Development Of Pacing-induced Heart Failure Research Articles

PO-03-088 TWO-DIMENSIONAL SPECKLE TRACKING ECHOCARDIOGRAPHY SHOWS THAT LEFT BUNDLE BRANCH PACING MAINTAINS LEFT VENTRICULAR GLOBAL LONGITUDINAL STRAIN AND CONTRACTILITY COMPARED TO RIGHT VENTRICULAR APICAL PACING

Pacemaker-dependent patients with right ventricular (RV) apical pacing are at increased risk for reduced left ventricular function, ventricular dyssynchrony, and the development of pacing-induced heart failure. Physiological pacing of the conduction system through the left bundle branch (LBB) has been shown to have improved synchrony of the ventricles and a more physiological activation sequence. Direct comparison of left ventricular (LV) strain using LBB and RVAP in paired experiments in the same animals or patients has not been published. Evaluate the changes to the left ventricular mechanics (global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and left ventricular ejection fraction (LVEF) through LBB pacing compared to RV pacing using two-dimensional speckle tracking echocardiography. Under anesthesia, six mixed breed hounds had pacing leads from two ICDs (CobaltTM XT DR, Medtronic, Inc) implanted at the RV apex (6947 Sprint Quattro SecureTM, Medtronic, Inc) and the LBB (3830 SelectSecureTM, Medtronic, Inc). Echocardiographic measurements were taken for sinus rhythm, LBB pacing, and RV pacing to evaluate the LV strain, and contractility. Two-dimensional speckle tracking was performed following the pacing procedure to determine GLS, and LVEF from the four-chamber apical views, GCS, and GRS from the short-axis views. In our study, LV GLS was maintained better during LBB pacing when compared to LV GLS during RV pacing. The magnitude of GLS was not significantly different between sinus and LBB pacing, but was significantly lower for RV pacing than both sinus and LBB pacing (Fig. A). GCS only showed a significant difference between sinus and RV pacing (Fig. B), while GRS did not show differences between any of the groups (Fig. C). Results for the LV ejection fraction followed a similar pattern as the GLS. There was not a significant difference in LVEF for sinus and LBB pacing, but LVEF was significantly lower for RV pacing compared to both sinus and LBB pacing (Fig. D). LBB pacing preserves GLS, and the LVEF better than RV apical pacing and is similar to sinus beats. This further supports LBB pacing as a preferred method of pacing for preserving contractility for patients with pacemakers.

Heart failure due to right ventricular apical pacing: the importance of flow patterns.

In patients receiving permanent cardiac electrical stimulation, a high burden of apical right ventricular pacing is associated with an increased incidence of heart failure. Despite the large body of electrocardiographic, echocardiographic, and pathological data, mechanisms underlying this serious complication are not fully understood. Moreover, the empirical use of alternative right ventricular pacing sites, both in the experimental and in the clinical setting, has not provided better results in terms of clinical outcome. Recent data derived by echocardiographic particle image velocimetry of intracardiac flows have shown abnormal flow patterns in patients with dyssynchrony of left ventricular wall contraction, and the reversion to normal flow dynamics after successful electrical cardiac resynchronization therapy. This suggests that a normal intraventricular flow pattern is strongly dependent on the highly coordinated contraction of the ventricular wall segments and that an abnormal sequence of wall contraction may trigger the development of overt heart failure. This review summarizes the state of the art on this topic, highlighting postulated underlying basic mechanisms linking abnormal flow with the development of pacing-induced heart failure. This research line suggests the importance of studying intraventricular fluid dynamics as a new powerful tool for a more complete understanding of mechanisms involved, and ultimately to prevent pacing-related heart failure.

Impaired hdl cholesterol efflux capacity during development of pacing-induced heart failure in minipig

Impaired hdl cholesterol efflux capacity during development of pacing-induced heart failure in minipig

Bradykinin restores left ventricular function, sarcomeric protein phosphorylation, and e/nNOS levels in dogs with Duchenne muscular dystrophy cardiomyopathy

Cardiomyopathy is a lethal result of Duchenne muscular dystrophy (DMD), but its characteristics remain elusive. The golden retriever muscular dystrophy (GRMD) dogs produce DMD pathology and mirror DMD patient's symptoms, including cardiomyopathy. We previously showed that bradykinin slows the development of pacing-induced heart failure. Therefore, the goals of this research were to characterize dystrophin-deficiency cardiomyopathy and to examine cardiac effects of bradykinin in GRMD dogs. At baseline, adult GRMD dogs had reduced fractional shortening (28 ± 2 vs. 38 ± 2% in control dogs, P < 0.001) and left ventricular (LV) subendocardial dysfunction leading to impaired endo-epicardial gradient of radial systolic velocity (1.3 ± 0.1 vs. 3.8 ± 0.2 cm/s in control dogs, P < 0.001) measured by echocardiography. These changes were normalized by bradykinin infusion (1 µg/min, 4 weeks). In isolated permeabilized LV subendocardial cells of GRMD dogs, tension-calcium relationships were shifted downward and force-generating capacity and transmural gradient of myofilament length-dependent activation were impaired compared with control dogs. Concomitantly, phosphorylation of sarcomeric regulatory proteins and levels of endothelial and neuronal nitric oxide synthase (e/nNOS) in LV myocardium were significantly altered in GRMD dogs. All these abnormalities were normalized in bradykinin-treated GRMD dogs. Cardiomyopathy in GRMD dogs is characterized by profound LV subendocardial dysfunction, abnormal sarcomeric protein phosphorylation, and impaired e/nNOS, which can be normalized by bradykinin treatment. These data provide new insights into the pathophysiological mechanisms accounting for DMD cardiomyopathy and open new therapeutic perspectives.

Loss of Intracellular and Intercellular Synchrony of Calcium Release in Systolic Heart Failure

Normal contraction of cardiac muscle requires a coordinated cellular mechanical response to the electric pacemaker signal that begins in the sinoatrial node and spreads through the conduction system and ultimately across the ventricular myocardium via gap junctions. In ventricular myocytes, depolarization by the action potential causes clusters of L-type calcium channels (LCCs) to open, allowing a small amount of Ca to enter the diadic cleft space between the sarcolemma and the sarcoplasmic reticulum (SR). When the Ca concentration in this space becomes sufficiently high to gate ryanodine receptors (RyRs), they open and release SR Ca into the cytoplasm, so that it can bind to and activate myofilaments, resulting in force development. Each cluster of LCCs on the sarcolemma, its opposing cluster of RyRs across the 10- to 12-nm diameter diadic cleft space, and associated SR regulatory proteins is a couplon.1 According to the local control theory of cardiac excitation-contraction (EC) coupling, couplons are activated independently. Independent activation of couplons depends on the extent of LCC activation, providing a mechanism for regulation of contractile force by stochastic recruitment of couplons.2 In systolic heart failure, numerous cellular defects in EC coupling and Ca regulation have been identified that contribute to contractile dysfunction (and ventricular arrhythmias), although there is a host of other major abnormalities leading to loss of force development, including fibrosis,3 defective energy metabolism,4 pH changes,5 heterogeneous conductance across connexin hemichannels,6 and defects in sarcomeric proteins.7 Thus, it is important to keep in mind that no single defect can explain the contractile dysfunction of systolic failure. Article see p 223 Recent studies of defective EC coupling in heart failure have addressed not only reductions in the extent and kinetics of Ca released in response to the action potential (ie, reduced recruitment of couplons and …

Ventricular ErbB2/ErbB4 activation and downstream signaling in pacing-induced heart failure

The neuregulin-1 (NRG-1)/ErbB system has emerged as a cardioprotective system that becomes activated during myocardial stress, most convincingly shown in response to cardiotoxic chemotherapy. Direct evidence of increased ventricular ErbB receptor activity in heart failure unrelated to cardiotoxic drugs is, however, limited. We investigated changes in NRG-1 expression, ErbB receptor phosphorylation and downstream activation of intracellular ErbB targets during rapid pacing and progressive ventricular dysfunction in the dog. Heart failure was induced in dogs by 7 weeks of rapid pacing. Ventricular function was assessed by echocardiography. Messenger RNA expression was investigated in ventricular biopsies using quantitative PCR. Activation of NRG-1/ErbB signaling and of downstream targets was investigated using immunoprecipitation and/or Western blotting. Over the course of 7 weeks of pacing and ventricular dilatation, ventricular levels of NRG-1, but not of other ErbB4 ligands, and of ADAM19, a protease promoting NRG-1 release, progressively increased. In parallel, levels of activated ErbB2 and ErbB4, phosphorylated at tyrosine residues 877/1248 and 1284 respectively, became progressively higher. Similarly, levels of total and phosphorylated PI-3 kinase increased. Surprisingly, however, and in contrast with activation of downstream targets of ErbB receptors in normal hearts, Akt and ERK1/2, remained inactivated. This study shows that ventricular ErbB2 and ErbB4 receptors become activated during the development of pacing-induced heart failure, but that downstream signaling is, at least partly, abrogated. Abrogation of cardioprotective signaling after ErbB activation is an unanticipated phenomenon in the progression of heart failure with possibly major pathophysiological significance. The underlying mechanisms should be further elucidated.

Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure

End-stage heart failure (HF) is characterized by changes in conduction velocity (CV) that predispose to arrhythmias. Here, we investigate the time course of conduction changes with respect to alterations in connexin 43 (Cx43) properties and mechanical function during the development of HF. We perform high-resolution optical mapping in arterially perfused myocardial preparations from dogs subjected to 0, 3, 7, 14, and 21 days of rapid pacing to produce variable degrees of remodeling. CV is compared with an index of mechanical function [left ventricular end-diastolic pressure (LVEDP)] and with dynamic changes in the expression, distribution, and phosphorylation of Cx43. In contrast to repolarization, CV was preserved during early stages of remodeling (3 and 7 days) and significantly reduced at later stages, which were associated with marked increases in LVEDP. Measurements of differentially phosphorylated Cx43 isoforms revealed early, sustained downregulation of pan-Cx43 that preceded changes in CV and LVEDP, a gradual rise in a dephosphorylated Cx43 isoform to over twofold baseline levels in end-stage HF, and a late abrupt increase in pan-Cx43, but not dephosphorylated Cx43, lateralization. These data demonstrate that 1) CV slowing occurs only at advanced stages of remodeling, 2) total reduction of pan-Cx43 is an early event that precedes mechanical dysfunction and CV slowing, 3) changes in Cx43 phosphorylation are more closely associated with the onset of HF, and 4) Cx43 lateralization is a late event that coincides with marked CV reduction. These data reveal a novel paradigm of remodeling based on the timing of conduction abnormalities relative to changes in Cx43 isoforms and mechanical dysfunction.

Plasma urocortin 1 in sheep: Regional sampling and effects of experimental heart failure

Although urocortin 1 (Ucn-1) has been reported to circulate in human plasma and be raised in heart failure, little, if any, information is available regarding the source of circulating Ucn-1. Accordingly, we have performed trans-organ arteriovenous sampling for measurement of Ucn-1 concentration in anesthetized sheep before and after development of pacing-induced heart failure. Arterial plasma Ucn-1 levels measured 15.2 ± 0.5 pmol/L in normal sheep and increased significantly following development of heart failure to 19.1 ± 1.6 ( p < 0.05). Small but significant positive arteriovenous gradients were observed across the hepatic and renal tissue beds in both states, with rises across the hind limb significant in normal animals and across the head in heart failure. This is the first report identifying sources of circulating Ucn-1.

Endogenous urocortins reduce vascular tone and renin–aldosterone/endothelin activity in experimental heart failure

To investigate the role of the endogenous urocortin peptides in heart failure (HF) through blockade of the corticotropin-releasing factor receptor 2 (CRF-R2). Eight sheep were administered the CRF-R2 antagonist CRF(9-41) (1.5 mg bolus) before (Normal) and after development of pacing-induced HF. Compared with controls, CRF(9-41) in HF significantly increased mean arterial pressure (MAP) (71+/-2 vs. 75+/-2 mmHg, P=0.0024) and calculated total peripheral resistance (CTPR) (33.3+/-5.2 vs. 39.4+/-5.9 mmHg/L/min, P=0.0455). Similar trends were observed in the Normal state (MAP 87+/-1 vs. 89+/-2 mmHg, P=0.0689; CTPR 21.9+/-2.0 vs. 24.4+/-2.4 mmHg/L/min, P=0.0731). Left atrial pressure was elevated similarly in both states (Normal P=0.0013; HF P=0.0298), whereas cardiac output tended to be reduced (Normal P=0.0614). CRF(9-41) increased plasma urocortin-I (Normal 10.3+/-0.8 vs. 19.8+/-1.3 pmol/L, P<0.001; HF 14.4+/-0.9 vs. 25.3+/-0.8 pmol/L, P<0.001), renin (Normal 0.34+/-0.06 vs. 0.41+/-0.02 nmol/L/hr, P=0.013; HF 1.14+/-0.29 vs. 1.57+/-0.36 nmol/L/hr, P=0.0326), aldosterone (Normal 370+/-62 vs. 563+/-99 pmol/L, P=0.0813; HF 662+/-141 vs. 1024+/-209 pmol/L, P=0.095), and endothelin-1 (HF 3.18+/-0.18 vs. 4.74+/-1.04 pmol/L, P=0.0087). MAP, CTPR, renin, and endothelin-1 responses to CRF-R2 antagonism were significantly greater in HF than in the Normal state (P=0.049, 0.0427, 0.0311, and 0.0412, respectively). These data suggest that the endogenous urocortin peptides contribute to the suppression of vascular tone and renin-angiotensin-aldosterone/endothelin activation in HF and thus, play a protective compensatory role in this disorder.

Valsartan restores sarcoplasmic reticulum function with no appreciable effect on resting cardiac function in pacing-induced heart failure.

Although angiotensin II receptor blockade is considered to be useful for the treatment of human heart failure, little beneficial hemodynamic effect has been shown in some experimental failing hearts. In this study, we assessed the effect of an angiotensin II receptor blocker, valsartan, on sarcoplasmic reticulum (SR) function, defectiveness of which is a major pathogenic mechanism in heart failure. SR vesicles were isolated from dog left ventricular muscle (normal or exposed to 4-week rapid ventricular pacing with or without valsartan). In the untreated and valsartan-treated paced dogs, cardiac function showed similar deterioration (compared with before pacing). However, both the density of beta-receptors and the contractile response to dobutamine were greater in the valsartan-treated paced dogs than in the untreated paced dogs. In untreated paced hearts, the ryanodine receptor was protein kinase A-hyperphosphorylated, showed an abnormal Ca2+ leak, and had a decreased amount of ryanodine receptor-bound FKBP12.6. No such phenomena were seen in the valsartan-treated paced hearts. Both the SR Ca2+ uptake function and the amount of Ca2+-ATPase were decreased in the untreated failing SR, but both were restored in the valsartan-treated SR. During the development of pacing-induced heart failure, valsartan preserved the density of beta-receptors and concurrently restored SR function without improving resting cardiac function.

Modulation of renal oxygen consumption by nitric oxide is impaired after development of congestive heart failure in dogs.

We investigated the role of nitric oxide (NO) in the modulation of renal O2 consumption in dogs with pacing-induced congestive heart failure (CHF). O2 consumption in the renal cortex (C) and medulla (M) of normal dogs and dogs with CHF was measured under control conditions and in the presence of increasing concentrations of three stimulators of NO production, bradykinin, ramiprilat, and amlodipine, or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Baseline O2 consumption (nmol O2/min per gram) was similar in the CHF group (C: 637+/-65; M: 618+/-83) and the control group (C: 601+/-58, M: 534+/-55). In normal dogs, bradykinin (10(-4) M), ramiprilat (10(-4) M), amlodipine (10(-5) M) and SNAP (10(-4) M) all significantly reduced O2 consumption in the cortex (-31.5+/-3.5%, -33+/-2.5%, -28.4+/-4.9%, -49.3+/-3.1%) and medulla (-26.9+/-2.2%, -31.4+/-2.2%, -23.1+/-1.3%, -48.3+/-4%), respectively. The responses to bradykinin, ramiprilat and amlodipine were significantly attenuated in dogs with CHF (C: -22.2+/-1.8%, -20.1+/-2.6%, -14.2+/-2.5%; M: -20.8+/-1.7%, -17.8+/-1.9%, -15.6+/-2.6%, respectively; p < 0.05). The responses in dogs with CHF were not altered by NO synthase blockade with L-NAME (10(-4) M). In contrast, in normal kidneys treatment with L-NAME significantly attenuated the response to all three stimuli of NO production. Responses to SNAP were not affected either by CHF or L-NAME. These data indicate that the role of NO production in the modulation of tissue O2 consumption in the kidney is impaired after the development of pacing-induced heart failure in dogs.

Beta-adrenergic receptor signaling: an acute compensatory adjustment-inappropriate for the chronic stress of heart failure? Insights from Gsalpha overexpression and other genetically engineered animal models.

Under normal physiological conditions, the heart must be able to increase its output 5-fold to supply the required blood flow to the coronary circulation and skeletal muscles during severe stress. This is normally met by ≈5-fold increases in myocardial contractility, ≈3-fold increases in heart rate, and additional increases in stroke volume.1 This increased load requires a commensurate increase in myocardial blood flow, because oxygen extraction across the heart is nearly complete, even under normal conditions. Accordingly, the design of the cardiovascular system evolved to conserve myocardial metabolic demand, and consequently coronary blood flow, at rest, but with considerable reserve that can be called on rapidly in times of stress. There is a host of compensatory adjustments, including changes in metabolic substrates and kinetics, as well as oxygen-carrying capacity, that may be recruited in response to stress. However, none is more important than the autonomic nervous system in general, and the sympathetic arm in particular, in terms of providing large, rapid changes in cardiac function. When this compensatory mechanism is unavailable, eg, after treatment with propranolol, the 3-fold increases in heart rate and 5-fold increases in myocardial contractility in response to exercise cannot be achieved.1 In this connection, it is recognized that heart failure is a state characterized by enhanced sympathetic tone, but when the failing myocardium is challenged by β-adrenergic stimulation in vivo or in vitro, the most frequent result is β-adrenergic downregulation or desensitization.2 3 4 5 An impairment of cardiac function leads to autocrine, paracrine, and neurohormonal adjustments, including a strong sympathetic component (Figure 1⇓); under acute conditions, these reflex adjustments are beneficial, as noted above. However, when the sympathetic nervous system is chronically and tonically stimulated, as occurs in the pathogenesis of heart failure, desensitization mechanisms are called into play, such that the …

Reduced NO-dependent arteriolar dilation during the development of cardiomyopathy

Our previous studies have suggested that there is reduced nitric oxide (NO) production in canine coronary blood vessels after the development of pacing-induced heart failure. The goal of these studies was to determine whether flow-induced NO-mediated dilation is altered in coronary arterioles during the development of heart failure. Subepicardial coronary arterioles (basal diameter 80 microm) were isolated from normal canine hearts, from hearts with dysfunction but no heart failure, and from hearts with severe cardiac decompensation. Arterioles were perfused at increasing flow or administered agonists with no flow in vitro. In arterioles from normal hearts, flow increased arteriolar diameter, with one-half of the response being NO dependent and one-half prostaglandin dependent. Shear stress-induced dilation was eliminated by removing the endothelium. Arterioles from normal hearts and hearts with dysfunction but no failure responded to increasing shear stress with dilation that reached a maximum at a shear stress of 20 dyn/cm(2). In contrast, arterioles from failing hearts showed a reduced dilation, reaching only 55% of the dilation seen in vessels of normal hearts at a shear stress of 100 dyn/cm(2). This remaining dilation was eliminated by indomethacin, suggesting that the NO-dependent component was absent in coronary microvessels after the development of heart failure. Similarly, agonist-induced NO-dependent coronary arteriolar dilation was markedly attenuated after the development of heart failure. After the development of severe dilated cardiomyopathy and heart failure, the NO-dependent component of both shear stress- and agonist-induced arteriolar dilation is reduced or entirely absent.

Cytokines are not a requisite part of the pathophysiology leading to cardiac decompensation.

An increase in circulating levels of proinflammatory cytokines has been proposed as an important pathogenic factor contributing to cardiac injury during chronic heart failure. To determine whether plasma levels of the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) increase during pacing-induced heart failure, we paced the hearts of seven dogs at 210 beats/min for 3 weeks and at 240 beats/min for an additional week to induce severe clinical signs of cardiac decompensation. Hemodynamic measurements and blood samples from the aorta and coronary sinus (CS) were taken at control, at 3 weeks, and in end-stage failure. Decompensated heart failure occurred at 29 +/- 1.8 days, when left ventricular (LV) end-diastolic pressure was 25 +/- 1.3 mmHg, LV systolic pressure was 92 +/- 4 mmHg, mean arterial pressure was 77 +/- 3 mmHg, and dP/dtmax was 1219 +/- 73 (all P < 0.05 vs control). Arterial concentration of IL-6 was 12 +/- 4.0 U/ml at control, 11 +/- 2.7 U/ml at 3 weeks, and 10 +/- 1.7 U/ml in end-stage failure (NS). At the same time points, IL-6 in CS plasma was 12 +/- 3.5, 13 +/- 2.8 and 11 +/- 2.4 U/ml, respectively (NS vs control and vs arterial concentrations). TNF-alpha did not reach detectable concentrations in arterial or CS blood at any time. TNF-alpha and IL-6 concentrations did not increase in arterial blood, were not released in the CS from the heart during the development of pacing-induced heart failure, and can not universally be implicated in the pathogenesis of all forms of cardiac dysfunction. Our findings are consistent with other data from patients in which severe heart failure was not associated with increased levels of circulating cytokines.

Pulmonary hemodynamics and endothelin levels in pacing-induced heart failure: During rest and exercise

Elevated plasma levels of endothelin (ET) have been reported to accompany the development of heart failure (HF), and therefore, this potent vasoconstrictive peptide has been postulated to contribute to the altered pulmonary hemodynamics that occur in this disease process. The overall goal of this study was to examine more carefully the relationship between ET levels in the pulmonary system and pulmonary hemodynamics in the normal and HF states, during both rest and exercise. This study used a porcine model of chronic rapid pacing that has been shown in previous studies to produce left ventricular dysfunction and neurohormonal system activation consistent with the syndrome of HF. Pigs (n = 10) were chronically instrumented to measure pulmonary and systemic hemodynamics, parenchymal flow, and ET content and to obtain blood samples from the pulmonary circuit in the conscious state. Measurements were performed in the normal control state and again following the development of pacing-induced HF (240 beats/min per 21 days), both at rest and during treadmill exercise (3 mph, 15° incline, 12 minutes). With HF, under ambient resting conditions, a threefold increase in pulmonary plasma ET occurred and was accompanied by a fivefold increase in pulmonary vascular resistance. During treadmill exercise, pulmonary plasma ET and pulmonary vascular resistance remained elevated in the HF group when compared with the normal state and were associated with a sixfold decrease in pulmonary parenchymal flow. Pulmonary parenchymal ET content was increased with HF when compared with values for normal control subjects (8.5 ± 0.6 vs 5.6 ± 0.8 fmol ET/mg protein, P < .05). Thus, the findings of this study suggest that in this model of HF, increased ET within the pulmonary circuit contributed to abnormalities in resistive properties and parenchymal flow.

Neural regulation of coronary vascular resistance: role of nitric oxide in reflex cholinergic coronary vasodilation in normal and pathophysiologic states.

A number of reflexes participate in the control of coronary vascular resistance through activation of the sympathetic or parasympathetic nervous system. Classically, activation of vagal efferent fibers to the heart results in vasodilation due to the release of acetylcholine and activation of muscarinic receptors. Recently, we have found that activation of a number of reflexes in conscious dogs, the Bezold-Jarisch reflex and the carotid chemoreflex in particular, results in cholinergic coronary vasodilation which is blocked by an inhibitor of nitric oxide synthesis, nitro-L-arginine. After the development of pacing-induced heart failure, the cholinergic dilation subsequent to activation of the Bezold-Jarisch or carotid chemoreflex is essentially abolished, since coronary blood vessels no longer produce nitric oxide. In contrast, after brief exercise training, there is a potentiation of Bezold-Jarisch reflex-induced coronary vasodilation since exercise upregulates nitric oxide production by coronary blood vessels. Since the Bezold-Jarisch reflex may be important as a compensatory mechanism during acute myocardial infarction, and the carotid chemoreflex is the acute mechanisms responsible for ameliorating systemic hypoxemia, the role of nitric oxide in reflex cholinergic coronary vasodilation may be essential in the compensatory vascular adjustments evoked by these and other reflexes.

Inhibition of vascular contractions to α-adrenoceptor agonists by polymyxin B: impact of heart failure state

In this study, the effects of polymyxin B (a protein kinase C inhibitor) on α-adrenoceptor stimulation of the canine dorsal pedal artery and saphenous vein were examined. In addition, the question was asked, whether these effects could be altered by the impact of a heart failure state? Blood vessels were obtained at three time points during the development of pacing-induced heart failure in the dog; control (non-paced), 1 week paced and end-stage heart failure. Concentration-effect curves were constructed to the α-adrenoceptor agonists, namely, noradrenaline and phenylephrine in the absence and presence of polymyxin B (2 × 10 −5 and 10 −4 M). Responses to noradrenaline and phenylephrine were enhanced in the saphenous vein, but not in the dorsal pedal artery, following the onset of heart failure. In the dorsal pedal artery, polymyxin B was found to inhibit the contractions developed to noradrenaline and phenylephrine to a significant degree (P < 0.05) at control and end-stage heart failure. In contrast, in the saphenous vein, polymyxin B inhibited responses developed to noradrenaline and phenylephrine at all time points studied. This inhibition was always more marked against noradrenaline compared to phenylephrine and, similar to the dorsal pedal artery, became more pronounced at end-stage heart failure. Furthermore, the vein was always more sensitive compared to the artery. Interestingly, as heart failure developed, a non-classical broad concentration-effect curve was evident. The high affinity component was more sensitive to inhibition by polymyxin B. This component was absent at end-stage heart failure in response to phenylephrine. In this latter case, no inhibition was seen with polymyxin indicating that it is the high affinity component which renders polymyxin B's sensitivity. Whether these effects relate to specific receptor populations is discussed. It can be concluded that some constituent of the α 1-adrenoceptor-mediated contraction involves protein kinase C activation. Therefore, protein kinase C may play a vital role in regulating vascular smooth muscle reactivity which may be an important mechanism in the pathogenesis of disease, i.e., heart failure and hypertension.

Pulmonary vasoconstriction with serotonin, norepinephrine and histamine following development of canine pacing-induced heart failure of varying duration

Pulmonary vasoconstriction in response to the amines serotonin (5HT), norepinephrine (NE) and histamine (Hist) was evaluated after the development of pacing-induced heart failure. The duration of heart failure evaluated was varied to test whether early hyperreactivity, noted with NE after 4 wk of pacing (Townsley et al., Circ. Res., in press, 1994) would be sustained. Dogs were paced at high heart rates (225-245 bpm) for 32 (4 wk group, n = 11 ) or 51 (7 wk group, n = 10) days. As a result, left ventricular shortening fraction fell (to 16.1 + 0.5 and 15.3 ± 0.3 %, respectively) compared to controls (35.0 ± 1.1%, p < 0.05, n = 15). Lung lobes were then isolated under pentobarbital anesthesia, ventilated (30% O 2, 5% CO2), and perfused with autologous blood at the highest isogravimetric f low possible. The actual blood f lows in the 4 and 7 wk groups were not different from that in controls (0.43 ± 0.02 I/min). However, when f low was normalized to 100g initial lobar wet wt, total vascular resistance was found to be Change in Pulmonary Vascular Resistance increased by 192 and 218% in the 4 and 7 wk groups (p< 0.05), respectively,

Myocardial B-adrenergic receptor function during the development of pacing-induced heart failure

Myocardial B-adrenergic receptor function during the development of pacing-induced heart failure

Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure.

The development of pacing-induced heart failure was studied in chronically instrumented, conscious dogs paced at a rate of 240 beats/min for 1 d (n = 6), 1 wk (n = 6), and 3-4 wk (n = 7). Left ventricular (LV) dP/dt was decreased (P < 0.0125) at 1 d, LV end-diastolic pressure and heart rate were increased (P < 0.0125) at 1 wk, but clinical signs of heart failure were only observed after 3-4 wk of pacing. Plasma norepinephrine rose (P < 0.0125) after 1 d of pacing, whereas LV norepinephrine was reduced (P < 0.0125) only after 3-4 wk of pacing. Both the fraction of beta-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased (P < 0.0125) after 1 d of pacing. Total beta-adrenergic receptor density was not changed at any time point, but beta 1-adrenergic receptor density was decreased (P < 0.0125) after 1 wk. The functional activity of the guanine nucleotide binding protein, Gs, was not reduced, but the Gi alpha 2 isoform of the alpha subunit of the GTP-inhibitory protein rose after 3-4 wk of pacing. Thus, myocardial beta-adrenergic signal transduction undergoes change shortly (1d) after the initiation of pacing, before heart failure develops. The mechanism of beta-adrenergic receptor dysfunction in pacing-induced heart failure is characterized initially by elevated plasma levels of catecholamines, uncoupling of beta-adrenergic receptors, and a defect in the adenylyl cyclase catalytic unit. Selective down-regulation of beta 1-adrenergic receptors, increases in Gi alpha 2, and decreases in myocardial catecholamine levels occur as later events.