Activity In Congestive Heart Failure Research Articles

Oxidative Products of Catecholamines During Heightened Sympathetic Activity Due to Congestive Heart Failure: Possible Role of Antioxidants.

The past several decades have shown the functional status of sympathetic activity in congestive heart failure. The results, particularly through clinical and basic studies in heart failure, indicate an increased sympathetic neural activity. The definitive and compelling evidence of the involvement of catecholamines is the demonstration that many drugs that are therapeutically useful in the treatment of heart failure also affect the sympathetic nervous system at various sites, including its synthesis, release and uptake of catecholamines and a decreased plasma norepinephrine level. Although it is not surprising that the sympathetic system is altered as cardiac function is compromised in heart failure, it now appears that this system may overreact in chronic situations. The detrimental cardiovascular problems result in the production of aminochrome and free radicals. Antioxidant therapy to target the production of aminochrome from autooxidation of catecholamines should provide an insight into the future therapeutic goal in situations like congestive heart failure.

DIFFERENT FORMS OF AFFERENT NERVE INPUT IN CARDIAC AND RENAL DISEASE IN RATS?

Objective: Afferent nerve pathways form kidney and heart are said to control sympathetic renal nerve activity. In a renal disease model the responsiveness of afferent renal nerve units was shifted from units with highly active primary neurons (tonic response pattern) to units with neurons of very low activity upon stimulation (phasic response pattern). Afferent renal nerve activity was likely decreased. Likewise, afferent vagal nerve activity in congestive heart failure (CHF) had a lower frequency at saturation than controls. Hence we wanted to test the hypothesis that CHF the vagal afferent nerve pathway consists of a decreased number of highly active tonic sensory neurons in the nodose ganglion. Design and method: CHF was induced by coronary artery ligature, nephropathy by injections of an anti Thy1.1 antibody (OX7, 1.2 mg/kg). After a respective time (CHF 21 days, nephropathy 7 days after induction) nodose ganglion neurons with cardiac vagal afferents from CHF rats or neurons form dorsal root ganglia with renal afferents from rats with nephropathy were cultured. Current clamp was used to characterize neurons as tonic, i.e. sustained action potential (AP) firing or phasict, i.e. <5 APs upon current injection. More than 100 neurons were investigated. Results: In CHF rats, the number of neurons with a tonic response pattern did not differ from controls (64% vs. 70 %, ns). However, tonic cardiac neurons from CHF rats exhibited an increased production of action potentials compared (24.4+/-5.0 vs. 14.7+/-1.8 APs/10 s; p < 0.05; mean+/-SEM). In nephropathic rats, the number of neurons with a tonic response pattern decreased significantly (43% vs. 64 %, p < 0.05), but there was no difference in action potential production between groups. Conclusions: In congestive heart failure the number of afferent neurons with a tonic response pattern was not significantly altered. However, the action potential production of these neurons even significantly increased upon stimulation. Hence, in congestive heart failure vagal afferent neurons increase their sensitivity in the presence of impaired intracardiac receptors whereas in renal disease the responsiveness of the first part of the afferent pathway is impaired as a whole.

Ranolazine Improves Autonomic Balance in Heart Failure when added to Guideline-Driven Therapy

Background: The effect of ranolazine (RAN) on cardiac autonomic balance in congestive heart failure (CHF) was studied. Methods: Fifty-four CHF patients were randomized to (1) open-label RAN (RANCHF) added to usual therapy vs. (2) usual therapy (NORANCHF). Parasympathetic and sympathetic (P&S) measurements were taken at baseline and at 12 months. Results: A total of 16/27 (59%) patients in both groups had initially abnormal P&S measures, including high sympathovagal balance (SB), cardiovascular autonomic neuropathy (CAN) or both. High SB normalized in 10/12 (83%) RANCHF patients vs. 2/11 (18%) NORANCHF patients. SB became high in 5/11 (45%) NORANCHF vs. 1/11 (9%) RANCHF patients. CAN improved in 4/6 (67%) RANCHF patients vs. 5/7 (45%) NORANCHF patients. CAN developed in 1/11 (9%) RANCHF vs. 4/11 (36%) NORANCHF patients. Since improved P&S in RANCHF patients seemed independent of improved brain natriuretic peptide and impedance cardiography (BioZ) measurements, 5 day RAN was given to 30 subjects without CHF but with high SB or CAN. P&S improved in 90% of these subjects. Conclusions: RAN improves unfavorable P&S activity in CHF possibly by a direct effect upon autonomic sodium channels.

Ranolazine improves autonomic balance in heart failure when added to guideline-driven therapy.

The effect of ranolazine (RAN) on cardiac autonomic balance in congestive heart failure (CHF) was studied. Fifty-four CHF patients were randomized to (1) open-label RAN (RANCHF) added to usual therapy vs. (2) usual therapy (NORANCHF). Parasympathetic and sympathetic (P&S) measurements were taken at baseline and at 12 months. A total of 16/27 (59%) patients in both groups had initially abnormal P&S measures, including high sympathovagal balance (SB), cardiovascular autonomic neuropathy (CAN) or both. High SB normalized in 10/12 (83%) RANCHF patients vs. 2/11 (18%) NORANCHF patients. SB became high in 5/11 (45%) NORANCHF vs. 1/11 (9%) RANCHF patients. CAN improved in 4/6 (67%) RANCHF patients vs. 5/7 (45%) NORANCHF patients. CAN developed in 1/11 (9%) RANCHF vs. 4/11 (36%) NORANCHF patients. Since improved P&S in RANCHF patients seemed independent of improved brain natriuretic peptide and impedance cardiography (BioZ) measurements, 5 day RAN was given to 30 subjects without CHF but with high SB or CAN. P&S improved in 90% of these subjects. RAN improves unfavorable P&S activity in CHF possibly by a direct effect upon autonomic sodium channels.

Increased Rho kinase activity in congestive heart failure

Rho kinases (ROCKs) are the best characterized effectors of the small G-protein RhoA, and play a role in enhanced vasoconstriction in animal models of congestive heart failure (CHF). This study examined if ROCK activity is increased in CHF and how it is associated with the outcome in CHF. Patients admitted with CHF (n =178), disease controls (n =31), and normal subjects (n =30) were studied. Baseline ROCK activity was measured by phosphorylation of themyosin-binding subunit in peripheral leucocytes. The patients were followed up for 14.4 ± 7.2 months (range 0.5-26 months) or until the occurrence of cardiac death. The ROCK activity in CHF patients (2.93 ± 0.87) was significantly higher than that of the disease control (2.06 ± 0.38, P < 0.001) and normal control (1.57 ± 0.43, P < 0.001) groups. Similarly, protein levels of ROCK1 and ROCK2 as well as the activity of RhoA in CHF were significantly higher than in disease controls and normal controls (all P < 0.05). Dyspnoea at rest (β =0.338, P < 0.001), low left ventricular ejection fraction (β = -0.277, P < 0.001), and high creatinine (β =0.202, P =0.006) were independent predictors of the baseline ROCK activity in CHF. Forty-five patients died within 2 years follow-up (25.3%). Combining ROCK activity and N-terminal pro brain natriuretic peptide (NT-proBNP) had an incremental value (log rank χ(2) =11.62) in predicting long-term mortality when compared with only NT-proBNP (log rank χ(2) =5.16, P < 0.05). ROCK activity is increased in CHF and it might be associated with the mortality in CHF. ROCK activity might be a complementary biomarker to CHF risk stratification.

Bradykinin receptor blockade reduces sympathetic nerve response to muscle contraction in rats with ischemic heart failure

Previous animal and human studies have suggested that a muscle reflex engaged during contraction leads to heightened levels of sympathetic activity in congestive heart failure (CHF). The present experiment was designed to test the role for bradykinin, which is produced within contracting skeletal muscle and contributes to the muscle reflex through its action on kinin B(2) receptors located on the endings of thin fiber muscle afferents. CHF was induced in rats by myocardial infarction (MI) after coronary artery ligation. Echocardiography was performed to determine fractional shortening (FS), an index of the left ventricular function. In the decerebrate rats, we examined renal sympathetic nerve activity (RSNA) during 1 min intermittent (1 to 4 s stimulation to relaxation) contraction of left triceps surae muscles. RSNA responded synchronously as tension was developed, and the response was significantly (P < 0.05) greater in MI rats [+39 +/- 9% s(-1) (integrated RSNA over time); n = 16] with 20 +/- 2% of FS than that in control healthy rats (+19 +/- 2% s(-1); n = 16) with 49 +/- 2% of FS. Tension development did not differ significantly between the two groups of rats. Thirty minutes after intra-arterial injection into the hindlimb circulation of the kinin B(2) receptor antagonist, HOE-140 (2 microg/kg), the RSNA response to contraction was significantly reduced in the MI rats (+26 +/- 7% s(-1)) but not in the control rats (+17 +/- 2% s(-1)). These data suggest that bradykinin within contracting muscle is part of the exaggerated muscle reflex seen in CHF.

Amelioration of Cardiac Remodeling in Congestive Heart Failure by β-Adrenoceptor Blockade is Associated with Depression in Sympathetic Activity

This study investigated whether improvement in cardiac function and attenuation of cardiac remodeling by some beta-adrenoceptor (beta-AR) antagonists were associated with a depression in sympathetic activity in congestive heart failure (CHF) due to myocardial infarction (MI). Although cardiac dysfunction, hypertrophy and dilatation as well as increased plasma level of catecholamines are known to occur in CHF, the relationship between these parameters is poorly understood. Three weeks after occlusion of the coronary artery, rats were treated daily with 20 and 75 mg/kg of either atenolol or propranolol for 5 weeks. Sham-operated rats served as controls. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated the MI-induced cardiac hypertrophy, increases in left ventricular (LV) end-diastolic pressure, LV end-systolic volume and LV end-diastolic volume as well as depressions in LV systolic pressure, LV fractional shortening and cardiac output. PR interval was decreased and QT( c ) interval was increased in CHF; these alterations were ameliorated by both atenolol and propranolol. The increased level of plasma epinephrine in CHF was also depressed by both low and high doses of atenolol and propranolol whereas the increased level of plasma norepinephrine was reduced by high but not low doses of these drugs. The results indicate that the beneficial effects of beta-AR antagonists on cardiac remodeling and heart dysfunction in CHF may be due to the blockade of beta-ARs in the myocardium and a depression in the sympathetic activity.

Both enalapril and losartan attenuate sarcolemmal Na+-K+-ATPase remodeling in failing rat heart due to myocardial infarctionThis article is one of a selection of papers published in the special issue Bridging the Gap: Where Progress in Cardiovascular and Neurophysiologic Research Meet.

To investigate the mechanisms underlying the depressed sarcolemmal (SL) Na(+)-K(+)-ATPase activity in congestive heart failure (CHF), different isoforms and gene expression of Na(+)-K(+)-ATPase were examined in the failing left ventricle (LV) at 8 weeks after myocardial infarction (MI). In view of the increased activity of renin-angiotensin system (RAS) in CHF, these parameters were also studied after 5 weeks of treatment with enalapril (10 mg x kg-1 x day-1), an angiotensin-converting enzyme inhibitor, and losartan (20 mg.kg-1.day-1), an angiotensin II type 1 receptor antagonist, starting at 3 weeks after the coronary ligation in rats. The infarcted animals showed LV dysfunction and depressed SL Na(+)-K(+)-ATPase activity. Protein content and mRNA levels for Na(+)-K(+)-ATPase alpha2 isoform were decreased whereas those for Na(+)-K(+)-ATPase alpha3 isoform were increased in the failing LV. On the other hand, no significant changes were observed in protein content or mRNA levels for Na(+)-K(+)-ATPase alpha1 and beta1 isoforms. The treatment of infarcted animals with enalapril or losartan improved LV function and attenuated the depression in Na(+)-K(+)-ATPase alpha2 isoform as well as the increase in alpha3 isoform, at both the protein and mRNA levels; however, combination therapy with enalapril and losartan did not produce any additive effects. These results provide further evidence that CHF due to MI is associated with remodeling of SL membrane and suggest that the blockade of RAS plays an important role in preventing these alterations in the failing heart.

Altered Na+/Ca2+-exchanger activity due to downregulation of Na+/K+-ATPase 2-isoform in heart failure

The Na+/K+-ATPase (NKA) alpha2-isoform is preferentially located in the t-tubules of cardiomyocytes and is functionally coupled to the Na+/Ca(+-exchanger (NCX) and Ca2+ regulation through intracellular Na+ concentration ([Na+]i). We hypothesized that downregulation of the NKA alpha2-isoform during congestive heart failure (CHF) disturbs the link between Na+ and Ca2+, and thus the control of cardiomyocyte contraction. NKA isoform and t-tubule distributions were studied using immunocytochemistry, confocal and electron microscopy in a post-infarction rat model of CHF. Sham-operated rats served as controls. NKA and NCX currents (I NKA and I NCX) were measured and alpha2-isoform current (I NKA,alpha2) was separated from total I NKA using 0.3 microM ouabain. Detubulation of cardiomyocytes was performed to assess the presence of alpha2-isoforms in the t-tubules. In CHF, the t-tubule network had a disorganized appearance in both isolated cardiomyocytes and fixed tissue. This was associated with altered expression patterns of NKA alpha1- and alpha2-isoforms. I NKA,alpha2 density was reduced by 78% in CHF, in agreement with decreased protein expression (74%). When I NKA,alpha2 was blocked in Sham cardiomyocytes, contractile parameters converged with those observed in CHF. In Sham, abrupt activation of I NKA led to a decrease in I NCX, presumably due to local depletion of [Na+]i in the vicinity of NCX. This decrease was smaller when the alpha2-isoform was downregulated (CHF) or inhibited (ouabain), indicating that the alpha2-isoform is necessary to modulate local [Na+]i close to NCX. Downregulation of the alpha2-isoform causes attenuated control of NCX activity in CHF, reducing its capability to extrude Ca2+ from cardiomyocytes.

Left Stellate Ganglion and Vagal Nerve Activity and Cardiac Arrhythmias in Ambulatory Dogs With Pacing-Induced Congestive Heart Failure

The purpose of this study was to determine the patterns of autonomic nerve activity in congestive heart failure (CHF). The relationship between autonomic nerve activity and cardiac arrhythmias in CHF is unclear. We implanted radiotransmitters in 6 dogs for continuous (24/7) simultaneous monitoring of left stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and electrocardiography before and after pacing-induced CHF. Congestive heart failure increased both SGNA and VNA. The SGNA but not VNA manifested a circadian variation pattern. There was extensive sinus node fibrosis. We analyzed 2,263 episodes of prolonged (>3 s) sinus pauses (PSP) and 1,420 long (>10 s) episodes of paroxysmal atrial tachycardia (PAT). Most (95.3%) PSP episodes occurred at night, and 56% were preceded by a short burst of SGNA that induced transient sinus tachycardia. Long PAT episodes were typically (83%) induced by simultaneous SGNA and VNA discharge, followed by VNA withdrawal. Premature ventricular contractions and ventricular tachycardia were preceded by elevated SGNA. The reduction of sympathovagal balance at night in ambulatory dogs was due to reduced sympathetic discharge rather than a net increase of vagal discharge. The tachybrady syndrome in CHF might be triggered by an intermittent short burst of SGNA that resulted in tachycardia and sinus node suppression. Simultaneous sympathovagal discharge is a cause of long PAT episodes. These data indicate that there is an association between the specific patterns of autonomic nerve discharges and cardiac arrhythmia during CHF.

Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy

Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.

A questionnaire-based assessment of daily physical activity in heart failure.

Type and dose of daily energy expenditure (DEE) play a major role in modulations of health status and an increased knowledge of these dimensions of physical activity in congestive heart failure (CHF) patients would be valuable for clinical and epidemiological aims. We propose a new self-administered DEE questionnaire adapted to CHF patients and tested its validity. One hundred and five stable CHF participants, NYHA class I-IV, LVEF=33.2+/-6.1% performed an incremental symptom-limited Vo(2) (peak) test and filled in the questionnaire for DEE calculation. Reproducibility (n=24), sensitivity (n=21) of the questionnaire and inter-observer variability (n=105) were tested. Intensity levels were identified from DEE and their relationships to Vo(2)(peak), ventilatory and anthropometric characteristics were assessed by simple and multiple regression models. Reproducibility and sensitivity were high (r=0.98 and 0.88, respectively, P<0.0001) and inter-observer error reached 1.37%. DEE was highly correlated to physical activity energy expenditure (r=0.96, P<0.0001). Relationships between DEE, Vo(2)(peak), V(E)/Vo(2) and anthropometric characteristics were significant. An activity level above 3 MET was the best intensity criteria related to Vo(2)(peak) (r=0.62, P<0.0001) and DEE (r=0.80, P<0.0001). The questionnaire seems reproducible, sensible and valid for DEE estimation. Vo(2)(peak) appears related to DEE and especially to activities above 3 MET in CHF.

A questionnaire-based assessment of daily physical activity in heart failure

Type and dose of daily energy expenditure (DEE) play a major role in modulations of health status and an increased knowledge of these dimensions of physical activity in congestive heart failure (CHF) patients would be valuable for clinical and epidemiological aims. We propose a new self-administered DEE questionnaire adapted to CHF patients and tested its validity. One hundred and five stable CHF participants, NYHA class I–IV, LVEF=33.2±6.1% performed an incremental symptom-limited Vo2 (peak) test and filled in the questionnaire for DEE calculation. Reproducibility (n=24), sensitivity (n=21) of the questionnaire and inter-observer variability (n=105) were tested. Intensity levels were identified from DEE and their relationships to Vo2(peak), ventilatory and anthropometric characteristics were assessed by simple and multiple regression models. Reproducibility and sensitivity were high (r=0.98 and 0.88, respectively, P<0.0001) and inter-observer error reached 1.37%. DEE was highly correlated to physical activity energy expenditure (r=0.96, P<0.0001). Relationships between DEE, Vo2(peak), VE/Vo2 and anthropometric characteristics were significant. An activity level above 3 MET was the best intensity criteria related to Vo2(peak) (r=0.62, P<0.0001) and DEE (r=0.80, P<0.0001). The questionnaire seems reproducible, sensible and valid for DEE estimation. Vo2(peak) appears related to DEE and especially to activities above 3 MET in CHF.

Validity of ambulatory accelerometry to quantify physical activity in heart failure.

The purpose was to assess the validity of a novel Activity Monitor to quantify physical activity in congestive heart failure. The Activity Monitor is based on long-term ambulatory monitoring of signals from body-fixed accelerometers. Information can be obtained on which mobility-related activity is performed, when, how intense, and for how long. Ten patients performed several functional activities. Continuous registrations of accelerometer signals were made and the output was compared with visual analysis of simultaneously made video recordings (reference method). Overall results showed an agreement between both methods of 90%. Percentages of sensitivity and predictive value were higher than 80% for most activities. Overall number of transitions was determined well (Activity Monitor, 153; video, 149; p = 0.33). It was concluded that the Activity Monitor is a valid instrument to quantify several aspects of everyday physical activity in congestive heart failure.

Supplemental oxygen does not modulate responses to acetylcholine or ascorbic acid in the forearm of patients with congestive heart failure

Despite providing symptomatic relief in patients with congestive heart failure (CHF), supplemental oxygen (O2) has been demonstrated to increase total peripheral resistance. The present study investigated the possibility that O2 inhalation reduces nitric oxide (NO) bioavailability, using endothelium-dependent (acetylcholine) and -independent (phentolamine) vasodilators, and the antioxidant ascorbic acid. Ten patients (nine male and one female) with primary left ventricular failure participated in the study. Forearm venous occlusion plethysmography was used to study blood flow responses to acetylcholine and the α-adrenergic antagonist phentolamine during inhalation of either room air or 100% O2, with and without the simultaneous infusion of ascorbic acid. Neither O2 inhalation (3.9±0.4 compared with 3.8±0.3 ml⋅min-1⋅100 ml-1) nor ascorbic acid infusion (5.2±0.4 compared with 5.5±0.4 ml⋅min-1⋅100 ml-1) affected resting forearm blood flow. The percentage increase from basal blood flow after acetylcholine infusion was not altered by either O2 inhalation or ascorbic acid infusion (room air, 140±55%; O2, 118±46%; ascorbic acid, 147±39%; ascorbic acid+O2, 109±31%). O2 inhalation did, however, reduce the dilation induced by phentolamine (room air, 131±24%; O2, 80±14%; P &lt; 0.05). These data indicate that oxygen inhalation does not increase forearm vascular resistance. Secondly, preservation of reactivity to acetylcholine during O2 inhalation suggests that degradation of NO by O2-derived free radicals is not enhanced. Attenuation of phentolamine-induced vasodilation during O2 inhalation, however, implies increased adrenergic activity, which may possibly exacerbate the detrimental effects of elevated sympathetic activity in CHF.

Supplemental oxygen does not modulate responses to acetylcholine or ascorbic acid in the forearm of patients with congestive heart failure

Despite providing symptomatic relief in patients with congestive heart failure (CHF), supplemental oxygen (O(2)) has been demonstrated to increase total peripheral resistance. The present study investigated the possibility that O(2) inhalation reduces nitric oxide (NO) bioavailability, using endothelium-dependent (acetylcholine) and -independent (phentolamine) vasodilators, and the antioxidant ascorbic acid. Ten patients (nine male and one female) with primary left ventricular failure participated in the study. Forearm venous occlusion plethysmography was used to study blood flow responses to acetylcholine and the alpha-adrenergic antagonist phentolamine during inhalation of either room air or 100% O(2), with and without the simultaneous infusion of ascorbic acid. Neither O(2) inhalation (3.9+/-0.4 compared with 3.8+/-0.3 ml.min(-1).100 ml(-1)) nor ascorbic acid infusion (5.2+/-0.4 compared with 5.5+/-0.4 ml.min(-1).100 ml(-1)) affected resting forearm blood flow. The percentage increase from basal blood flow after acetylcholine infusion was not altered by either O(2) inhalation or ascorbic acid infusion (room air, 140+/-55%; O(2), 118+/-46%; ascorbic acid, 147+/-39%; ascorbic acid+O(2), 109+/-31%). O(2) inhalation did, however, reduce the dilation induced by phentolamine (room air, 131+/-24%; O(2), 80+/-14%; P<0.05). These data indicate that oxygen inhalation does not increase forearm vascular resistance. Secondly, preservation of reactivity to acetylcholine during O(2) inhalation suggests that degradation of NO by O(2)-derived free radicals is not enhanced. Attenuation of phentolamine-induced vasodilation during O(2) inhalation, however, implies increased adrenergic activity, which may possibly exacerbate the detrimental effects of elevated sympathetic activity in CHF.

Identification of Changes in Cardiac Phospholipase C Activity in Congestive Heart Failure

Although phosphoinositide-specific phospholipase C (PLC) is involved in signal transduction mechanisms of the myocardial cell, very little is known about its status in congestive heart failure (CHF). We have examined the PLC activity in sarcolemmal and cytosolic fractions isolated from the viable left ventricle of rats at 8 weeks (moderate stage of CHF) and 16 weeks (severe stage of CHF) after occlusion of the left anterior descending coronary artery; the hypertrophied right ventricle was used for comparison. At 8 weeks, the hydrolysis of phosphatidylinositol 4,5-bisphosphate by sarcolemmal PLC was reduced by 37% of sham control values only in the left ventricle, whereas at 16 weeks, PLC-mediated hydrolysis was depressed in both left and right ventricles by 25% and 30%, respectively. The hydrolysis of phosphatidylinositol 4-monophosphate (PIP) was reduced by 25% of control value only in the severely failing left ventricle, while the phosphatidylinositol (PI) hydrolysis remained unaltered. Kinetic studies of PLC activity in the left ventricle showed a depression of Vmaxat moderate and severe failure stages, whereas the affinity for the substrate was increased in the left ventricle at 8 weeks and decreased in the right ventricle at 16 weeks. The only difference observed between experimental and control groups at the cytosolic level, was a significant enhancement of PLC activity in the severely failing left ventricle when PIP was given as a substrate, and in the corresponding right ventricle when PI was the substrate. The results of this study identify time-related defects in sarcolemmal PLC in right and left ventricles during the development of CHF due to myocardial infarction.

Decreased expression of cardiac sarcoplasmic reticulum Ca(2+)-pump ATPase in congestive heart failure due to myocardial infarction.

Myocardial infarction in rats induced by occluding the left coronary artery for 4, 8 and 16 weeks has been shown to result in congestive heart failure (CHF) characterized by hypertrophy of the viable ventricular myocardial tissue. We have previously demonstrated a decreased calcium transport activity in the sarcoplasmic reticulum (SR) of post-myocardial infarction failing rat hearts. In this study we have measured the steady state levels of the cardiac SR Ca(2+)-pump ATPase (SERCA2) mRNA using Northern blot and slot blot analyses. The relative amounts of SERCA2 mRNA were decreased with respect to GAPDH mRNA and 28 S rRNA in experimental failing hearts at 4 and 8 weeks post myocardial infarction by about 20% whereas those at 16 weeks declined by about 35% of control values. The results obtained by Western blot analysis, revealed that the immunodetectable levels of SERCA2 protein in 8 and 16 weeks postinfarcted animals were decreased by about 20% and 30%, respectively. The left ventricular SR Ca(2+)-pump ATPase specific activity was depressed in the SR preparations of failing hearts as early as 4 weeks post myocardial infarction and declined by about 65% at 16 weeks compared to control. These results indicate that the depressed SR Ca(2+)-pump ATPase activity in CHF may partly be due to decreased steady state amounts of SERCA2 mRNA and SERCA2 protein in the failing myocardium.

809-2 Effect of Digoxin on Cardiac Sympathetic Activity in Congestive Heart Failure

The effect of cardiac glycosides on cardiac sympathetic activity in congestive heart failure (CHF) remains uncertain. We measured total body and cardiac norepinephrine spillover (NESP) using the norepinephrine isotope-dilution technique at baseline and 30 minutes after digoxin (0.25 mg iv). LV pressure, its first derivative (Millar), and systemic BP were also measured before and after digoxin. We studied 15 patients with CHF; 5 with normal LV filling pressures (LVEOP ≤ 14, mean 9 ± 2 mmHg). and 10 with high LV filling pressures (LVEOP &gt; 14. mean 26 ± 3 mmHg). The groups had similar baseline HR, BP. and LV +dP/dt. The high LVEOP group had a lower EF (20 ± 2 vs 34 ± 2%, p &lt; 0.05), a lower CI (1.7 ± 0.2 vs 2.8 ± 0.3 L/min/m 2 , p &lt; 0.05), and higher mean PA pressures (31 ± 4vs 14 ± 2 mmHg, p &lt; 0.05) at baseline, as compared to the normal LVEOP group. HR, BP, LVEOP, LV +dp/dt, coronary sinus blood flow, and total body NESP did not change in either group following digoxin. Cardiac NESP was unchanged in response to digoxin in the normal LVEOP group. Importantly, digoxin caused a consistent reduction in cardiac NESP in the high LVEOP group: LVEDP Cardiac NESP (pmol/min) Baseline Digoxin ≤ 14 mmHg 91 ± 28 111 ± 36 &gt; 14 mmHg 189 ± 63 159 ± 57 * All data expressed as mean ± SEM * p = 0.016, by paired t test This study demonstrates that the acute administration of digoxin reduces cardiac NESP in patients with CHF and high LV filling pressures. This reduction in cardiac sympathetic activity appears to be mediated by a non-hemodynamic mechanism, since digoxin in the dose used in this study did not cause changes in either the loading conditions or the contractile state of the LV

I defibrillation threshold

The purpose of this study was to determine the patterns of autonomic nerve activity in congestive heart failure (CHF).The relationship between autonomic nerve activity and cardiac arrhythmias in CHF is unclear.We implanted radiotransmitters in 6 dogs for continuous (24/7) simultaneous monitoring of left stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and electrocardiography before and after pacing-induced CHF.Congestive heart failure increased both SGNA and VNA. The SGNA but not VNA manifested a circadian variation pattern. There was extensive sinus node fibrosis. We analyzed 2,263 episodes of prolonged (>3 s) sinus pauses (PSP) and 1,420 long (>10 s) episodes of paroxysmal atrial tachycardia (PAT). Most (95.3%) PSP episodes occurred at night, and 56% were preceded by a short burst of SGNA that induced transient sinus tachycardia. Long PAT episodes were typically (83%) induced by simultaneous SGNA and VNA discharge, followed by VNA withdrawal. Premature ventricular contractions and ventricular tachycardia were preceded by elevated SGNA.The reduction of sympathovagal balance at night in ambulatory dogs was due to reduced sympathetic discharge rather than a net increase of vagal discharge. The tachybrady syndrome in CHF might be triggered by an intermittent short burst of SGNA that resulted in tachycardia and sinus node suppression. Simultaneous sympathovagal discharge is a cause of long PAT episodes. These data indicate that there is an association between the specific patterns of autonomic nerve discharges and cardiac arrhythmia during CHF.