Rapid Left Ventricular Pacing Research Articles

Direct Rapid Left Ventricular Wire Pacing during Balloon Aortic Valvuloplasty.

Background: Rapid ventricular pacing is mandatory for optimal balloon positioning during aortic valvuloplasty (BAV) in patients with severe aortic stenosis. We aimed to assess the safety and efficacy of direct left ventricular (LV) guidewire pacing in comparison with regular pacing induced by temporary pacemaker (PM) placement in the right ventricle. Methods: Direct rapid LV pacing was provided with a 0.035″ guidewire. Baseline clinical characteristics, echocardiographic and procedural data, as well as complication rates, were compared between the two groups. Results: A total of 202 patients undergoing BAV were enrolled (49.5% with direct LV guidewire pacing). The pacing success rate was 100%. In the direct LV guidewire pacing group, we found a lower radiation dose, shorter fluoroscopy and overall procedural time (0.16 vs. 0.28 Gy, p = 0.02; 5.4 vs. 10.3 min, p = 0.01; 17 vs. 25 min, p = 0.01; respectively). In addition, the complication rate was lower in that group (cardiac tamponades, vascular access site complications, blood transfusions rate, and in-hospital mortality: 0% vs. 3.9%; 4.0% vs. 15.7%; 2.0% vs. 12.7%; 2.0% vs. 9.8%, p = 0.01 for all, respectively). Conclusions: Direct rapid LV guidewire pacing is a simple, safe and effective option for BAV with a reduced complication rate compared to a temporary PM placed in the right ventricle.

Characterization of 3-dimensional papillary muscle displacement in in vivo ovine models of ischemic/functional mitral regurgitation

ObjectivePapillary muscle (PM) displacement contributes to ischemic/functional mitral regurgitation (IMR/FMR). The displaced PMs pull the mitral leaflets into the left ventricle (ie, toward the apex) thus hampering leaflet coaptation. Intuitively apical leaflet tethering results from apical PM displacement. The 3-dimensional directions of PM displacement are, however, incompletely characterized. MethodsData from in vivo ovine models of IMR (6-8 weeks of posterolateral infarction, n = 12) and FMR (9-21 days of rapid left ventricular pacing, n = 11) were analyzed. All sheep had radiopaque markers implanted on the anterior and posterior PM (PPM) tips, around the mitral annulus, and on the left ventricular apex. To explore 3-dimensional PM displacement directions, differences in marker coordinates were calculated at end-systole before and during IMR/FMR using a right-handed coordinate system centered on the mitral annular “saddle horn” with the y-axis passing through the apical marker. ResultsNo apical PM displacement was observed during either IMR or FMR. The anterior PM displaced laterally during FMR. Posterolateral PPM displacement was observed during IMR and FMR. ConclusionsExperimental in vivo ovine models suggest posterolateral PPM displacement as a predominant pathomechanism leading to apical leaflet tethering during IMR/FMR.

Abstract 265: Identification of MicroRNA in an Ovine Model of Heart Failure

Introduction: The sheep ( Ovis aries ) provides a large animal model in cardiovascular research including heart failure (HF). However, microRNA (miR) related work in the sheep model has been limited due to a paucity of information regarding oar-miR. The aim of this study was to identify novel oar-miRs in myocardium and examine their regulation in HF and HF recovery. Methods: Heart tissue was harvested from sheep undergoing 1. HF induced by rapid left ventricular (LV) pacing at 225bpm for 14 days, 2. HF recovery (HF-R) after discontinuation of pacing for an additional 14 days and 3. Sham. LV miRs were examined using next generation deep sequencing (NGS), miR array and stem-loop qPCR. Sequences were aligned with miRBase v20.0 and mapped to ovine genome and miRBase Mature BLAST search engine. Plasma was collected to assess natriuretic peptides (ANP and BNP). Results: Three miR libraries were generated from NGS and a total of 619 miRs were detected. Of these, 93 were oar-miRs; 49 novel miRs (high confidence) mapped to ovine genome and perfectly aligned to mature miRs in other organisms (miRBase v20.0); 69 putative novel miRs (high confidence) that mapped to ovine genome and aligned partially to mature miRs of other species in miRBase v20.0; 168 miRs (low confidence) that mapped to ovine genome but unaligned to any known mature miRs; and 240 miRs (low confidence) that were unmapped to the sheep genome but aligned to either miRBase mature hsa-/mmu-/rno-miRs. Plasma BNP and ANP increased 19-folds and 18- folds respectively in HF, and returned to baseline in HF-R. MiR levels in HF model were examined using miR array. About 1000 miRs were detected from array and at least 301 of them were overlapped with NGS data. Using miR array profiling followed by stem-loop qPCR validation, we found that myocardial enriched miR-133b-3p, miR-208b-3p, miR-21-5p and miR-125a-5p, -125b-5p, -126-3p, -210-3p, and 29a-3p were significantly upregulated in HF (p<0.05 vs. Sham). All trended downwards towards baseline levels during recovery (HF-R) but only miR-210 was significant (p<0.001 vs. HF). Conclusion: We identified 118 novel oar-miRs with high confidence and 408 potential oar-miRs, which is a solid foundation for miR function studies using sheep models. We also identified miR changes in HF and HF-R.

The Impact of Rapid Left Ventricular Pacing during Pediatric Aortic Valvuloplasty on Postprocedural Aortic Insufficiency.

This study aims to determine efficacy and safety of rapid left ventricular pacing (RLVP) during balloon aortic valvuloplasty and effect on development of postprocedural aortic insufficiency (AI) in children. This is a retrospective comparison of 56 children (mean age 18.3 month; 1 day-15 years of age) who underwent valvuloplasty by using RLVP with standard method (without pacing) during same time period (74 children; mean age 12.6 month; 1 day-18 years of age). The systolic valvular gradient decreased from a mean 67 ± 20.4 mm Hg (26-120 mm Hg) before the procedure to a mean 27.6 ± 17.8 mm Hg (0-120 mm Hg) after the procedure. Procedure failed in two of the patients (3.6%) who received the RLVP; only two patients developed severe AI. Among those patients who underwent the standard method procedure failed in 6 patients (8.3%), whereas severe AI was seen in 15 (20.2%). RLVP decreased the incidence of postprocedure severe AI significantly (P < .01) but it had no effect on the gradient reduction of the procedure (P > .05). RLVP did not change the procedure duration, but decreased the duration of fluoroscopy significantly (P < .01). RLVP can be used effectively and safely for pacing during balloon aortic valvuloplasty procedures in all age groups; it decreases procedural failure rate, eases the procedure and prevents the development of AI through the stabilization of the balloon.

Improved Hemodynamics with the Use of Prophylactic Infusion of Epinephrine and/or Norepinephrine during Transcatheter Aortic Valve Replacement (TAVR)

Background: Transcatheter Aortic Valve Replacement (TAVR) is a new minimally-invasive surgical procedure in which a bioprosthetic aortic valve is placed via a small skin incision in the groin, over either the left or right iliac artery. TAVR was recently approved by the FDA as a treatment option for aortic stenosis in patients who may be too frail to undergo open heart surgery. Anesthetic management of TAVR is complicated by the fact that rapid left ventricular pacing (to at least 180 beats per minute) is required at multiple points throughout the procedure. Aim: This rapid pacing creates a profound pathophysiologic stress on the heart, sometimes leading to severe left ventricular dysfunction and resultant complete hemodynamic collapse. We report that the use of prophylactic infusion of epinephrine and/or norepinephrine in patients undergoing TAVR results in improved recovery from rapid pacing as reflected by intraoperative trends in systolic systemic blood pressure and systolic pulmonary arterial pressure. Cases: Here we report three cases. During the first of these, we reacted to intraoperative hemodynamic changes by administering boluses of vasoactive medications as needed. During the other two cases, we preemptively infused vasopressors to facilitate a more rapid recovery from some of the hemodynamic disturbance associated with either TAVR or rapid pacing. Conclusion: The two patients in this series who were managed with a preemptive strategy had higher ratios of systemic systolic blood pressure to pulmonary arterial systolic blood pressure at the end of the case than did the patient who was managed reactively. This suggests that the preemptive strategy may lead to decreased left ventricular impairment and improved overall cardiac function after TAVR.

Hemodynamic, Hormonal, and Renal Effects of (Pro)Renin Receptor Blockade in Experimental Heart Failure

The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administration produced a dose-dependent decrease in plasma renin activity (P=0.004), with similar trends observed for plasma angiotensin II and aldosterone (P=0.093 and P=0.088, respectively). Circulating natriuretic peptides, endothelin-1, and catecholamine levels were unchanged. HRP also induced a reduction in plasma sodium concentrations relative to control (P=0.024), a natriuresis (P=0.046), and a tendency for creatinine excretion and clearance to improve. (P)RR antagonism in experimental HF resulted in cardiovascular and renal benefits in association with inhibition of the renin-angiotensin-aldosterone system. These findings suggest that (P)RR contributes to pressure/volume regulation in HF and identifies the receptor as a potential therapeutic target in this disease.

The contribution of reactive oxygen species and p38 mitogen‐activated protein kinase to myofilament oxidation and progression of heart failure in rabbits

The formation of reactive oxygen species (ROS) is increased in heart failure (HF). However, the causal and mechanistic relationship of ROS formation with contractile dysfunction is not clear in detail. Therefore, ROS formation, myofibrillar protein oxidation and p38 MAP kinase activation were related to contractile function in failing rabbit hearts. Three weeks of rapid left ventricular (LV) pacing reduced LV shortening fraction (SF, echocardiography) from 32 +/- 1% to 13 +/- 1%. ROS formation, as assessed by dihydroethidine staining, increased by 36 +/- 8% and was associated with increased tropomyosin oxidation, as reflected by dimer formation (dimer to monomer ratio increased 2.28 +/- 0.66-fold in HF vs. sham, P < 0.05). Apoptosis (TdT-mediated dUTP nick end labelling staining) increased more than 12-fold after 3 weeks of pacing when a significant increase in the phosphorylation of p38 MAP kinase and HSP27 was detected (Western blotting). Vitamins C and E abolished the increases in ROS formation and tropomyosin oxidation along with an improvement of LVSF (19 +/- 1%, P < 0.05 vs. untreated HF) and prevention of apoptosis, but without modifying p38 MAP kinase activation. Inhibition of p38 MAP kinase by SB281832 counteracted ROS formation, tropomyosin oxidation and contractile failure, without affecting apoptosis. Thus, p38 MAP kinase activation appears to be upstream rather than downstream of ROS, which impacts on LV function through myofibrillar oxidation. p38 MAP kinase inhibition is a potential target to prevent or treat HF.

Urocortin 1 administration from onset of rapid left ventricular pacing represses progression to overt heart failure

Urocortin 1 (Ucn1) may be involved in the pathophysiology of heart failure (HF), but the impact of Ucn1 administration on progression of the disease is unknown. The aim of this study was to investigate the effects of Ucn1 in sheep from the onset of cardiac overload and during the subsequent development of HF. Eight sheep underwent two 4-day periods of HF induction by rapid left ventricular pacing (225 beats/min) in conjunction with continuous infusions of Ucn1 (0.1 microg.kg(-1).h(-1) iv) and a vehicle control (0.9% saline). Compared with control, Ucn1 attenuated the pacing-induced decline in cardiac output (2.43 +/- 0.46 vs. 3.70 +/- 0.89 l/min on day 4, P < 0.01) and increases in left atrial pressure (24.9 +/- 1.0 vs. 11.9 +/- 1.1 mmHg, P < 0.001) and peripheral resistance (38.7 +/- 9.4 vs. 25.2 +/- 6.1 mmHg.l(-1).min, P < 0.001). Ucn1 wholly prevented increases in plasma renin activity (4.02 +/- 1.17 vs. 0.87 +/- 0.1 nmol.l(-1).h(-1), P < 0.001), aldosterone (1,313 +/- 324 vs. 413 +/- 174 pmol/l, P < 0.001), endothelin-1 (3.8 +/- 0.5 vs. 2.0 +/- 0.1 pmol/l, P < 0.001), and vasopressin (10.8 +/- 4.1 vs. 1.8 +/- 0.2 pmol/l, P < 0.05) during pacing alone and blunted the progressive increases in plasma epinephrine (2,132 +/- 697 vs. 1,250 +/- 264 pmol/l, P < 0.05), norepinephrine (3.61 +/- 0.73 vs. 2.07 +/- 0.52 nmol/l, P < 0.05), and atrial (P < 0.05) and brain (P < 0.01) natriuretic peptide levels. Ucn1 administration also maintained urine sodium excretion (0.75 +/- 0.34 vs. 1.59 +/- 0.50 mmol/h on day 4, P < 0.05) and suppressed pacing-induced declines in creatinine clearance (P < 0.05). These findings indicate that Ucn1 treatment from the onset of cardiac overload has the ability to repress the ensuing hemodynamic and renal deterioration and concomitant adverse neurohumoral activation, thereby delaying the development of overt HF. These data strongly support a use for Ucn1 as a therapeutic option early in the course of the disease.

RETRACTED: Carvedilol restore cardiac calcium release channel structure and function in heart failure

The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. In the present study, we used a well-characterized canine model of pacing-induced HF to show that Carvedilol both restores the normal stoichiometry of the RyR2 macromolecular complex and normalizes the function of the channel. A rapid cardiac pacing regimen that results in severe HF was used. Animals were assigned to 1 of 4 groups: (1) normal without heart instrumentation (n=6), (2) HF (n=6), (3) HF treated with Carvedilol (n=6), and (4) normal without heart instrumentation plus Carvedilol (n=6). In groups 2 and 3, after baseline measurements had been obtained, rapid left ventricular (LV) pacing was initiated at 210 bpm for 3 weeks, followed by an additional week of pacing at 240 bpm with an external pacemaker. Carvedilol was begun 2 weeks after initiation of pacing and continued for 2 weeks. Carvedilol was begun 2 weeks after baseline measurement for the control dogs with heart instrumentation. SR membranes were prepared from canine ventricular tissue, protein concentration was measured by Bradford assay. Here, we show that systemic oral administration of Carvedilol reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure. These results may, in part, explain the improved cardiac function observed in heart failure patients treated with Carvedilol.

Inhibition of Na+/H+‐exchanger with sabiporide attenuates the downregulation and uncoupling of the myocardial β‐adrenoceptor system in failing rabbit hearts

Chronic heart failure (HF) is characterized by left ventricular (LV) structural remodeling, impaired function, increased circulating noradrenaline (NA) levels and impaired responsiveness of the myocardial beta-adrenoceptor (betaAR)-adenylyl cyclase (AC) system. In failing hearts, inhibition of the sodium/proton-exchanger (NHE)-1 attenuates LV remodeling and improves LV function. The mechanism(s) involved in these cardioprotective effects remain(s) unclear, but might involve effects on the impaired betaAR-AC system. Therefore, we investigated whether NHE-1 inhibition with sabiporide (SABI; 30 mg kg(-1) day(-1) p.o.) might affect myocardial betaAR density and AC activity in relation to changes in LV end-diastolic diameter (LVEDD) and LV systolic fractional shortening (LVS-FS) after 3 weeks of rapid LV pacing in rabbits. After 3 weeks of rapid LV pacing LVEDD was significantly increased (Shams 17+/-0.2 mm, n=9 vs 3 wksHF 20+/-0.5 mm, n=8; P<0.05) and LVS-FS decreased (Shams 31+/-1%, n=9 vs 3 wksHF 10+/-1%, n=8; P<0.05). SABI treatment significantly improved LV function independent of whether rabbits were treated after 1 week of pacing (3 wksHF+2 wksSABI (n=7): LVEDD 18+/-1 mm; LVS-FS 16+/-4%) or before pacing (3 wksHF+3wksSABI (n=9): LVEDD 18+/-1 mm; LVS-FS 18+/-6%). After 3 weeks of rapid LV pacing, SABI treatment significantly attenuated increases in serum NA content (Shams 0.83+/-0.19, 3 wksHF 2.68+/-0.38, 3 wksHF+2 wksSABI 1.22+/-0.32, 3 wksHF+3wksSABI 1.38+/-0.33 ng ml(-1)). Moreover, betaAR density (Shams 64+/-5, 3 wksHF 38+/-3, 3 wksHF+2 wksSABI 48+/-4, 3 wksHF+3 wksSABI 55+/-3 fmol mg(-1) protein) and responsiveness (isoprenaline-stimulated AC activity. (Shams 57.6+/-4.9, 3 wksHF 36.3+/-6.0, 3 wksHF+2 wksSABI 56.9+/-6.0, 3 wksHF+3 wksSABI 54.5+/-4.8 pmol cyclic AMP mg(-1) protein(-1) min(-1)) were significantly improved in SABI-treated rabbits. From the present data we cannot address whether the improved betaAR-AC system permitted improved LV function and/or whether the improved LV function resulted in less activation of the sympathetic nervous system and by this in a reduced stimulation of the betaAR-AC system. Accordingly, additional studies are needed to fully establish the cause-and-effect relationship between NHE-1 inhibition and the restoration of the myocardial betaAR system.

Effects of ischemia on myocardial function during rapid left ventricular pacing

Introduction Coronary artery disease is often accompanied with deterioration in left ventricular function. Left ventricular pacing has been shown to improve cardiac function in chronic heart failure. However, data are limited about left ventricular pacing during acute ischemia. Therefore, we studied the effects of acute myocardial ischemia on myocardial function during left ventricular pacing. Methods In 8 anesthetized dogs, the left ventricle was rapidly paced (180 bpm) from a basolateral and apicoseptal site during normal perfusion and mild and severe ischemia of the left anterior descending coronary artery. Effects on myocardial function were measured at each level of ischemia before and during pacing. Results Significant differences ( p < 0.05) between basolateral and apicoseptal pacing were found for segmental shortening (12.1 ± 1.6 vs. 10.8 ± 1.6%), and QRS duration (77.3 ± 4.1 vs. 85.7 ± 3.8 ms) at normal coronary perfusion. During mild ischemia, significant differences ( p < 0.05) were seen for myocardial contractility d P/d t max (1277 ± 197 vs. 1158 ± 156 mm Hg/s), segmental shortening (10.3 ± 1.9 vs. 8.1 ± 1.7%), left ventricular end-systolic pressure (76.9 ± 7.5 vs. 69.6 ± 7.9 mm Hg), and QRS duration, and for myocardial contractility d P/d t max (1033 ± 209 vs. 917 ± 207 mm Hg/s) and left ventricular end-systolic pressure (69.2 ± 13.5 vs. 62.2 ± 15.0 mm Hg) during severe ischemia. There were no significant differences in coronary blood flow during pacing from both sites. Conclusions During acute myocardial ischemia, depression of left ventricular function was lowest, when pacing from a left ventricular basolateral site. The effects of rapid left ventricular pacing were amplified by reduced coronary perfusion pressures. The choice of pacing site did not relevantly influence coronary blood flow.

Haemodynamic changes during halothane, sevoflurane and desflurane anaesthesia in dogs before and after the induction of severe heart failure

The effects of desflurane and sevoflurane on the failing myocardium are still uncertain. We investigated the effects of different concentrations of sevoflurane, desflurane and halothane in dogs with pacing induced chronic heart failure. Global (left ventricular pressure, left ventricular dP/dt, Konigsbergtransducer) and regional myocardial function (systolic segment length shortening, ultrasonic crystals) were measured in chronically instrumented dogs with tachycardia induced severe congestive heart failure. Measurements were performed in healthy dogs and after induction of heart failure in the awake state and during anaesthesia with 0.75, 1.0, 1.25 and 1.75 minimum alveolar concentration (MAC) of halothane, sevoflurane or desflurane. The anaesthetics reduced dP/dtmax in a dose-dependent manner in healthy dogs (dP/dtmax decreased to 43-53% of awake values at 1.75 MAC). Chronic rapid left ventricular pacing increased heart rate and left ventricular end-diastolic pressure and decreased mean arterial pressure, left ventricular systolic pressure and dP/dtmax. The reduction in contractility was similar in the failing myocardium (to 41-50% of awake values at 1.75 MAC). Segmental shortening was reduced during anaesthesia by 50-62% after pacing compared with 22-44% in normal hearts. While there were similar effects of the different anaesthetics on diastolic function in healthy dogs, after induction of heart failure a more pronounced increase of the time constant of isovolumic relaxation and a greater decrease of dP/dtmin was observed with sevoflurane than with desflurane, indicating a stronger depression of diastolic function. While the negative inotropic effects of sevoflurane and desflurane were similar in normal and in the failing myocardium in vivo, desflurane led to a better preservation of diastolic function in the failing myocardium.

Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits.

In hearts with chronic left ventricular (LV) systolic dysfunction secondary to hypertension or myocardial infarction, MAPK phosphorylation and/or activity are increased. Whether other settings of LV dysfunction not associated with ischemia-reperfusion are also characterized by increased MAPK phosphorylation or activity is unknown. After 3 wk of rapid LV pacing (400 beats/min), eight rabbits displayed clinical signs of heart failure (HF), and echocardiography revealed an increase in LV end-diastolic diameter from 15.6 +/- 0.7 (means +/- SE) to 18.8 +/- 0.7 mm and a reduced shortening fraction from 31 +/- 1to10 +/- 2% (both P < 0.05). Morphological alterations in HF included increased numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cardiomyocytes, extent of fibrosis, and cross-sectional cardiomyocyte area. Total p38 MAPK did not differ between failing and normal hearts (n = 8). However, p38 MAPK phosphorylation [164,488 +/- 29,323 vs. 43,565 +/- 14,817 arbitrary units (AU), P < 0.05, densitometry] and the activities of p38 MAPK-alpha and -beta were increased in failing compared with normal hearts (149,441 +/- 38,381 and 170,430 +/- 32,952 vs. 68,815 +/- 28,984 and 81,788 +/- 22,774 AU, respectively, both P < 0.05). In failing compared with normal hearts, total and phosphorylated JNK46 and JNK54 MAPK were increased, whereas total and phosphorylated ERK MAPK remained unchanged. In pacing-induced HF, p38 and JNK MAPK phosphorylation as well as p38 MAPK activity was increased. Further studies will have to define whether or not chronic specific blockade of MAPK activity can interfere with apoptosis/fibrosis and thereby attenuate the progression of HF.

Lipid peroxidation-derived aldehydes and oxidative stress in the failing heart: role of aldose reductase.

Lipid peroxidation-derived aldehydes (LP-DA) can propagate oxidative injury and are detoxified by the aldose reductase (AR) enzyme pathway in myocardium. Whether there are alterations in the AR axis in heart failure (HF) is unknown. Sixteen instrumented dogs were studied before and after either 24 h or 4 wk of rapid left ventricular (LV) pacing (early and late HF, respectively). Six unpaced dogs served as controls. In early HF, there was subtle depression of LV performance (maximum rate of LV pressure rise, P < 0.05 vs. baseline) but no chamber enlargement, whereas in late HF there was significant (P < 0.05) contractile depression and LV dilatation. Oxidative stress was increased at both time points, indexed by tissue malondialdehyde, total glutathione, and free C6-C9 LP-DA (P < 0.025 vs. control). AR protein levels and activity decreased progressively during HF (P < 0.025 early/late HF vs. control); however, AR mRNA expression decreased only in late HF (P < 0.005 vs. early HF and control). DNA binding of tonicity-responsive enhancer binding protein (TonEBP, a transcriptional regulator of AR) paralleled AR mRNA, declining >50% in late HF (P < 0.025 vs. control). We conclude that AR levels and attendant myocardial capacity to detoxify LP-DA decline during the development of HF. In early HF, decreased AR occurs due to a translational or posttranslational mechanism, whereas in late HF reduced TonEBP transcriptional activation and AR downregulation contribute significantly. Reduced AR-mediated LP-DA metabolism contributes importantly to LP-DA accumulation in the failing heart and thus may augment chronic oxidative injury.

Load sensitivity of left ventricular relaxation in normal and failing hearts: evidence of a nonlinear biphasic response.

This investigation sought to define the effect of heart failure (HF) on the load sensitivity of left ventricular (LV) relaxation and to correlate alterations in load sensitivity with the variables of ejection timing, systolic load profile and elastic recoil. Nine dogs instrumented with LV micromanometers and piezoelectric crystals were studied before and after HF produced by prolonged rapid LV pacing. After pharmacologic autonomic blockade and atrial pacing at 160 bpm, hemodynamic measurements were recorded at steady-state and during vena caval occlusion. LV relaxation for individual beats during caval occlusion was assessed using tau, the monoexponential time constant, and systolic load was estimated using end-systolic circumferential force (ESF). The tau-ESF relation was nonlinear and biphasic, with an initial decrease in tau followed by a delayed increase, and was described by a parabolic equation with a curvilinearity coefficient a. Examination of ejection variables and systolic load profile indicated that the initial acceleration of relaxation reflected the influence of increased elastic recoil, whereas the late slowing reflected the influence of earlier end-ejection and delayed systolic loading. HF produced significant baseline prolongations of tau (P < 0.005), time to relaxation onset (P < 0.001) and time to peak force (P < 0.015) compared to control. The curvilinearity coefficient of the tau-ESF relation was significantly increased (18.1 +/- 20.1.10(-5) vs. 3.99 +/- 2.89.10(-5) g-2, P = 0.048), indicating increased load sensitivity of relaxation. This increased load sensitivity correlated with delayed onset but increased overall magnitude of the effects of earlier end-ejection and late systolic loading on relaxation. The tau-ESF relationship during transient load reduction is nonlinear and biphasic with an initial acceleration of relaxation, reflecting the impact of elastic recoil, and delayed slowing, reflecting changes in ejection timing and systolic loading sequence. This relation is more curvilinear in the failing heart, indicating increased load sensitivity of LV relaxation. These changes primarily occur due to alterations in the impact of ejection timing and systolic load profile rather than increased elastic recoil.

Diastolic Dysfunction and Collagen Structure in Canine Pacing-Induced Heart Failure

Heart failure is characterized not only by systolic, but also by diastolic dysfunction. The present study tested whether or not diastolic dysfunction is associated with changes in tissue properties and collagen network structure. Heart failure was induced in seven chronically instrumented, conscious dogs by rapid left ventricular pacing (250 min−1). After 2–5 [mean: 4±1 (s.d.)] weeks pacing, heart failure was apparent from clinical symptoms (ascites, cachexia, edema, exercise intolerance) and hemodynamic parameters (significant increases of heart rate and left ventricular end-diastolic pressure and decreases of left ventricular maximal pressure, dP/dtmaxand systolic wall thickening). The left ventricle was dilated, as indicated by a decrease of end-diastolic wall thickness (6.3±2.0v7.2±2.1 mmP<0.05; sonomicrometry). The left ventricular end-diastolic pressure—strain relation (strain: relative change of end-diastolic wall thickness) was obtained during alterations of loading conditions by inferior caval vein and descending thoracic aortic occlusion. The slope of this relation increased from 85±20 to 428±188 in heart failure, indicating an increase of left ventricular stiffness. Collagen was stained with picrosirius red and analyzed using polarized light microscopy. In heart failure, the collagen volume fraction remained unchanged (1.9±1.2v2.3±1.3%; N.S.), while the nonuniformity of collagen orientation, as reflected by its standard deviation, was increased (11.1±1.8v6.1±0.4 oP<0.05). The nonuniformity of collagen fiber orientation correlated with left ventricular stiffness [r=0.75].

Cardiovascular effects of xenon in isoflurane-anesthetized dogs with dilated cardiomyopathy.

Clinical interest in xenon has been rekindled recently by new recycling systems that have decreased its relative cost. The cardiovascular effects of xenon were examined in isoflurane-anesthetized dogs before and after the development of rapid left ventricular (LV) pacing-induced cardiomyopathy. Dogs (n = 10) were chronically instrumented to measure aortic and LV pressure, LV subendocardial segment length, and aortic blood flow. Hemodynamics were recorded, and indices of LV systolic and diastolic function and afterload were determined in the conscious state and during 1.5 minimum alveolar concentration isoflurane anesthesia alone and combined with 0.25, 0.42, and 0.55 minimum alveolar concentration xenon in dogs with and without cardiomyopathy. Administration of xenon to healthy dogs anesthetized with isoflurane decreased heart rate and increased the time constant (tau) of isovolumic relaxation but did not alter arterial and LV pressures, preload recruitable stroke work slope, and indices of LV afterload. Chronic rapid LV pacing increased the baseline heart rate and LV end-diastolic pressure, decreased arterial and LV systolic pressures, and produced LV systolic and diastolic dysfunction. Administration of xenon to isoflurane-anesthetized, cardiomyopathic dogs did not alter heart rate, arterial and LV pressures, myocardial contractility, and indices of early LV filling and regional chamber stiffness. More pronounced increases in tau were accompanied by increases in total arterial resistance during administration of xenon to isoflurane-anesthetized cardiomyopathic compared with healthy dogs. The results indicate that xenon produces minimal cardiovascular actions in the presence of isoflurane in dogs with and without experimental dilated cardiomyopathy.

Amino-terminal proBNP in ovine plasma: evidence for enhanced secretion in response to cardiac overload.

We have recently identified a novel amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) in the circulation of humans, the concentration of which increases progressively as the left ventricle fails. To clarify the origins of NT-proBNP in experimental animals, we have developed an RIA for NT-proBNP based on residues 52-71 of ovine proBNP-(1-103) and used it to study cardiac processing, secretion, and metabolism of BNP in sheep with cardiac overload induced by coronary artery ligation (CAL) or rapid left ventricular pacing (rLVP). The concentration of NT-proBNP in left atrial plasma extracts drawn from normal control sheep was threefold that of mature BNP. Size-exclusion and reverse-phase HPLC analyses of plasma extracts coupled to RIA revealed a single peak of immunoreactive (ir) NT-proBNP [ approximately 8,000 relative molecular weight (Mr)], quite distinct from a single peak of ir-mature BNP ( approximately 3,000 Mr). In contrast, ovine cardiac tissue contained only a single immunoreactive peak of high-molecular-weight BNP ( approximately 11,000 Mr), consistent in size with proBNP-(1-103). Sampling from the cardiac coronary sinus in normal control sheep (n = 5) and sheep with CAL (n = 5) revealed that the molar ratio of NT-proBNP to mature BNP was similar. There was a significant gradient of both mature and NT-proBNP across the heart in normal sheep, whereas after CAL the gradient was significant for mature BNP only. In both forms of cardiac overload (CAL and rLVP), left atrial plasma levels of NT-proBNP were significantly increased above normal levels, in contrast with mature BNP levels, which were raised only in the rLVP group of animals. Blockade of natriuretic peptide metabolism in sheep with heart failure (induced by rLVP) raised mature BNP levels threefold but did not affect levels of NT-proBNP. In conclusion, these studies show that NT-proBNP is formed from proBNP stores during secretion and, compared with mature BNP, accumulates in plasma because metabolism of NT-proBNP appears to differ from that of mature BNP. Although its function, if any, remains unclear, plasma NT-proBNP may prove to be a sensitive marker of cardiac overload and/or decompensation.

Dexmedetomidine produces similar alterations in the determinants of left ventricular afterload in conscious dogs before and after the development of pacing-induced cardiomyopathy.

The authors tested the hypothesis that intravenous dexmedetomidine produces alterations in left ventricular (LV) afterload that are deleterious to cardiac performance in conscious dogs with pacing-induced cardiomyopathy. Dogs (n = 8) were fitted with instruments for long-term measurement of LV and aortic blood pressure, aortic blood flow, and subendocardial segment length and received dexmedetomidine (1.25, 2.5, and 5 microg/kg) in a cumulative manner before and after 19+/-3 (mean +/- SEM) days of rapid LV pacing. LV afterload was measured with aortic input impedance [Zin(omega)] and quantified with a three-element Windkessel model. Hemodynamics and Zin(omega)) were assessed under control conditions and 5 and 60 min after administration of each dose. Dexmedetomidine caused early and late decreases in heart rate, the maximum rate of increase of LV pressure, mean aortic blood flow, and stroke volume in dogs before and after pacing. Dexmedetomidine caused similar early increases in total arterial resistance and decreases in total arterial compliance in dogs before and after pacing. Early dexmedetomidine-induced increases in resistance and decreases in compliance caused similar reductions in mean aortic blood flow in cardiomyopathic compared with healthy dogs. Resistance and compliance returned to control values, and characteristic aortic impedance decreased late after dexmedetomidine in healthy dogs. In contrast, resistance remained elevated late after dexmedetomidine in dogs with dilated cardiomyopathy. Dexmedetomidine causes similar alterations in hemodynamics and LV afterload in conscious dogs with and without pacing-induced cardiomyopathy.

Characterization of excitation-contraction coupling in conscious dogs with pacing-induced heart failure.

In isolated cardiac preparations of non-failing hearts from different species, including man, there is a positive force-frequency relation which is reversed into a negative relation in preparation from failing hearts. Whether or not such relations between ventricular function and heart rate hold true in the in situ heart is not clear at present. Mechanical restitution and postextrasystolic potentiation might serve as alternative measures of excitation-contraction coupling. Eleven dogs were instrumented with a left ventricular micromanometer, ultrasonic crystals for the measurement of regional wall thickness, two hydraulic occluders around the descending aorta and the inferior caval vein, and left atrial and ventricular pacing leads with a subcutaneous pacemaker. Left ventricular dP/dtmax, as an isovolumic phase index, and systolic wall thickening, as an ejection phase index, were plotted versus heart rate, and heart rate was increased by left atrial pacing from rest to 200 min-1 in increments of 25 min-1. In a subset of dogs, left ventricular filling was controlled and the frequency range expanded by the bradycardic agent UL-FS 49. Measurements were performed in the presence and absence of autonomic blockade (hexamethonium, atropine). Mechanical restitution and postextrasystolic potentiation were determined as normalized dP/dtmax and systolic wall thickening, respectively, of the extra- and postextrasystolic beat versus defined variations of the extrasystolic time interval (250-550 ms). Following control studies, heart failure was induced by rapid left ventricular pacing at 250 min-1 for 20 days +/- 6 (SD) and measurements repeated. Isolated left ventricular trabeculae from non-failing and failing hearts were studied during stimulation at 0.2-4 Hz. Only with filling control and in the absence of autonomic blockade, was there a slightly positive relation between dP/dtmax and heart rate in the control state. Otherwise, the relation of dP/dtmax to heart rate was flat both in the control state and in heart failure. The relation between systolic wall thickening and heart rate in the control state was negative, unless filling was controlled, and it was flat in heart failure. In contrast, the time constants of mechanical restitution and postextrasystolic potentiation were increased significantly with heart failure from 91 +/- 25 (SD) to 164 +/- 13 ms and from 107 +/- 18 to 156 +/- 4 ms, respectively, for dP/dtmax and from 76 +/- 22 to 162 +/- 10 ms and from 101 +/- 17 to 160 +/- 17 ms, respectively, for systolic wall thickening. These time constants were, however, insensitive to UL-FS 49 and autonomic blockade. There was a negative force-frequency relation in left ventricular trabeculae from non-failing hearts at higher calcium concentrations, where it was flat in trabeculae from failing hearts. Time constants of mechanical restitution and postextrasystolic potentiation are more sensitive than the steady state relation of ventricular function and heart rate to characterize the impairment of excitation-contraction coupling in heart failure.