causal relation between DTI-determined mitral annular long-axis (longitudinal mode) and short-axis (radial mode) oscillations in healthy subjects. Selected pathological examples provide mechanistic insight and illustrate the value and potential role of regional (longitudinal and radial) DF indexes in fully characterizing normal vs. impaired DF states.     

Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy

We have shown previously that the glucagon-like peptide-1 (GLP-1)-(7-36) amide increases myocardial glucose uptake and improves left ventricular (LV) and systemic hemodynamics in both conscious dogs with pacing-induced dilated cardiomyopathy (DCM) and humans with LV systolic dysfunction after acute myocardial infarction. However, GLP-1-(7-36) is rapidly degraded in the plasma to GLP-1-(9-36) by dipeptidyl peptidase IV (DPP IV), raising the issue of which peptide is the active moiety. By way of methodology, we compared the efficacy of a 48-h continuous intravenous infusion of GLP-1-(7-36) (1.5 pmol.kg(-1).min(-1)) to GLP-1-(9-36) (1.5 pmol.kg(-1).min(-1)) in 28 conscious, chronically instrumented dogs with pacing-induced DCM by measuring LV function and transmyocardial substrate uptake under basal and insulin-stimulated conditions using hyperinsulinemic-euglycemic clamps. As a result, dogs with DCM demonstrated myocardial insulin resistance under basal and insulin-stimulated conditions. Both GLP-1-(7-36) and GLP-1-(9-36) significantly reduced (P < 0.01) LV end-diastolic pressure [GLP-1-(7-36), 28 +/- 1 to 15 +/- 2 mmHg; GLP-1-(9-36), 29 +/- 2 to 16 +/- 1 mmHg] and significantly increased (P < 0.01) the first derivative of LV pressure [GLP-1-(7-36), 1,315 +/- 81 to 2,195 +/- 102 mmHg/s; GLP-1-(9-36), 1,336 +/- 77 to 2,208 +/- 68 mmHg] and cardiac output [GLP-1-(7-36), 1.5 +/- 0.1 to 1.9 +/- 0.1 l/min; GLP-1-(9-36), 2.0 +/- 0.1 to 2.4 +/- 0.05 l/min], whereas an equivolume infusion of saline had no effect. Both peptides increased myocardial glucose uptake but without a significant increase in plasma insulin. During the GLP-1-(9-36) infusion, negligible active (NH2-terminal) peptide was measured in the plasma. In conclusion, in DCM, GLP-1-(9-36) mimics the effects of GLP-1-(7-36) in stimulating myocardial glucose uptake and improving LV and systemic hemodynamics through insulinomimetic as opposed to insulinotropic effects. These data suggest that GLP-1-(9-36) amide is an active peptide.