The decreased oxygen uptake during progressive exercise in ischemia-induced heart failure is due to reduced cardiac output rate.

We tested the hypothesis that the inability to increase cardiac output during exercise would explain the decreased rate of oxygen uptake (VO2) in recent onset, ischemia-induced heart failure rats. Nine normal control rats and 6 rats with ischemic heart failure were studied. Myocardial infarction was induced by coronary ligation. VO2 was measured during a ramp protocol test on a treadmill using a metabolic mask. Cardiac output was measured with a flow probe placed around the ascending aorta. Left ventricular end-diastolic pressure was higher in ischemic heart failure rats compared with normal control rats (17 +/- 0.4 vs 8 +/- 0.8 mmHg, P = 0.0001). Resting cardiac index (CI) tended to be lower in ischemic heart failure rats (P = 0.07). Resting heart rate (HR) and stroke volume index (SVI) did not differ significantly between ischemic heart failure rats and normal control rats. Peak VO2 was lower in ischemic heart failure rats (73.72 +/- 7.37 vs 109.02 +/- 27.87 mL min(-1) kg(-1), P = 0.005). The VO2 and CI responses during exercise were significantly lower in ischemic heart failure rats than in normal control rats. The temporal response of SVI, but not of HR, was significantly lower in ischemic heart failure rats than in normal control rats. Peak CI, HR, and SVI were lower in ischemic heart failure rats. The reduction in VO2 response during incremental exercise in an ischemic model of heart failure is due to the decreased cardiac output response, largely caused by depressed stroke volume kinetics.

The decreased oxygen uptake during progressive exercise in ischemia-induced heart failure is due to reduced cardiac output rate

We tested the hypothesis that the inability to increase cardiac output during exercise would explain the decreased rate of oxygen uptake (VO2) in recent onset, ischemia-induced heart failure rats. Nine normal control rats and 6 rats with ischemic heart failure were studied. Myocardial infarction was induced by coronary ligation. VO2 was measured during a ramp protocol test on a treadmill using a metabolic mask. Cardiac output was measured with a flow probe placed around the ascending aorta. Left ventricular end-diastolic pressure was higher in ischemic heart failure rats compared with normal control rats (17 ± 0.4 vs 8 ± 0.8 mmHg, P = 0.0001). Resting cardiac index (CI) tended to be lower in ischemic heart failure rats (P = 0.07). Resting heart rate (HR) and stroke volume index (SVI) did not differ significantly between ischemic heart failure rats and normal control rats. Peak VO2 was lower in ischemic heart failure rats (73.72 ± 7.37 vs 109.02 ± 27.87 mL min-1 kg-1, P = 0.005). The VO2 and CI responses during exercise were significantly lower in ischemic heart failure rats than in normal control rats. The temporal response of SVI, but not of HR, was significantly lower in ischemic heart failure rats than in normal control rats. Peak CI, HR, and SVI were lower in ischemic heart failure rats. The reduction in VO2 response during incremental exercise in an ischemic model of heart failure is due to the decreased cardiac output response, largely caused by depressed stroke volume kinetics.

Acupuncture effects on reflex responses to mental stress in humans.

In animal studies, acupuncture has been shown to be sympathoinhibitory, but it is unknown if acupuncture is sympathoinhibitory in humans. Nineteen healthy volunteers underwent mental stress testing pre- and postacupuncture. Muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate during mental stress were compared pre- and postacupuncture. Control acupuncture consisted of acupuncture at nonacupoints and "no-needle" acupuncture. Acupuncture had no effect on resting MSNA, blood pressure, or heart rate. After real acupuncture, the increase in mean arterial pressure (pre- vs. postacupuncture 4.5 vs. 1.7 mmHg, P < 0.001), but not MSNA or heart rate, was blunted during mental stress. Similarly, following nonacupoint acupuncture, the increase in mean arterial pressure was blunted during mental stress (5.4 vs. 2.9 mmHg, P < 0.0003). No-needle acupuncture had no effect on these variables. In conclusion, acupuncture at traditional acupoints, nonacupoints, and no-needle acupuncture does not modulate baseline MSNA or MSNA responses to mental stress in normal humans. Acupuncture significantly attenuates the increase in blood pressure during mental stress. Needling nonacupoints, but not "no-needle" acupuncture, have a similar effect on blood pressure.

Exaggerated muscle mechanoreflex control of reflex renal vasoconstriction in heart failure.

In heart failure (HF) patients, reflex renal vasoconstriction during exercise is exaggerated. We hypothesized that muscle mechanoreceptor control of renal vasoconstriction is exaggerated in HF. Nineteen HF patients and nineteen controls were enrolled in two exercise protocols: 1) low-level rhythmic handgrip (mechanoreceptors and central command) and 2) involuntary biceps contractions (mechanoreceptors). Renal cortical blood flow was measured by positron emission tomography, and renal cortical vascular resistance (RCVR) was calculated. During rhythmic handgrip, peak RCVR was greater in HF patients compared with controls (37 +/- 1 vs. 27 +/- 1 units; P < 0.01). Change in (Delta) RCVR tended to be greater as well but did not reach statistical significance (10 +/- 1 vs. 7 +/- 0.9 units; P = 0.13). RCVR was returned to baseline at 2-3 min postexercise in controls but remained significantly elevated in HF patients. During involuntary muscle contractions, peak RCVR was greater in HF patients compared with controls (36 +/- 0.7 vs. 24 +/- 0.5 units; P < 0.0001). The Delta RCVR was also significantly greater in HF patients compared with controls (6 +/- 1 vs. 4 +/- 0.6 units; P = 0.05). The data suggest that reflex renal vasoconstriction is exaggerated in both magnitude and duration during dynamic exercise in HF patients. Given that the exaggerated response was elicited in both the presence and absence of central command, it is clear that intact muscle mechanoreceptor sensitivity contributes to this augmented reflex renal vasoconstriction.

Adenosine enhances neuroexcitability by inhibiting a slow postspike afterhyperpolarization in rabbit vagal afferent neurons.

BACKGROUND: Electrophysiological mechanisms by which adenosine may activate cardiac afferent neurons are unknown. Slow afterhyperpolarizations (AHPs) follow action potentials in a subset of vagal C afferents, rendering them inexcitable. The purpose of this study was to test the hypothesis that adenosine increases vagal neuronal excitability by blocking slow AHPs and to determine the adenosine receptor subtype mediating these effects. METHODS AND RESULTS: Using the perforated patch-clamp technique, we identified cultured adult rabbit nodose ganglion cells with slow AHPs in current-clamp mode. Trains of 100 current pulses at 20% above threshold were injected, with an interspike interval of 100 ms, and the number of action potentials triggered were counted and reported as the action potential response rate. During adenosine (10 micromol/L), slow AHPs were suppressed and action potential response rate was augmented from 3.8+/-0.5% at baseline to 28+/-7% after adenosine (P:=0.0009). The selective A(2)-adenosine receptor agonist NECA but not the A(1)-adenosine agonist CCPA replicated the adenosine effect. The selective A(2A)-adenosine antagonist ZM 241385 (10 nmol/L) but not the A(1) adenosine antagonist DPCPX (5 micromol/L) abolished the adenosine effect. We considered two alternative hypotheses: (1) A(2)-receptor-mediated suppression of I(Ca) leading to smaller increases in intracellular Ca during stimulation, resulting in less activation of I(K(Ca)) and consequent suppression of slow AHPs, or (2) A(2)-receptor-mediated elevation of cAMP directly suppressing slow AHPs. Under voltage-clamp conditions, adenosine did not significantly inhibit I(Ca), making the latter hypothesis more likely. CONCLUSIONS: Adenosine inhibits slow AHPs in vagal afferent neurons. This effect is most likely caused by A(2A)-receptor-mediated stimulation of cAMP production.

Abnormal neurovascular control during exercise is linked to heart failure severity.

The purpose of this study was to determine if abnormalities of sympathetic neural and vascular control are present in mild and/or severe heart failure (HF) and to determine the underlying afferent mechanisms. Patients with severe HF, mild HF, and age-matched controls were studied. Muscle sympathetic nerve activity (MSNA) and forearm vascular resistance (FVR) in the nonexercising arm were measured during mild and moderate static handgrip. MSNA during moderate handgrip was higher at baseline and throughout exercise in severe HF vs. mild HF (peak MSNA 67 +/- 3 vs. 54 +/- 3 bursts/min, P < 0.0001) and higher in mild HF vs. controls (33 +/- 3 bursts/min, P < 0.0001), but the change in MSNA was not different between the groups. The change in FVR was not significantly different between the three groups during static exercise. During isolation of muscle metaboreceptors, MSNA and blood pressure remained elevated in normal controls and mild HF but not in severe HF. During mild handgrip, the increase in MSNA was exaggerated in severe HF vs. controls and mild HF, in whom MSNA did not increase. In summary, the increase in MSNA during static exercise in severe HF appears to be attributable to exaggerated central command or muscle mechanoreceptor control, not muscle metaboreceptor control.

Exaggerated renal vasoconstriction during exercise in heart failure patients.

BACKGROUND: During static exercise in normal healthy humans, reflex renal cortical vasoconstriction occurs. Muscle metaboreceptors contribute importantly to this reflex renal vasoconstriction. In patients with heart failure, in whom renal vascular tone is already increased at rest, it is unknown whether there is further reflex renal vasoconstriction during exercise. METHODS AND RESULTS: Thirty-nine heart failure patients (NYHA functional class III and IV) and 38 age-matched control subjects (controls) were studied. Renal blood flow was measured by dynamic positron emission tomography. Graded handgrip exercise and post-handgrip ischemic arrest were used to clarify the reflex mechanisms involved. During sustained handgrip (30% maximum voluntary contraction), peak renal vasoconstriction was significantly increased in heart failure patients compared with controls (70+/-13 versus 42+/-1 U, P=0.02). Renal vasoconstriction returned to baseline in normal humans by 2 to 5 minutes but remained significantly increased in heart failure patients at 2 to 5 minutes and had returned to baseline at 20 minutes. In contrast, during post-handgrip circulatory arrest, which isolates muscle metaboreceptors, peak renal vasoconstriction was not greater in heart failure patients than in normal controls. In fact, the increase in renal vasoconstriction was blunted in heart failure patients compared with controls (20+/-5 versus 30+/-2 U, P=0.05). CONCLUSIONS: During sustained handgrip exercise in heart failure, both the magnitude and duration of reflex renal vasoconstriction are exaggerated in heart failure patients compared with normal healthy humans. The contribution of the muscle metaboreceptors to reflex renal vasoconstriction is blunted in heart failure patients compared with normal controls.

Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure.

The extent to which abnormal endothelium-dependent vasodilator mechanisms contribute to abnormal resting vasoconstriction and blunted reflex vasodilation seen in heart failure is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vascular tone that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. Thirteen advanced heart-failure patients (New York Heart Association III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine (20 microg/min), or L-arginine (10 mg/min) was infused into the brachial artery, and forearm blood flow was measured by venous plethysmography at rest and during mental stress. At rest, acetylcholine decreased forearm vascular resistance in normal subjects, but this response was blunted in heart failure. During mental stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm vascular resistance was not greater than during saline control in heart failure [saline control vs. acetylcholine (7 +/- 3 vs. 6 +/- 3, P = NS) or vs. L-arginine (9 +/- 2 units, P = NS)]. The increase in forearm blood flow was not greater than during saline control in heart failure [saline control vs. acetylcholine (1. 2 +/- 0.3 vs. 1.3 +/- 0.3, P = NS), or vs. L-arginine (1.2 +/- 0.2 ml x min(-1) x 100 ml(-1), P = NS)]. Furthermore, during mental stress with nitroprusside, the decrease in forearm vascular resistance was not greater than during saline control [saline control vs. nitroprusside (7 +/- 3 vs. 5 +/- 4 ml x min(-1) x 100 g(-1), P = NS)], and the increase in forearm blood flow was not greater than during saline control [saline control vs. nitroprusside (1.2 +/- 0.3 vs. 1.3 +/- 0.5 ml x min(-1) x 100 g(-1), P = NS)]. Because the endothelial-independent agent nitroprusside was unable to restore resting and reflex vasodilation to normal in heart failure, we conclude that impaired endothelium-mediated vasodilation with acetylholine-nitric oxide cannot be the principal cause of the attenuated resting- or reflex-mediated vasodilation in heart failure.

The treatment of heart failure: the role of neurohumoral activation.

Neurohumoral activation refers to increased activity of the sympathetic nervous system, renin-angiotensin system, vasopressin and atrial natriuretic peptide. It is now known that neurohumoral activation contributes to the transition from ventricular dysfunction to clinical heart failure, and is an independent predictor of poor prognosis in heart failure. Although the treatment of heart failure has traditionally focused on drugs to improve ventricular function, there is increasing evidence that therapeutic modulation of neurohumoral activation is a key to successful treatment of heart failure. For example, there is mounting evidence that angiotensin converting enzyme inhibitors (the unquestioned cornerstone for treatment of heart failure), beta receptor blockers, digitalis, and endurance exercise training exert their benefit in heart failure in large part through neurohumoral modulation. This observation--discussed in this brief review--highlights the concept that compensatory neurohumoral activation to decreased cardiac function may itself contribute to the development of heart failure and its poor prognosis.

Localization and functional effects of adenosine A1 receptors on cardiac vagal afferents in adult rats.

There is evidence to suggest that during ischemia adenosine acts on cardiac vagal afferent neurons to activate systemic reflexes and to modulate cardiac nociception. The purpose of this study was to determine whether adenosine receptors are present and have direct cellular electrophysiological actions on cardiac vagal afferent neurons. In radioreceptor assays of nodose ganglion tissue from rats, binding was detectable for A1 (39.6 +/- 1.2 fmol/mg protein) but not A2a adenosine receptors. These findings were confirmed using the complementary approach of receptor-labeling autoradiography. Using in situ hybridization, we saw specific labeling over approximately 50% of neurons in the nodose ganglia, but not over nonneuronal cells. In colabeling studies, cardiac vagal afferent neurons were identified by retroneuronal labeling with fluororuby. Of cardiac vagal afferents approximately one-half were strongly positive for A1 adenosine receptors (immunocytochemistry). In patch-clamping experiments, adenosine inhibited peak inward calcium current in 7 of 11 cells by 48 +/- 13%. In conclusion, adenosine A1 receptors reside on a subset of vagal afferent neurons, including cardiac vagal afferents, and have electrophysiological effects that modulate neuroexcitability in cultured nodose ganglion neurons.

Impact of acute mental stress on sympathetic nerve activity and regional blood flow in advanced heart failure: implications for 'triggering' adverse cardiac events.

BACKGROUND: Evidence is accumulating that specific "triggers," such as intense psychological stress, may precipitate myocardial infarction and sudden death. Patients with advanced heart failure have increased resting sympathoexcitation, which has been directly related to increased mortality. The impact of triggers on sympathetic nerve activity and regional blood flow in heart failure has not been examined in patients with heart failure. METHODS AND RESULTS: Twenty-seven patients with heart failure (NYHA functional class III or IV) and 26 age-matched normal control subjects were studied. Muscle sympathetic nerve activity, heart rate, mean arterial pressure, forearm blood flow, and renal blood flow were measured during mental stress testing with mental arithmetic and Stroop color word test. Patients with heart failure had elevated levels of resting muscle sympathetic nerve activity and heart rate. Mental stress significantly increased muscle sympathetic nerve activity and heart rate in both patients with heart failure and control subjects, although the magnitude of increases tended to be blunted in patients with heart failure. Nevertheless, absolute levels of sympathetic activity in patients with heart failure remained significantly higher than levels in control subjects during mental stress. The decrease in renal blood flow in patients with heart failure was similar to that of control subjects, despite greater resting renal vasoconstriction. The increase in forearm blood flow during mental stress testing in patients with heart failure was blunted compared with that of control subjects. CONCLUSIONS: Patients with heart failure do not have augmented muscle sympathetic nerve activity responses to mental stress, despite elevated resting levels of sympathetic activity, but they do have markedly higher absolute levels of sympathetic nerve activity during mental stress as well as at rest.

Mechanisms and implications of autonomic nervous system dysfunction in heart failure.

Neurohumoral activation characterizes heart failure. Patients with the greatest amount of neurohumoral activation, as estimated by plasma norepinephrine levels, have the worst prognosis. The fundamental mechanisms underlying this neurohumoral activation remain unknown, however. Recent data support the hypothesis that early sympathetic dysregulation in heart failure is attributable to early attenuation of cardiac and arterial baroreceptor control of sympathetic nerve activity. Neurohumoral excitation is organ specific, affecting the heart first. Neurohumoral activation follows a stepwise pattern, with resistance to atrial natriuretic peptide and marked sympathetic activation characterizing a transition period from left ventricular dysfunction to overt heart failure. Renin-angiotensin-aldosterone system activation then occurs. Additional abnormalities of afferent systems, such as augmented muscle metaboreceptor sensitivity and increased peripheral chemoreceptor sensitivity, may modulate the sympathetic activation in established heart failure. Brain ouabainlike activity has been shown to cause sympathetic excitation in two animal models of heart failure and may play a key (although presently undefined) role in neurohumoral excitation in humans with heart failure. Therapies that interrupt, or even reverse, the neurohumoral activation in heart failure hold the greatest promise for the growing patient population afflicted with this syndrome.

Modulation of renal cortical blood flow during static exercise in humans.

During static exercise, several reflex systems that increase sympathetic nerve activity, heart rate, arterial pressure, and cardiac output are activated. At rest, the renal circulation receives the most blood flow per tissue weight of any organ in the body. However, the renal circulatory response to static exercise has not been studied in humans because of technical limitations in methods for measuring rapid changes in renal blood flow. The aim of this study was to determine the renal blood flow response to static exercise in healthy humans and, specifically, to clarify the reflex mechanisms underlying this response. Renal cortical blood flow was measured using dynamic positron emission tomography and the blood flow agent oxygen-15 water. Graded handgrip exercise, posthandgrip circulatory arrest, and administration of intra-arterial adenosine were performed to clarify the mechanisms controlling renal blood flow during static exercise. The major new findings in this study are that in healthy humans (1) renal cortical blood flow decreases (basal versus handgrip, 4.4 +/- 0.1 versus 3.5 +/- 0.1 mL.min-1.g-1; P = .008) and renal cortical vascular resistance increases (basal versus handgrip, 17 +/- 1 versus 26 +/- 2 U; P = .01) in response to static handgrip exercise; (2) central command and/or the mechanoreflex contributes importantly to the early decrease in renal blood flow (basal versus handgrip, 4.2 +/- 0.2 versus 3.5 +/- 0.3 mL.min-1.g-1; P = .04) and to the increase in renal cortical vascular resistance (basal versus handgrip, 20 +/- 1 versus 25 +/- 2 U; P = .04); (3) the muscle metaboreflex contributes to further decreases in renal blood flow (basal versus posthandgrip circulatory arrest, 4.3 +/- 0.1 versus 3.5 +/- 0.2 mL.min-1.g-1; P = .002) and increases in renal cortical vascular resistance (basal versus handgrip, 18 +/- 1 versus 25 +/- 3 U; P = .002); and (4) exogenous adenosine activates the muscle metaboreflex producing reflex renal vasoconstriction and decreased renal blood flow, which may implicate endogenous adenosine generated during ischemic exercise as a potential activator of the muscle metaboreflex during ischemic handgrip exercise.

Improving survival for patients with atrial fibrillation and advanced heart failure.

OBJECTIVES: We attempted to determine whether changes in heart failure therapy since 1989 have altered the prognostic significance of atrial fibrillation. BACKGROUND: Atrial fibrillation occurs in 15% to 30% of patients with heart failure. Despite the recognized potential for adverse effects, the impact of atrial fibrillation on prognosis is controversial. METHODS: Two-year survival for 750 consecutive patients discharged from a single hospital after evaluation for heart transplantation from 1985 to 1989 (Group I, n = 359) and from 1990 to April 1993 (Group II, n = 391) was analyzed in relation to atrial fibrillation. In Group I, class I antiarrhythmic drugs and hydralazine vasodilator therapy were routinely allowed. In Group II, amiodarone and angiotensin-converting enzyme inhibitors were first-line antiarrhythmic and vasodilating drugs. RESULTS: A history of atrial fibrillation was present in 20% of patients in Group I and 24% of those in Group II. Patients with atrial fibrillation in the two groups had similar clinical and hemodynamic profiles. Among patients with atrial fibrillation, those in Group II had a markedly better 2-year survival (0.66 vs. 0.39, p = 0.001) and sudden death-free survival (0.84 vs. 0.70, p = 0.01) than those in Group I. In each time period, survival was worse for patients with than without atrial fibrillation in Group I (0.39 vs. 0.55, p = 0.002) but not in Group II (0.66 vs. 0.75, p = 0.09). CONCLUSIONS: The prognosis of patients with advanced heart failure and atrial fibrillation is improving. These findings support the practice of avoiding class I antiarrhythmic drugs in this group and may reflect recent beneficial changes in heart failure therapy.

Dynamics of muscle sympathetic nerve activity in advanced heart failure patients.

Muscle sympathetic nerve activity (MSNA) is increased in patients with heart failure compared with healthy subjects. We applied spectral and correlation techniques to determine if qualitative as well as quantitative differences in MSNA differentiate heart failure patients from healthy subjects. We recorded MSNA, heart rate, and respiration in 11 heart failure patients and 10 healthy humans. Our results are as follows. 1) Statistically significant low-frequency modulation of MSNA at 0.029 +/- 0.002 Hz (mean +/- SE; range 0.026-0.038 Hz) was found in 10 of 11 heart failure patients but in only 2 of 10 healthy controls (differences between groups, P < 0.01; chi 2 test). 2) Heart rate and respiration also demonstrated significant low-frequency modulation in a similar range. 3) Spectral and correlation techniques revealed that low-frequency modulation of MSNA was highly correlated with low-frequency modulation of respiration in heart failure patients, but not in healthy subjects. In contrast, low-frequency modulation of MSNA did not correlate well with low-frequency modulation of heart rate. In summary, low-frequency modulation of respiration is coupled to low-frequency modulation of MSNA in heart failure patients, but not in normal subjects. We speculate that this low-frequency modulation of respiration may represent subclinical Cheyne-Stokes breathing, which has marked qualitative effects on MSNA in patients with heart failure.

Improving survival for patients with advanced heart failure: a study of 737 consecutive patients.

OBJECTIVES: This study sought to determine whether survival and risk of sudden death have improved for patients with advanced heart failure referred for consideration for heart transplantation as advances in medical therapy were systematically implemented over an 8-year period. BACKGROUND: Recent survival trials in patients with mild to moderate heart failure and patients after a myocardial infarction have shown that angiotensin-converting enzyme inhibitors are beneficial, type I antiarrhythmic drugs can be detrimental, and amiodarone may be beneficial in some groups. The impact of advances in therapy may be enhanced or blunted when applied to severe heart failure. METHODS: One-year mortality and sudden death were determined in relation to time, baseline variables and therapeutics for 737 consecutive patients referred for heart transplantation and discharged home on medical therapy from 1986 to 1988, 1989 to 1990 and 1991 to 1993. Medical care was directed by a single team of physicians with policies established by consensus. From 1986 to 1990, the hydralazine/isosorbide dinitrate combination or angiotensin-converting enzyme inhibitors were the initial vasodilators, and class I antiarrhythmic drugs were allowed. After 1990, captopril was the initial vasodilator, given to 86% of patients compared with 46% of patients before 1989. After mid-1989, class I agents were routinely withdrawn, and amiodarone was used for frequent ventricular ectopic beats or atrial fibrillation (53% of patients after 1990 vs. 10% before 1989). RESULTS: The total 1-year mortality rate decreased from 33% before 1989 to 16% after 1990 (p = 0.0001), and sudden death decreased from 20% to 8% (p = 0.0006). Adjusted for clinical and hemodynamic variables in multivariate proportional hazards models, total mortality and sudden death were lower after 1990. CONCLUSIONS: The large reduction in mortality, particularly in sudden death, from advanced heart failure since 1990 may reflect an enhanced impact of therapeutic advances shown in large randomized trials when they are incorporated into a comprehensive approach in this population. This improved survival supports the growing practice of maintaining potential heart transplant candidates on optimal medical therapy until clinical decompensation mandates transplantation.

Amiodarone and torsades de pointes in patients with advanced heart failure.

Amiodarone is considered to be safe in patients with prior QT prolongation and torsades de pointes taking class I antiarrhythmic agents who require continued antiarrhythmic drug therapy. However, the safety of amiodarone in advanced heart failure patients with a history of drug-induced torsades de pointes, who may be more susceptible to proarrhythmia, is unknown. Therefore, the objective of this study was to assess amiodarone safety and efficacy in heart failure patients with prior antiarrhythmic drug-induced torsades de pointes. We determined the history of torsades de pointes in 205 patients with heart failure treated with amiodarone, and compared the risk of sudden death in patients with and without such a history. To evaluate the possibility that all patients with a history of torsades de pointes would be at high risk for sudden death regardless of amiodarone treatment, we compared this risk in patients with a history of torsades de pointes who were and were not subsequently treated with amiodarone. Of 205 patients with advanced heart failure, 8 (4%) treated with amiodarone had prior drug-induced torsades de pointes. Despite similar severity of heart failure, the 1-year actuarial sudden death risk was markedly increased in amiodarone patients with than without prior torsades de pointes (55% vs 15%, p = 0.0001). Similarly, the incidence of 1-year sudden death was markedly increased in patients with prior torsades de pointes taking amiodarone compared with such patients who were not subsequently treated with amiodarone (55% vs 0%, p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of pace mapping QRS configuration and conduction delay to ventricular tachycardia reentry circuits in human infarct scars.

OBJECTIVES: This study sought to determine the relation of the paced QRS configuration and conduction delay during pace mapping to reentry circuit sites in patients with ventricular tachycardia late after myocardial infarction. BACKGROUND: The QRS configuration produced by ventricular pacing during sinus rhythm (pace mapping) can locate focal idiopathic ventricular tachycardias during catheter mapping, but postinfarction reentry circuits may be relatively large and contain regions of slow conduction. We hypothesized that for postinfarction ventricular tachycardia, 1) pacing during sinus rhythm at reentry circuit sites distant from the exit from the scar would produce a QRS configuration different from the tachycardia; and 2) a stimulus to QRS delay during pace mapping may be a useful guide to reentry circuit slow conduction zones. METHODS: Catheter mapping and ablation were performed in 18 consecutive patients with ventricular tachycardia after myocardial infarction. At 85 endocardial sites in 13 patients, 12-lead electrocardiograms (ECGs) were recorded during pace mapping, and participation of each site in a reentry circuit was then evaluated by entrainment techniques during induced ventricular tachycardia or by application of radiofrequency current. RESULTS: Pace maps resembled tachycardia at < 30% of likely reentry circuit sites identified by entrainment criteria and at only 1 (9%) of 11 sites where radiofrequency current terminated tachycardia. Analysis of the stimulus to QRS interval during entrainment with concealed fusion showed that the conduction time from the pacing site to the exit from the scar was longer at sites where the pace map did not resemble tachycardia. Evidence of slow conduction during pace mapping, with a stimulus to QRS interval > 40 ms was observed at > or = 70% of reentry circuit sites. CONCLUSIONS: At many sites in postinfarction ventricular reentry circuits, the QRS configuration during pace mapping does not resemble the ventricular tachycardia QRS complex, consistent with relatively large reentry circuits or regions of functional conduction block during ventricular tachycardia. A stimulus to QRS delay during pace mapping is consistent with slow conduction and may aid in targeting endocardial sites for further evaluation during tachycardia.

Evidence for preserved cardiopulmonary baroreflex control of renal cortical blood flow in humans with advanced heart failure. A positron emission tomography study.

BACKGROUND: The effect of cardiopulmonary baroreflexes on the renal circulation in healthy humans and patients with heart failure is unknown because of the technical limitations of studying the renal circulation. Positron emission tomography (PET) imaging is a new method to measure renal cortical blood flow in humans that is precise, rapid, reproducible, and noninvasive. The purpose of this study was to compare the effect of acute cardiopulmonary baroreceptor unloading by phlebotomy on regional blood flow in healthy humans and humans with advanced heart failure. METHODS AND RESULTS: We compared renal cortical blood flow and forearm blood flow in 10 healthy volunteers and 8 patients with heart failure (left ventricular ejection fraction, 0.24 +/- 0.02) during cardiopulmonary baroreceptor unloading with phlebotomy (450 mL). The major findings of this study are: (1) At rest, renal cortical blood flow is markedly diminished in humans with heart failure compared with healthy humans (heart failure, 2.4 +/- 0.1 versus healthy, 4.3 +/- 0.2 mL.min-1.g-1, P < .001). (2) In healthy humans, during phlebotomy, forearm blood flow decreased substantially (basal, 3.3 +/- 0.4 versus phlebotomy, 2.6 +/- 0.3 mL.min-1.100 mL-1, P = .02) and renal cortical blood flow decreased slightly but significantly (basal, 4.3 +/- 0.2 versus phlebotomy, 4.0 +/- 0.3 mL.min-1.g-1, P = .01). (3) The small magnitude of reflex renal vasoconstriction is not explained by the inability of the renal circulation to vasoconstrict, since the cold pressor stimulus induced substantial decreases in renal cortical blood flow in healthy subjects (basal, 4.4 +/- 0.1 versus cold pressor, 3.7 +/- 0.1 mL.min-1.g-1, P = .003). (4) In humans with heart failure, during phlebotomy, forearm blood flow did not change (basal, 2.6 +/- 0.3 versus phlebotomy, 2.7 +/- 0.2 mL.min-1.100 mL-1, P = NS), but renal cortical blood flow decreased slightly but significantly (basal, 2.4 +/- 0.1 versus phlebotomy, 2.1 +/- 0.1 mL.min-1.g-1, P = .01). (5) The cold pressor stimulus induced substantial decreases in renal cortical blood flow in patients with heart failure (basal, 2.9 +/- 0.1 versus cold pressor, 2.3 +/- 0.1 mL.min-1.g-1, P = .008). Thus, in patients with heart failure, there is an abnormality in cardiopulmonary baroreflex control of the forearm circulation but not the renal circulation. CONCLUSIONS: This study demonstrates the power of PET imaging to study normal physiological and pathophysiological reflex control of the renal circulation in humans and describes the novel finding of selective dysfunction of cardiopulmonary baroreflex control of one vascular region but its preservation in another in patients with heart failure.

Long-term efficacy of amiodarone for the maintenance of normal sinus rhythm in patients with refractory atrial fibrillation or flutter.

The purpose of this study was to examine the efficacy and safety of amiodarone to maintain sinus rhythm in patients with refractory atrial fibrillation or flutter. One hundred ten patients with atrial fibrillation or flutter, refractory to > or = 1 class I antiarrhythmic agents (mean +/- SD 2.5 +/- 1.5, median 2), were given low-dose amiodarone (mean maintenance dose 268 +/- 100 mg/day) to determine its efficacy to maintain normal sinus rhythm after chemical or electrical cardioversion. Fifty-three patients had chronic and 57 patients had paroxysmal atrial fibrillation or flutter. Mean age of the study population was 60 +/- 13 years, and the mean follow-up was 36 +/- 38 months (range 31 days to 137 months). Actuarial rates for maintenance of sinus rhythm were 0.87, 0.70, and 0.55 at 1, 3, and 5 years, respectively. Twenty-one patients (19%) with arrhythmia recurrence had an increase in amiodarone dose, and after a mean additional follow-up of 2.5 years, 86% remained in normal sinus rhythm. The only observed predictor of atrial fibrillation or flutter recurrence was paroxysmal arrhythmia (40% recurrence vs 9% in patients with chronic atrial fibrillation or flutter; p < 0.001). Actuarial rates for withdrawal because of adverse effects were 0.08, 0.22, and 0.30 at 1, 3, and 5 years, respectively. The most frequent adverse effects necessitating withdrawal were skin discoloration (4.5%), pulmonary fibrosis (3.6%; none fatal), and thyroid toxicity (2.7%). No deaths occurred during the study period. In conclusion, amiodarone sinus rhythm in patients with atrial fibrillation or flutter, with a relatively low incidence of adverse effects necessitating withdrawal.