Rate Of Left Ventricular Pressure Development Research Articles

Systolic Dysfunction of the Heart in Type 1 Diabetes Mellitus.

Impaired insulin synthesis is accompanied by hyperglycemia and the development of diabetic cardiomyopathy. Echocardiography and left-ventricular catheterization were employed for studying the contractile function of the left ventricle in 2 weeks after administration of streptozotocin (60 mg/kg). The results obtained by both methods were similar and indicated the development of systolic dysfunction with a 27% decrease in cardiac output. The invasive study showed that the maximum rate of left-ventricular pressure development, the contractility index, and systolic left-ventricular pressure were within the normal range, but the peak ejection rate was reduced by 28%. BP was normal, but the vascular stiffness index was increased by about 1.5 times and inversely correlated with the peak ejection rate (r=-0.69). The results showed that systolic dysfunction in type 1 diabetes model was due to reduced ejection from the left ventricle at normal rate of left-ventricular pressure development.

Compensatory Changes of the Diastole under Conditions of Inflow Restriction to the Heart.

This work was designed to study changes in the mechanical properties of rat myocardium during short-term (2-3 sec) compression of the lower vena cava. A catheter was inserted into the left ventricle, allowing simultaneous measurement of left-ventricular volume and pressure. The decrease in the left-ventricular end-diastolic volume caused by inflow restriction was accompanied by less pronounced decrease in the left-ventricular stroke volume and maximum rate of left-ventricular pressure development. This was coincided with accelerated relaxation and deeper fall of the minimum left-ventricular diastolic pressure. The lower was left-ventricular end-systolic volume, the greater was the degree of these changes. It is assumed that the "restoring force" that naturally appears under conditions of low filling of the left ventricle is determined by elastic N2B part of the titin molecule that is compressed during strong shortening of myofibrils and accelerates their return to the previous length during relaxation. As a result of better filling of the left ventricle, the heart can maintain left-ventricular stroke volume at the appropriate level.

The effect of allogeneic cardiac stem cells in left ventricular geometry and function in a rat model of myocardial infarction.

The development of heart failure after acute myocardial infarction (MI) was related to left ventricular (LV) pathological remodeling and dysfunction. Cardiac stem cells (CSCs) provided a new option to treat acute MI. This study was to investigate the effects of CSCs on structural and functional alteration in acute MI. Acute MI was induced in 20 Sprague-Dawley rats by ligation of the left anterior descending coronary artery. Two weeks after MI, animals were randomized into CSCs or control group. LV geometry and function were echocardiographically measured at baseline, 2, 4, and 6weeks after MI. After measuring hemodynamics at 6weeks after MI, hearts were harvested for tracing CSCs stained by PKH26 and testing expression of VEGF-α/TGF-β1 by RT-PCR and ELISA. Two weeks after MI, there were significant decreases in interventricular septal systolic and diastolic thickness (IVSTs/d), while increases in LV systolic and diastolic dimension (LVDs/d). Consequently, this contributed to decreases in ejection fraction (EF) and fractional shorting (FS). With the treatment of CSCs for 4weeks, significant better ejection fraction (EF) and fractional shorting (FS) were achieved in CSCs group accompanied by the reduction in LV systole and diastole dimension (LVDs/d). Besides, a significant improvement in the maximal rate of LV pressure development and decline (peak +dP/dt and -dP/dt, respectively) was observed. Moreover, significantly higher VEGF-α was expressed in CSCs group rather than TGF-β1. CSCs significantly prevented structural and functional deterioration after MI with increasing expression of VEGF-α.

Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice.

Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, is costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. We previously showed that a single intravenous (IV) injection of AAV8.UCn2 increases plasma UCn2 and left ventricular (LV) systolic and diastolic function for at least 7 months in normal mice. Here we test the hypothesis that IV delivery of AAV8.UCn2 increases function of the failing heart. Myocardial infarction (MI, by coronary ligation) was used to induce heart failure, which was assessed by echocardiography 3 weeks after MI. Mice with LV ejection fraction (EF) <25% received IV delivery of AAV8.UCn2 (5×1011 gc) or saline, and 5 weeks later echocardiography showed increased LV EF in mice that received UCn2 gene transfer (p=0.01). In vivo physiological studies showed a 2-fold increase in peak rate of LV pressure development (LV +dP/dt; p<0.0001) and a 1.6-fold increase in peak rate of LV pressure decay (LV −dP/dt; p=0.0007), indicating increased LV systolic and diastolic function in treated mice. UCn2 gene transfer was associated with increased peak systolic Ca2+ transient amplitude and rate of Ca2+ decline and increased SERCA2a expression. In addition, UCn2 gene transfer reduced Thr286 phosphorylation of Cam kinase II, and increased expression of cardiac myosin light chain kinase, findings that would be anticipated to increase function of the failing heart. We conclude that a single IV injection of AAV8.UCn2 increases function of the failing heart. The simplicity of IV injection of a vector encoding a gene with beneficial paracrine effects to increase cardiac function is an attractive potential clinical strategy.

Clinical evaluation of heart failure: agreement among tests (648.4)

Congestive heart failure (CHF) is the most common cause of nonelective hospitalization of subjects over the age of 65 in the US. CHF clinical status is evaluated by ejection fraction (EF), symptoms, and exercise tolerance. Although difficult to apply clinically, a gold standard of left ventricular (LV) function is the rate of LV pressure development (+dP/dt). We tested the hypothesis that EF, symptoms, and exercise treadmill test (ETT) duration would correlate with each other and with +dP/dt. Subjects with symptomatic CHF (62 ± 2 yo; EF 30 ± 2%; n = 27) underwent measurement of EF, symptoms (Kansas City Cardiomyopathy Questionnaire Score, KCCQS), ETT duration, and +dP/dt (via cardiac catheterization). EF and +dP/dt were measured before and during dobutamine infusion. Results were compared using Pearson’s correlation analysis. Overall, tests correlated poorly. The only significant correlations were between KCCQS and +dP/dt. KCCQS correlated with both basal +dP/dt (r = ‐0.47, p = 0.021) and stimulated +dP/dt (r = ‐0.63, p &lt; 0.001). KCCQS and stimulated +dP/dt were correlated regardless of ischemic (r = ‐0.69, p = 0.026) or non‐ischemic etiology (r = ‐0.56, p = 0.038).Conclusion: EF, ETT, and symptoms are not correlated in CHF patients. Using +dP/dt as a gold standard, EF and ETT do not correlate as well with LV function as symptoms do. EF and ETT may be less effective measures of LV function than commonly believed.Grant Funding Source: Supported by National Institutes of Health grants (P01 HL66941, HL088426, HL081741, and HL107200)

FKBP12.6 overexpression does not protect against remodelling after myocardial infarction

Reducing the open probability of the ryanodine receptor (RyR) has been proposed to have beneficial effects in heart failure. We investigated whether conditional FKBP12.6 overexpression at the time of myocardial infarction (MI) could improve cardiac remodelling and cell Ca(2+) handling. Wild-type (WT) mice and mice overexpressing FKBP12.6 (Tg) were studied on average 7.5 ± 0.2 weeks after MI and compared with sham-operated mice for in vivo, myocyte function and remodelling. At baseline, unloaded cell shortening in Tg was not different from WT. The [Ca(2+)](i) transient amplitude was similar, but sarcoplasmic reticulum (SR) Ca(2+) content was larger in Tg, suggesting reduced fractional release. Spontaneous spark frequency was similar despite the increased SR Ca(2+) content, consistent with a reduced RyR channel open probability in Tg. After MI, left ventricular dilatation and myocyte hypertrophy were present in both groups, but more pronounced in Tg. Cell shortening amplitude was unchanged with MI in WT, but increased with MI in Tg. The amplitude of the [Ca(2+)](i) transient was not affected by MI in either genotype, but time to peak was increased; this was most pronounced in Tg. The SR Ca(2+) content and Na(+)- Ca(2+) exchanger function were not affected by MI. Spontaneous spark frequency was increased significantly after MI in Tg, and larger than in WT (at 4 Hz, 2.6 ± 0.4 sparks (100 μm)(-1) s(-1) in Tg MI versus 1.6 ± 0.2 sparks (100 μm)(-1) s(-1) in WT MI; P < 0.05). We conclude that FKPB12.6 overexpression can effectively reduce RyR open probability with maintained cardiomyocyte contraction. However, this approach appears insufficient to prevent and reduce post-MI remodelling, indicating that additional pathways may need to be targeted.

Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts

Positive inotropic drugs may attenuate or exacerbate the deleterious effects of ischemia and reperfusion (IR) injury on excitation-contraction coupling in hearts. We 1) quantified the phase-space relationship between simultaneously measured myoplasmic Ca2+ concentration ([Ca2+]) and isovolumetric left ventricular pressure (LVP) using indexes of loop area, orientation, and position; and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca2+] and rate of LVP development in intact hearts during administration of positive inotropic drugs before and after global IR injury. Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer solution (37 degrees C, 1.25 mM CaCl2). [Ca2+] was measured ratiometrically by indo 1 fluorescence by using a fiber-optic probe placed at the left ventricular free wall. LVP was measured by using a saline-filled latex balloon and transducer. Drugs were infused for 2 min, 30 min before, and for 2 min, 30 min after 30-min global ischemia. IR injury worsened Ca2+-contraction coupling, as seen from decreased orientation and repositioning of the loop rightward and downward and reduced cooperativity of contraction and relaxation with or without drugs. Dobutamine (4 microM) worsened, whereas dopamine (8 microM) improved Ca2+-contraction coupling before and after IR injury. Dobutamine and dopamine improved cooperativity of contraction and relaxation after IR injury, whereas only dopamine increased cooperativity of relaxation before IR injury. Digoxin (1 microM) improved Ca2+-contraction coupling and cooperativity of contraction after but not before ischemia. Levosimendan (1 microM) did not alter Ca2+-contraction coupling or cooperativity, despite producing concomitant increases in contractility, relaxation, and Ca2+ flux before and after ischemia. Dynamic indexes based on LVP-[Ca2+] diagrams (area, shape, position) can be used to identify and measure alterations in Ca2+-contraction coupling during administration of positive inotropic drugs in isolated hearts before and after IR injury.

Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures

Transgenic animal models have provided a vital insight into the pathogenesis of cardiovascular disease, but functional cardiac assessment is often limited by high heart rates and small heart size. We hypothesized that in the presence of concentric left ventricular (LV) hypertrophy (LVH), load-sensitive measures of contractility may be misinterpreted as overestimating global cardiac function, because the normal function of excess sarcomeres may displace a greater volume of blood during contraction. Conductance catheter technology was used to evaluate pressure-volume (P-V) relationships as a load-insensitive method of assessing cardiac function in vivo in 18-wk-old heterozygous (mRen-2)27 transgenic rats (a model of LVH), compared with age-matched Sprague-Dawley (SD) controls. Anesthetized animals underwent echocardiography followed by P-V loop analysis. Blood pressure, body weight, and heart rate were higher in the Ren-2 rats (P < 0.05). Load-sensitive measures of systolic function, including fractional area change, fractional shortening, ejection fraction, and positive peak rate of LV pressure development, were greater in the Ren-2 than control animals (P < 0.05). Load-insensitive measures of systolic function, including the preload recruitable stroke work relationship and the end-systolic P-V relationship, were not different between Ren-2 and SD rats. Regional wall motion assessed by circumferential shortening velocity suggested enhanced circumferential fiber contractility in the Ren-2 rats (P = 0.02), but tissue Doppler imaging, used to assess longitudinal function, was not different between groups. Although conventional measures suggested enhanced systolic function in the Ren-2 rat, load-insensitive measures of contractility were not different between Ren-2 and SD animals. These findings suggest that the normal range of values for load-sensitive indexes of contractility needs to be altered according to the degree of LVH. To accurately identify changes in systolic function, we suggest that a combination of echocardiography with assessment of load-insensitive measures be used routinely.

The role of toxic oxygen metabolites in a young model of thermal injury.

Production of oxygen-free radicals has been proposed as one pathophysiologic mechanism for postburn cardiac contractile dysfunction in adults. To examine this hypothesis in young subjects, we studied the cardiac effects of polyethylene glycol-superoxide dismutase (PEG-SOD) and PEG-catalase (PEG-CAT), each given as 20 U/g of body weight with fluid resuscitation (Parkland formula), after a third-degree burn constituting 33% of the total body surface area in young (6- to 7-day old) guinea pigs (group 3, n = 12). Fluid-treated burns without scavenger therapy (group 2, n = 15) and sham burn controls (group 1, n = 15) were included. Animals were killed 24 hours postburn, and hearts were studied in vitro (Langendorff). Compared with sham burn controls, fluid-treated burns (group 2) had significant cardiac dysfunction as indicated by a lower peak systolic left ventricular (LV) pressure (LVP: 67 +/- 2 vs. 57 +/- 4 mm Hg, p = 0.01, mean +/- SEM), maximal rate of LV pressure development (+dP/dt max: 1169 +/- 45 vs. 988 +/- 45 mm Hg/second, p = 0.01), and fall (-dP/dt max: 1109 +/- 45 vs. 919 +/- 49 mm Hg/second, p = 0.01). In addition, LV function curves calculated for group 2 were shifted downward and to the right of those calculated for sham burn controls in the direction of contractile depression, p = 0.01. PEG-SOD/PEG-CAT treatment in burns did not significantly improve LVP (60 +/- 5 mm Hg), but scavenger therapy improved +/-dP/dt max values (1112 +/- 74 and 988 +/- 98 mm Hg/second, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of left ventricular relaxation in isolated ejecting heart by endogenous nitric oxide.

Nitric oxide (NO) modulates myocardial contractile behavior in several isolated preparations, e.g., cardiac myocytes and papillary muscles, via elevation of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). We have recently reported that the exogenous NO donor, sodium nitroprusside, selectively modulates left ventricular (LV) relaxation in the isolated ejecting guinea pig heart, independent of coronary flow. We now report the effects of endogenously released NO on LV performance in this preparation (constant heart rate and loading). Both bradykinin (1 nM, n = 6) and substance P (100 nM, n = 6) accelerated early LV relaxation (maximum change in time constant, tE, -10.5 +/- 1.6 and -13.4 +/- 2.1%, respectively; both P < 0.05), without significantly altering early systolic parameters (e.g., rate of LV pressure development). These effects were inhibited by hemoglobin (P < 0.05; n > or = 6), which inactivates NO. Bradykinin (100 nM, n = 10) had an additional negative inotropic effect, which was not inhibited by hemoglobin. Neither agonist altered relaxation in isolated papillary muscles. These data suggest that endogenous NO, probably released from coronary microvascular endothelial cells, modulates LV relaxation in the intact heart.

Left ventricular functional capacity in the endurance-trained rodent

Cardiac myosin P-light chain phosphorylation [P-LC(P)] has been proposed to augment myocardial force production. This study was undertaken to examine the potential for cardiac myosin P-LC(P) for both equivalent heart rate and work load in exercising endurance-trained and nontrained rodents. A 10-wk training protocol elicited a significant reduction in submaximal running O2 uptake while enhancing peak O2 uptake (-17 and 10%, respectively, P less than 0.05). Left ventricular functional index during submaximal exercise, obtained with a high-fidelity Millar ultraminiature pressure transducer, indicated that the trained animals were able to maintain peak left ventricular pressure (LVP) in comparison to their sedentary counterparts, even though both heart rate and rate of LVP development were significantly reduced (P less than 0.05). When expressed on the basis of equivalent submaximal heart rate, peak LVP was augmented in the trained animals. Cardiac myosin P-LC(P) was examined under two conditions known to produce disparate responses in trained vs. sedentary animals. For an equivalent work load, we observed parallel increases in P-LC(P) (20%) and systolic pressure (17%) in both groups, even though the trained animals exhibited significantly lower heart rates (P less than 0.05). For an equivalent heart rate, training evoked a significant increase in systolic pressure (26%, P less than 0.05) and caused a slight increase in P-LC(P) relative to the nontrained controls. Cardiac myosin adenosinetriphosphatase was reduced approximately 10% in the trained animals (P less than 0.05), commensurate with a 2.0-fold increase in the V3 (low adenosinetriphosphatase) isomyosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic effects of prenalterol in patients with severe congestive heart failure--NYHA III-IV.

In 12 patients with severe congestive heart failure due to ischaemic heart disease (n = 6) and due to congestive cardiomyopathy (n = 6) the haemodynamic effects of a new beta 1-agonist, prenalterol, were studied. Left ventricular (LV) function was studied before and 20 min after infusion of 12 mg prenalterol. Heart rate was kept constant by atrial pacing at a rate of 100 min-1 unless intrinsic heart rate exceeded it. As a sign of positive inotropic support, prenalterol enhanced peak rate of LV pressure development (dP/dt) from 1160 +/- 100 mm Hg/s to 1590 +/- 190 mm Hg/s (p less than 0.005). In the mean LV end-diastolic and end-systolic volume determined by cineventriculography and two-dimensional echocardiography decreased. LV stroke work index measured with both methods increased with 4 ml/m and 5 ml/m, respectively (p less than 0.02). LV ejection fraction was improved by 6% and 8% (p less than 0.005). Increase of peak fall of left ventricular pressure (dP/dt) (1050 +/- 60 mm Hg/s to 1270 +/- 100 mm Hg/s, p less than 0.005) and shortening of time constant (T) of pressure fall from 64.5 +/- 5.0 ms to 44.5 +/- 6.0 ms (p less than 0.005) demonstrated the improved LV relaxation. Analysis of LV volume and myocardial compliance revealed decrease of left ventricular stiffness. Thus, LV filling pressure was reduced from 22.1 +/- 4 mm Hg to 14 +/- 3.5 mm Hg (p less than 0.001). Pressure volume analysis showed a significant increase of LV power and work, as well as a slight decrease of wall stress. Our study could demonstrate, even in patients with severe heart failure, a sustained positive inotropic effect of prenalterol leading to an improved left ventricular contractility, relaxation and compliance. LV power and work was enhanced. The increase of oxygen demand seemed to be counterbalanced by an improved perfusion of particularly subendocardial layers indicated by an increased transmyocardial pressure gradient.