Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure.

BACKGROUND: Previous studies have shown that marked changes in myocardial mitochondrial structure and function occur in human cardiac failure. To further understand the cellular events and to clarify their role in the pathology of cardiac failure, we have examined mitochondrial enzymatic function and peptide content, and mitochondrial DNA (mtDNA) integrity in a canine model of pacing-induced cardiac failure. METHODS: Myocardium and skeletal muscle tissues were evaluated for levels of respiratory complex I-V and citrate synthase activities, large-scale mtDNA deletions as well as peptide content of specific mitochondrial enzyme subunits. Levels of circulating and cardiac tumor necrosis factor-alpha (TNF-alpha), and of total aldehyde content in left ventricle were also assessed. RESULTS: Specific activity levels of complex III and V were significantly lower in both myocardial and skeletal muscle tissues of paced animals compared to controls. In contrast, activity levels of complex I, II, IV and citrate synthase were unchanged, as was the peptide content of specific mitochondrial enzyme subunits. Large-scale mtDNA deletions were found to be more likely present in myocardial tissue of paced as compared to control animals, albeit at a relatively low proportion of mtDNA molecules (<0.01% of wild-type). In addition, the reduction in complex III and V activities was correlated with elevated plasma and cardiac TNF-alpha levels. Significant increases in left ventricle aldehyde levels were also found. CONCLUSIONS: Our data show reductions in specific mitochondrial respiratory enzyme activities in pacing-induced heart failure which is not likely due to overall decreases in mitochondrial number, or necrosis. Our findings suggest a role for mitochondrial dysfunction in the pathogenesis of cardiac failure and may indicate a commonality in the signaling for pacing-induced mitochondrial dysfunction in myocardial and skeletal muscle. Increased levels of TNF-alpha and oxidative stress appear to play a contributory role.

Specific and non-specific measurements of tissue angiotensin II cascade members.

Although angiotensin II (ANG II) has been the focal regulatory peptide of the renin-angiotensin system, its proteolytic fragments have recently been demonstrated to have biological effects. Conventional measurement of angiotensins involves radioimmunoassay (RIA), which is a sensitive binding technique capable of measuring low physiological concentrations. However, ANG II antibody cross-reacts with ANG II and its fragments (ANG II cascade), rendering RIA measurement alone to be a non-specific measure of immunoreactive ANG II (ir-ANG II). On the other hand, high-performance liquid chromatography (HPLC) is capable of separating immunoreactive ANG II cascade members, but may not be sensitive enough to detect these low peptide concentrations often present in biological samples. Consequently, a reverse-phase HPLC method, with triethylammoniun formate as an ion-pair reagent, was developed to separate ANG II and its fragments, ANG III, ANG IV and ANG V. This HPLC separation was applied to extracts from normal canine hearts and ANG II cascade immunoreactive fractions were collected. Collected fractions were quantified by RIA, with the use of separate standard curves. The isocratic HPLC separation of ANG II, ANG III, ANG IV and ANG V was achieved in less than 5 min with adjacent peaks having baseline resolution. Measured cardiac left ventricle ANG III, ANG IV and ANG V concentrations (mean+/-SD) were 5.3+/-2.2,4.0+/-1.0 and 3.1+/-1.0 fmol/g (n=9), respectively. There was a significant difference (P=0.003, n=9) between left ventricular immunoreactive ANG II and 'true' ANG II, corrected for recovery rates of 86.2+/-22.5 and 53.5+/-16.2 fmol/g, respectively. We conclude that the combination of HPLC with RIA ensures the specific measurement of the ANG II cascade family members while non-chromatographic processing of tissue renders ANG II measurement non-specific. In addition, the use of triethylammonium formate as mobile phase additive is superior in the HPLC separation of the angiotensins.

Neurohormonal activation in severe heart failure: relations to patient death and the effect of treatment with flosequinan.

BACKGROUND: Flosequinan is a direct-acting vasodilator that exerts beneficial hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that long-term administration of flosequinan is associated with increased mortality rate. To explore a possible role of neurohormonal activation on this adverse outcome, we conducted a substudy to examine the plasma levels of 3 neurohormonal systems known to have prognostic implications in heart failure. METHODS: At 20 participating Canadian centers, paired plasma samples at baseline and 1 month after randomization for the measurement of N-terminal atrial natriuretic peptide (N-ANP), angiotensin II, and norepinephrine were obtained in 234 patients (114 receiving flosequinan and 120 receiving placebo). RESULTS: Treatment with flosequinan was associated with a decline in median plasma N-ANP levels (2139 pmol/L at baseline to 1625 pmol/L at 1 month [P =. 0001]), unchanged plasma angiotensin II levels (40 to 50 pmol/L [P =. 2700]), and a modest increase in plasma norepinephrine levels (391 to 439 pg/mL [P =.002]). These changes were not observed in the placebo group. Multivariate analysis of baseline variables revealed that plasma norepinephrine level predicted patients' death whereas analysis incorporating both baseline and 1-month variables indicated that plasma N-ANP level predicted patients' death. Furthermore, in the flosequinan group, a significant decline in plasma N-ANP level was observed in the survivors only. On multivariate analysis of baseline and 1-month data, the increase in plasma norepinephrine level did not predict the increase in heart rate associated with the use of flosequinan, suggesting that the 2 effects might be mediated by separate mechanisms. CONCLUSIONS: Results of our study demonstrate that in patients with severe heart failure, baseline norepinephrine level predicts death. Flosequinan increases plasma norepinephrine level and heart rate in these patients through mechanisms that override its beneficial hemodynamic effects. Our study reinforces the concept that the direct actions of a pharmacologic agent may have a more profound impact on the prognosis of these patients than the hemodynamic effects.

Simultaneous separation of angiotensin and endothelin peptide families by high-performance liquid chromatography: application to the specific radioimmunoassay measurement of angiotensin II or endothelin-1 from tissue.

Currently available measurements of endogenous angiotensin II (ANG II) and endothelin-1 (ET-1) concentrations by radioimmunoassay (RIA) lack specificity to ANG II or ET-1. ANG II and ET-1 antibodies cross-react with immuno-reactive angiotensin and endothelin family members, respectively. We have therefore developed an ion-pair reversed-phase high-performance liquid chromatography (HPLC) for simultaneously separating angiotensin and endothelin peptides and enhancing RIA specificity in the measurement of ANG II and ET-1. The developed HPLC separation was applied to canine myocardium extracts; ANG II or ET-1 fractions were collected and quantified by RIA. Elution times for both peptide families, ANG I, ANG II, ANG III, ANG IV, ANG II(4-8), bET-1, ET-1, ET-2 and ET-3 were within 25 min. In normal canine myocardium from the right atrium, right ventricle, left atrium and left ventricle, ANG II concentrations were 39+/-11, 28+/-21, 31+/-11 and 21+/-8 fmol/g and ET-1 concentrations were 43+/-16, 42+/-19, 55+/-21 and 57+/-34 fmol/g (mean+/-SD, N=7), respectively. The combination of HPLC with RIA renders the measurement of ANG II or ET-1 specific and convenient, and saves time. This HPLC separation may be applied to the specific measurement of other immuno-reactive angiotensin and endothelin peptides.

ARCTIC: assessment of haemodynamic response in patients with congestive heart failure to telmisartan: a multicentre dose-ranging study in Canada.

BACKGROUND: The aim of this study was to examine the acute hemodynamic and neurohormonal effects of the angiotensin II antagonist telmisartan relative to placebo in patients with chronic symptomatic (New York Heart Association class II to III) congestive heart failure and to explore the dose-response relation for these effects. METHODS AND RESULTS: After baseline hemodynamic and neurohormonal measurements made with the use of a pulmonary artery and radial arterial catheter, 82 patients were randomly assigned to placebo or 10, 20, 40, or 80 mg of telmisartan in a double-blind fashion. Hemodynamic and neurohormonal measurements were carried out over 24 hours. Telmisartan caused significant decreases in systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures with evidence of a dose-response relation for each of these parameters. The drug had no significant effects on heart rate, cardiac index, or systemic vascular resistance. Telmisartan did not have consistent effects on either plasma norepinephrine or plasma atrial natriuretic peptide levels, although it did cause significant increases in both plasma renin activity and angiotensin II levels at higher doses. CONCLUSIONS: The acute administration of the angiotensin II antagonist telmisartan was associated with significant dose-dependent reductions in systemic arterial blood pressure and pulmonary pressures. Long-term follow-up studies are required to translate changes in hemodynamic parameters into a clinical benefit.

Reduced pulmonary metabolism of endothelin-1 in canine tachycardia-induced heart failure.

OBJECTIVES: Plasma endothelin-1 (ET-1) increases in congestive heart failure (CHF). The pulmonary vascular bed could contribute to this increase through a reduced clearance. We evaluated the effect of tachycardia-induced CHF on pulmonary ET-1 kinetics. To discern between changes due to variations in pulmonary hemodynamics from true alterations of endothelial cell functions, we quantified ET-1 kinetics in isolated rat lungs under variable pressure and flow-rate conditions. METHODS AND RESULTS: Indicator-dilution studies were performed in anesthetized dogs (n = 14) before and 3 weeks after rapid ventricular pacing and in isolated lungs from healthy rats (n = 4). In isolated lungs, graded increases in perfusion rate from 5-25 ml/min caused gradual reductions in ET-1 extraction from 60 +/- 1.5% to 17 +/- 4.9% (mean +/- S.D.). The capacity to clear ET-1 from the circulation, as computed from the permeability-surface area product (PS), however did not vary over this range of flows. CHF increased plasma ET-1 (11.2 +/- 11.4 vs. 5.2 +/- 1.6 fmol/ml, p < 0.01), did not affect pulmonary ET-1 extraction (29.4 +/- 12.5% vs. 29.9 +/- 12.9%), but decreased the PS (8.3 +/- 5.4 cm3/s vs. 14.4 +/- 9.9 cm3/s, p = 0.038). Contrary to the invariability of the PS in normal isolated rat lungs, CHF was associated with a positive relationship between the PS and pulmonary plasma flow (r = 0.65, p < 0.01). ET-1 binding studies in lung tissues showed no significant variations in ETA and ETB receptors densities but revealed a threefold decrease in binding affinity (p < 0.01) that may explain the reduced clearance. CONCLUSION: CHF causes a reduction of pulmonary ET-1 clearance that likely contributes to the increased circulating ET-1 levels and reflects pulmonary metabolic dysfunction associated with this condition.

Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure.

OBJECTIVES: We examined the effects of chronic type A endothelin receptor (ETA) blockade in a dog model of pacing-induced cardiomyopathy. METHODS: Eight dogs received an ETA antagonist, LU 135252 (50 mg/kg orally daily) and nine dogs received a matching placebo starting at day three of pacing and continued for the remainder of the three weeks of pacing. RESULTS: In the placebo group, the mean pulmonary artery pressure and left ventricular end diastolic pressure increased from 16 +/- 3 and 8 +/- 2 mmHg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mmHg, respectively, at two weeks (both p < 0.001 versus baseline). Cardiac output declined from 3.5 +/- 0.7 to 1.9 +/- 0.6 l/min (p < 0.001). In the treatment group, LU 135252 attenuated the increase in mean pulmonary artery and left ventricular end diastolic pressure (16 +/- 3 and 9 +/- 1 mmHg at baseline to 29 +/- 3 and 27 +/- 3 mmHg, respectively, at two weeks (p < 0.001), and the decline in cardiac output (3.2 +/- 0.3 to 2.6 +/- 0.8 l/min, p < 0.01; p < 0.05 versus placebo for the three parameters). Systemic and pulmonary vascular resistance increased only in the placebo group. Left ventricular end-diastolic volume increased to a similar degree. However, LU 135252 attenuated the increase in plasma norepinephrine level (placebo, 1.2 +/- 0.5 to 3.7 +/- 1.9 pmol/l; treatment, 0.8 +/- 0.3 to 2.4 +/- 0.6 pmol/l; both p < 0.001 versus baseline; p < 0.05 versus placebo). CONCLUSION: Our results suggest that endothelin-1 plays a role in the hemodynamic perturbations in canine pacing-induced cardiomyopathy. The favourable hemodynamic effects without concomitant aggravation of neurohormonal activation suggests that ETA receptor blockade may be beneficial in the treatment of heart failure.

Does a hypertonic saline load predict fluid retention in pacing induced heart failure?

OBJECTIVE: We examined the response to hypertonic saline challenge (SC) as a potential predictor of fluid retention during heart failure induced by rapid ventricular pacing. METHODS: Twelve dogs (22 +/- 4 kg) were given an intra-arterial bolus of 30 ml of 20% saline after establishing baseline fluid intake and urine output (24 h). Dogs were classified according to whether they drank more (Group A) or less (Group B) than the amount required to dilute the s.c. to isotonicity. Fluid retention was then assessed during heart failure after rapid ventricular pacing according to a graded ordinal scale and correlated with the responses to s.c.. RESULTS: No difference was noted in baseline fluid intake (1112 +/- 236 ml in Group A vs. 809 +/- 129 ml in Group B). Five hours after s.c. cumulative water intake was significantly greater in Group A than in Group B (1018 +/- 136 vs. 591 +/- 17 ml) (P < 0.01). Urine sodium concentration was 113 +/- 11 and 124 +/- 28 mmol/l at baseline in Group A and B, respectively; increased to 190 +/- 21 and 295 +/- 59 mmol/l at 5 h and remained elevated 24 h after s.c., 177 +/- 60 and 274 +/- 55 mmol/l (both P < 0.01 for within-group comparisons vs. baseline). Urine sodium concentration was less in Group A than in Group B at 5 and 24 h (P < 0.05). The fluid retention score was greater in Group A (3.6 +/- 0.5) than in Group B (0.8 +/- 0.4) (P < 0.01). Fluid retention in heart failure correlated with water intake after the pre-pacing s.c. (r = 0.68, P < 0.025) and inversely with urine concentrating ability (r = -0.58, P < 0.05). Furthermore, water intake and urine concentrating ability following the s.c. were inversely related (r = -0.67, P < 0.02). CONCLUSIONS: We conclude that normal dogs may be classified according to their fluid intake after s.c.. Those dogs that drank excessively and produced a dilute urine were more likely to retain fluid during pacing-induced heart failure. Hence, fluid intake and the ability to excrete a concentrated urine after a saline challenge may be useful variables to predict fluid retention in pacing-induced heart failure.

Biatrial appendage hypertrophy but not ventricular hypertrophy: a unique feature of canine pacing-induced heart failure.

BACKGROUND: The canine model of pacing-induced heart failure is characterized by an absence of ventricular hypertrophy despite severe hemodynamic stress and neurohormonal activation. Given the mode of ventricular pacing, hypertrophy might occur in the atrial appendage. METHODS AND RESULTS: Seventeen dogs underwent continuous right ventricular pacing for 3 weeks to severe heart failure. Twelve normal dogs served as control subjects. Pacing produced marked increases in both pulmonary capillary wedge pressure (7.6 +/- 1.8 mmHg at baseline to 32.6 +/- 7.5 mmHg at 3 weeks, P < .001) and right atrial pressure (6.5 +/- 1.8 to 15.1 +/- 2.4 mmHg, P < .001), marked increases in normalized left ventricular volume (3.0 +/- 0.5 to 4.6 +/- 0.5 mL/kg, P < .001) and left atrial volume (1.0 +/- 0.2 to 2.6 +/- 0.5 mL/kg, P < .001), but no change in left ventricular mass (2.3 +/- 0.4 to 2.6 +/- 0.5 g/kg, differences not significant), indicating no ventricular hypertrophy. Compared to the control dogs, total heart weight in the test animals was similar, but both the left appendage (0.18 +/- 0.04 vs 0.10 +/- 0.03 g/kg, P < .001) and right atrial appendage (0.15 +/- 0.03 vs 0.12 +/- 0.02 g/kg, P = .004) were much heavier than those of the control dogs. CONCLUSIONS: Rapid right ventricular pacing in the dog induces severe heart failure associated with a dichotomous response in the atrial appendage versus the ventricle. Aside from being a useful heart failure model that simulates the human condition, this unique feature may have physiologic implications in terms of atrial mechanical and endocrine functions and have applications for future studies into the mechanisms of cardiac remodeling and hypertrophy.

Plasma and cardiac tissue atrial and brain natriuretic peptides in experimental heart failure.

OBJECTIVES: This study evaluated the role of changes in heart rate, cardiac filling pressures and cardiac tissue atrial and brain natriuretic peptides in the modulation of their plasma levels in a model of heart failure. BACKGROUND: Atrial and brain natriuretic peptides constitute a dual natriuretic peptide system that regulates circulatory homeostasis. METHODS: The effects of 1) acute ventricular pacing, 2) acute volume expansion, and 3) volume expansion after 1 week of continuous pacing on plasma atrial and brain natriuretic peptide levels were compared in eight dogs. Atrial and ventricular tissue levels of the peptides were examined in 5 normal dogs (control group), 21 dogs paced for 1 week (group 1) and 10 dogs paced for 3 weeks (group 2). RESULTS: Both acute pacing and volume expansion increased plasma atrial natriuretic peptide levels (from 53 +/- 41 to 263 +/- 143 pg/ml [mean +/- SD], p < 0.01, and from 38 +/- 23 to 405 +/- 221 pg/ml, p < 0.001, respectively). After 1 week, there was a marked increase in plasma levels of atrial natriuretic peptide, but the level did not increase further with volume expansion (from 535 +/- 144 to 448 +/- 140 pg/ml, p = 0.72). By contrast, plasma brain natriuretic peptide levels increased only modestly with acute pacing (from 12 +/- 4 to 20 +/- 8 pg/ml, p < 0.05) and after pacing for 1 week (from 13 +/- 4 to 48 +/- 20 pg/ml, p < 0.05) but did not change with acute or repeat volume expansion. In groups 1 and 2, atrial tissue levels of atrial natriuretic peptide (1.9 +/- 1.3 and 2.0 +/- 0.9 ng/mg, respectively) were lower than those in the control group (11.7 +/- 6.8 ng/mg, both p < 0.001), whereas ventricular levels were similar to those in the control group. Atrial tissue brain natriuretic peptide levels in groups 1 and 2 were similar to those in the control group. However, ventricular levels in group 2 (0.018 +/- 0.006 ng/mg) were increased compared with those in the control group (0.013 +/- 0.006 ng/mg, p < 0.05) and in group 1 (0.011 +/- 0.006 ng/mg, p < 0.05). CONCLUSIONS: Atrial and brain natriuretic peptides respond differently to changes in heart rate and atrial pressures. Reduced atrial tissue atrial natriuretic peptide levels in heart failure may indicate reduced storage after enhanced cardiac release. However, the relatively modest change in cardiac tissue brain natriuretic peptide levels suggests that the elevated plasma levels may be mediated by mechanisms other than increased atrial pressures.

How does intermittent pacing modify the response to rapid ventricular pacing in experimental heart failure?

Rapid ventricular pacing is widely accepted as a useful model to produce heart failure. The heart failure is associated with reduced myocardial energy stores and absence of cardiac hypertrophy. In this study, it was hypothesized that a modification of the protocol to intermittent pacing would permit time for partial recovery of myocardial energetics leading to improved cardiac function and development of hypertrophy. Eight dogs underwent conventional continuous right ventricular pacing to a biologic endpoint of severe heart failure (group 1). Another eight dogs underwent an intermittent pacing protocol over 7 weeks, consisting of 48-hour pacing alternating with 24-hour sinus rhythm (group 2) so as to produce the same total exposure to continuous pacing as in group 1. Six additional normal dogs were used as control animals for tissue metabolic data. Although both paced groups had similar directional changes in hemodynamic, neurohormonal, and echocardiographic variables, the absolute increases in pulmonary capillary wedge and right atrial pressures in group 2 (13 +/- 8 and 3 +/- 4 mmHg, respectively) were less marked than in group 1 (29 +/- 5 and 12 +/- 4 mmHg, respectively; both P = .002). Group 2 also had a more modest rise in plasma atrial natriuretic peptide and norepinephrine concentrations. There was no significant increase, however, in left ventricular mass in either group, and myocardial adenosine 5'-triphosphate levels were reduced to a similar extent compared to the control animals. Intermittent pacing produces a less advanced syndrome of heart failure than continuous pacing. Furthermore, the data suggest that reduced energy stores are not the predominant mechanism for impaired cardiac function, although they may contribute to the failure to hypertrophy in this model.

Sarcoplasmic reticulum Ca-release channel and ATP-synthesis activities are early myocardial markers of heart failure produced by rapid ventricular pacing in dogs.

The contraction-relaxation cycle of the heart is dependent on a cycle of ATP production and utilization and a cycle of Ca uptake and Ca release by the sarcoplasmic reticulum (SR). Heart failure (HF) is associated with abnormalities of myocardial Ca and ATP cycling, but the time course of their development is unknown. This study tested the hypothesis that, compared with ATP-utilizing and Ca-uptake activities, decreases in ATP-synthesis and Ca-release activities occurred earlier in the development of HF and persisted longer during recovery from HF. HF was induced by right ventricular pacing of dogs at 250 beats/min. Dogs were studied after 1 week of pacing (n = 8, early HF), at HF (n = 11, severe HF), and 4 weeks after cessation of pacing (n = 9) and were compared with dogs not subjected to pacing. At early HF, there were decreased activities (p < 0.05) of the SR Ca-release channel (rate constant from 199 +/- 36 x 10(-4) to 90 +/- 16 x 10(-4) s-1), mitochondrial ATP synthesis (from 11.2 +/- 2.4 to 7.0 +/- 2.2 international units (IU)/g), and creatine kinase (CK) from 2028 +/- 266 to 1811 +/- 79 IU/g). The decreased Ca-channel activity was due to a 32% decrease in maximal activity (rate constant from 249 +/- 50 x 10(-4) to 170 +/- 29 x 10(-4) s-1) and to a 2-fold increase (from 19.1 +/- 12.4 to 42.0 +/- 14.2%) in inhibition of maximal channel activity (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Structural remodelling in heart failure: gelatinase induction.

OBJECTIVE: Rapid ventricular pacing in the dog produces severe congestive cardiac failure in association with neurohumoral activation and marked depression of cardiac function. This syndrome is associated with left ventricular dilation, significant wall thinning, assumption of a more globular shape and disruption of the cardiac collagen infrastructure, given that the fibrillar collagen network is a major determinant of cardiac architecture. The purpose of the present study was to investigate whether there was evidence of increased activity of matrix metalloproteinases. The authors speculated that it could play an important permissive role in myocyte realignment, thereby resulting in the changes in cardiac size and shape. DESIGN: Twenty-one male mongrel dogs underwent ventricular pacing and were allocated into one of three groups: early heart failure (n = 6), severe heart failure (n = 7) and recovered heart failure (n = 8). Measurements included echocardiographic and hemodynamic parameters, plasma noradrenaline levels, left ventricular noradrenaline levels and matrix metalloproteinase activity. RESULTS: The study showed gelatinase activity present in normal left ventricular tissue predominantly attributable to a 72 kDa gelatinase (85%) and, to a much lesser extent, by a 92 kDa gelatinase (15%). Levels of 92 kDa gelatinase increased slightly within one week and reached maximal levels with severe heart failure, where it represented over one-half of the total gelatinase activity. In animals allowed to recover for four weeks, 92 kDa gelatinase decreased significantly to approximately 50% of the levels observed at severe heart failure. The levels of 72 kDa gelatinase did not change significantly during any experimental condition. Significant correlations between 92 kDa percentage activity and systolic and diastolic left ventricular areas across all time-points were evident (r = 0.59 and 0.63, respectively, P < 0.05 for both). CONCLUSION: The association of 92 kDa gelatinase with changes in left ventricular area suggests a possible modulating role for this matrix metalloproteinase in disruption of the fibrillar components of the left ventricular extracellular matrix.

Recovery of attenuated baroreflex sensitivity in conscious dogs after reversal of pacing induced heart failure.

OBJECTIVE: Rapid ventricular pacing reliably induces severe congestive heart failure in dogs, with an associated attenuation of baroreflex sensitivity. Unique to this model is the capacity for rapid recovery of haemodynamics and plasma noradrenaline following the cessation of pacing; however, whether baroreflex sensitivity will similarly recover is unknown. The aims of this study were (1) to assess baroreflex control of heart rate in response to acute hypertensive and hypotensive stimuli during the development of and recovery from severe heart failure, and (2) to correlate baroreflex sensitivity with haemodynamic and echocardiographic indices and with noradrenaline concentrations. METHODS: Serial assessments were performed on six dogs paced to severe heart failure and then allow to recover for four weeks. R-R interval and systolic blood pressure were monitored during administrations of phenylephrine and nitroprusside and the slope (ms.mm Hg-1) of the resultant R-R interval-systolic blood pressure relationship was used to define baroreflex sensitivity. RESULTS: Control phenylephrine and nitroprusside derived slopes were 27.05(SD 7.88) and 17.1(11.03) ms.mm Hg-1 respectively. After one week of pacing the phenylephrine derived slope was unchanged while the nitroprusside slope tended to be attenuated. In severe heart failure, both slopes were severely attenuated, at 1.88(6.45) ms.mm Hg-1 (phenylephrine) and 4.21(3.28) ms.mm Hg-1 (nitroprusside) (both p < 0.05). Intrinsic heart rate, noradrenaline concentrations and cardiac filling pressures were raised at severe heart failure while cardiac output and systolic blood pressure were significantly reduced. Recovery of baroreflex control of heart rate was evident as early as 48 h following pacing cessation and was maintained after four weeks recovery. Haemodynamics, cardiac output, and noradrenaline also returned to control while cardiac dilatation persisted. Nitroprusside and phenylephrine derived slopes were inversely correlated with intrinsic heart rate and pulmonary arterial/capillary wedge pressures respectively. CONCLUSIONS: Despite marked attenuation of baroreflex control of heart rate at severe heart failure, rapid recovery was seen in response to both hypotensive and hypertensive stimuli. The speed with which recovery occurs suggests that attenuation of baroreflex sensitivity at severe heart failure is likely to be mediated by functional alterations rather than morphological damage.

Myocardial energetics and blood flow in acute rapid ventricular pacing.

The mechanism whereby chronic rapid ventricular pacing induces severe heart failure is unclear, but the phenomenon is associated with a reduction in left ventricular ATP levels. Accordingly, the current study was undertaken to evaluate the acute effects of rapid ventricular pacing on hemodynamics, left ventricular adenine nucleotide levels, myocardial blood flow, and oxygen consumption. Anesthetized dogs (n = 7) were studied in sinus rhythm and during 30 min of pacing at 250 beats/min. Pacing caused a significant (means +/- SD, all p < 0.001) decrease in cardiac output (3.0 +/- 0.6 to 2.0 +/- 0.6 L/min) and peak left ventricular systolic pressure (133 +/- 14 to 82 +/- 10 mmHg (1 mmHg = 133.3 Pa)) and an increase in pulmonary wedge pressure (10 +/- 2 to 18 +/- 3 mmHg). Following pacing, the peak first derivative of left ventricular pressure and the relaxation time constant, tau, remained unchanged compared with baseline values. Myocardial blood flow and oxygen consumption both increased by 70% with pacing. The transmural distribution of myocardial blood flow and myocardial lactate consumption remained unchanged. There was no change in left ventricular ATP or ADP levels with the observed increase in myocardial oxygen consumption. Therefore, the hemodynamic deterioration associated with acute rapid ventricular pacing, in contrast to that of chronic pacing, is not associated with perturbed myocardial energetics.

Left ventricular remodelling and disparate changes in contractility and relaxation during the development of and recovery from experimental heart failure.

OBJECTIVES: Canine pacing induced heart failure is characterised by impaired left ventricular contractility and relaxation, and clinical recovery after cessation of pacing. It is unclear whether the impairment is responsive to adrenergic stimulation. The aim of this study was to assess left ventricular contractility and relaxation and their response to beta adrenergic stimulation during heart failure and after recovery. METHODS: Eight dogs were paced (250 beats.min-1) for 3 weeks to severe heart failure and recovered for 4 weeks after cessation of pacing. During these periods, haemodynamic and echocardiographic measurements were made with and without beta adrenergic stimulation. RESULTS: At heart failure, impaired left ventricular contractility was evidenced by reduced dP/dt [1412(SD 156) mm Hg.s-1 from 2437(382) mm Hg.s-1 at control, p < 0.01] and a downward displacement of the velocity of circumferential fibre shortening-end systolic wall stress relation. Impaired left ventricular relaxation was evidenced by raised end diastolic pressure [35(6) mm Hg from 7(4) mm Hg at control, p < 0.01] and prolonged relaxation time constant tau [28(4) ms from 17(6) ms, p < 0.01]. The ability of beta adrenergic stimulation to augment contractility was reduced: there was blunted dP/dt response to dobutamine. The ability of beta adrenergic stimulation to shorten relaxation was maintained: there was a similar degree of shortening of tau by dobutamine. At recovery, dP/dt returned to control and the shortening-stress relation moved upward, suggesting return of contractility. The response of dP/dt to dobutamine was restored. However, tau remained prolonged indicating persistent abnormal relaxation. CONCLUSION: In pacing induced heart failure, there is a dissociation between the normal ability of beta adrenergic stimulation to augment contractility and shorten relaxation, and a differential capacity for recovery of contractility and relaxation.

Medical advances in the treatment of congestive heart failure.

The increased incidence and prevalence of congestive heart failure place a high priority on novel treatment strategies. Left ventricular ejection fraction remains the single most valuable measurement providing both diagnostic and prognostic insights. The most systematic approach to heart failure involves an objective assessment of functional disability, to include exercise tests such as a 6-minute walk under standardized conditions. Left ventricular dysfunction incites a host of neurohumoral compensations that are of fundamental importance in the heart failure syndrome expression. Both vasoconstrictor and vasodilator neurohormones are stimulated and provide new therapeutic opportunities. The therapeutic approach to heart failure begins with a strong emphasis on prevention, patient education, and self-participation in therapy with respect to both its monitoring and adjustment. Diuretics remain a mainstay of therapy but, in the face of severe heart failure, may become ineffectual, requiring constant infusion of loop-active diuretics, combination diuretics, or diuretics in association with concomitant low-dose dopamine infusion. Vasodilator therapy has been an important advance: combination hydralazine and nitrate therapy was initially shown to be efficacious in improving survival, and more recently, angiotensin-converting enzyme (ACE) inhibitors, in the form of enalapril, have shown incremental benefit on survival over this combination. Interestingly, there is now evidence from both SOLVD and SAVE to demonstrate an unexpected and, as yet, unexplained reduction in the frequency of both unstable angina and myocardial infarction. Although, on balance, the weight of evidence concerning the long-term efficacy of inotropic agents has been disappointing, especially as it relates to their unfavorable effects on survival, recent information on vesnarinone, an agent with a complex and diversified mechanism of action, suggests that with appropriate doses, improved symptoms and survival are possible. A substantial amount of new information from randomized placebo-controlled trials attests to the symptomatic relief, hemodynamic improvement, and gain in exercise performance achieved by digoxin. A long-term survival study is ongoing to assess its effects on mortality. beta-Blockers, especially metoprolol, appear beneficial in some patients with heart failure, possibly related to their reduction in sympathetic nervous activity and restoration of beta-receptor population, with resultant improved contractile performance, enhanced myocardial relaxation, and overall increase in cardiac efficiency. Based on available evidence, the best contemporary approach to treatment involves the use of ACE inhibitors coupled with diuretic therapy, either continuous or intermittent, to relieve central or peripheral congestion. The addition of digoxin or a hydralazine nitrate combination is a logical next step, with commencement of low-dose beta-blocker a reasonable option.(ABSTRACT TRUNCATED AT 400 WORDS)

Dual natriuretic peptide system in experimental heart failure.

OBJECTIVES: The objectives of this study were 1) to define in an experimental model of heart failure the time course of changes in plasma brain natriuretic peptide concentrations during the development of and recovery from heart failure, and 2) to relate the changes to changes in atrial natriuretic peptide concentration and hemodynamic status. BACKGROUND: Brain natriuretic peptide is a circulating peptide with homology to atrial natriuretic peptide. However, unlike the latter, its changes during heart failure and its relation to cardiac filling pressures have not been studied. METHODS: Eight male mongrel dogs underwent right ventricular pacing at 250 beats/min for 3 weeks until heart failure occurred and were followed up during recovery for 4 weeks after cessation of pacing. RESULTS: Heart failure was characterized by an increase in both left ventricular and end-diastolic pressure (6.6 +/- 4.1 mm Hg at the control measurements to 35.1 +/- 5.9 mm Hg at 3 weeks, p < 0.01) and right atrial pressure (6.7 +/- 1.1 to 11.4 +/- 2.1 mm Hg, p < 0.01). Recovery was accompanied by a return of cardiac filling pressures to control level. The time course of change of arterial plasma brain natriuretic peptide concentration was similar to that of atrial natriuretic peptide. Plasma concentrations of both peptides increased after 1 week of pacing (16 +/- 4 pg/ml at the control measurement to 59 +/- 20 pg/ml at 1 week, p < 0.001 for brain natriuretic peptide and 84 +/- 55 to 856 +/- 295 pg/ml, p < 0.001 for atrial natriuretic peptide). The level of both peptides then stayed level with no further increase at 3 weeks and returned to the control value by 4 weeks of recovery. There was an excellent correlation between plasma concentrations of the two peptides (r = 0.86, p < 0.001) and between the two peptides and cardiac filling pressures. However, compared with atrial natriuretic peptide, plasma brain natriuretic peptide concentration had a smaller percent increase during evolving heart failure and a slower rate of decline at recovery. CONCLUSIONS: Brain and atrial natriuretic peptide constitute a dual natriuretic system and are both responsive to changes in cardiac filling pressures in heart failure. However, brain natriuretic peptide appears to be less responsive than atrial natriuretic peptide.