Predicting depression from illness severity in cardiovascular disease patients: self-efficacy beliefs, illness perception, and perceived social support as mediators.

BACKGROUND: Many studies have investigated the relationships between cardiovascular diseases and patients' depression; nevertheless, few is still known as regard the impact of illness severity on depression and whether psychosocial variables mediate this association. PURPOSE: The aim of this study is to investigate the putative mediating role of illness representations, self-efficacy beliefs, and perceived social support on the relationship between illness severity and depression. METHODS: A total of 75 consecutive patients with cardiovascular disease (80 % men; mean age = 65.44, SD = 10.20) were enrolled in an Italian hospital. Illness severity was measured in terms of left ventricular ejection fraction, whereas psychological factors were assessed using self-report questionnaires. RESULTS: The relationship between left ventricular ejection fraction and depression was mediated by identity illness perception, self-efficacy beliefs in managing cardiac risk factors, and perceived social support. CONCLUSION: The treatment of depression in cardiovascular disease patients may therefore benefit from a psychological intervention focused on patients' illness representations, self-efficacy beliefs, and their perceived social support.

How does illness severity influence depression, health satisfaction and life satisfaction in patients with cardiovascular disease? The mediating role of illness perception and self-efficacy beliefs.

Numerous empirical studies have investigated the relationships between cardiovascular diseases (CVD) and patients' psychological well-being, with a focus almost exclusively on its dark side. Very little is known on the impact of illness severity on both negative and positive indicators of patients' well-being, as well as on the psychosocial variables that may mediate this association. Aim of the study was to investigate the impact of illness severity on depression as well as on health satisfaction and life satisfaction of patients undergoing a cardiovascular rehabilitation. It also aimed at testing the mediation of illness perception and self-efficacy beliefs in managing cardiac risk factors. The study involved 172 patients (mean age = 66.43 years; SD = 9.99 years; 76.2% men). Illness severity was measured in terms of left ventricular ejection fraction at discharge from the cardiology department, whereas all psychological dimensions were assessed one week later. Results showed significant relationships among illness severity, depression and health satisfaction that were fully mediated by illness perception and self-efficacy beliefs, but not significant relation between disease severity and life satisfaction (χ2 (1) = 2.30, p = n.s.). Overall, findings underline the importance of working on illness perception and self-efficacy beliefs to contrast depression and to improve health and life satisfaction in patients with CVD.

Individual patient meta-analysis of exercise training effects on systemic brain natriuretic peptide expression in heart failure.

BACKGROUND: Brain natriuretic peptide (BNP) predicts exercise performance and exercise training may modulate BNP and its N-terminal portion (NT-pro-BNP), we therefore conducted an individual patient analysis of exercise training effects on BNP and NT-pro-BNP. AIMS: To use an individual patient meta-analysis to relate changes in BNP, NT-pro-BNP, and peak VO(2); to link these changes to volume parameters of exercise training programmes (intensity etc.); and to identify patient characteristics likely to lead to greater improvements in BNP, NT-pro-BNP, and peak VO(2). DESIGN: Individual patient meta-analysis. METHODS: A systematic search was conducted of Medline (Ovid), Embase.com, Cochrane Central Register of Controlled Trials, and CINAHL (until July 2008) to identify randomized controlled trials of aerobic and/or resistance exercise training in systolic heart failure patients measuring BNP and/or NT-pro-BNP. Primary outcome measures were change in BNP, NT-pro-BNP, and peak VO2. Subanalyses were conducted to identify (1) patient groups that benefit most and (2) exercise programme parameters enhancing favourable changes in primary outcome measures. RESULTS: Ten randomized controlled studies measuring BNP or NT-pro-BNP met eligibility criteria, authors provided individual patient data for 565 patients (313 exercise and 252 controls). Exercise training had favourable effects on BNP (-28.3%, p < 0.0001), NT-pro-BNP (-37.4%, p = < 0.0001), and peak VO(2) (17.8%, p < 0.0001). The analysis showed a significant change in primary outcome measures; moreover, change in BNP (r = -0.31, p < 0.0001) and NT-pro-BNP (r = -0.22, p < 0.0001) were correlated with peak VO(2) change. CONCLUSION: Exercise training has favourable effects on BNP, NT-pro-BNP, and peak VO(2) in heart failure patients and BNP/NT-pro-BNP changes were correlated with peak VO(2) changes.

Changes of autonomic cardiac profile after a 3-week integrated body weight reduction program in severely obese patients.

The autonomic control of the heart is abnormal in obese subjects due to a prevalence of sympathetic over parasympathetic limb of the autonomic balance. We evaluated the effects of a short-term (3 weeks) integrated body weight reduction program (consisting of energy restricted diet and high-intensity exercise training) on heart rate variability (HRV) in severely obese, normotensive patients. The HRV was evaluated both in the time and frequency domain over a 18-hour Holter recording period obtained before and at the end of the third week. Three-week body weight reduction program reduced BMI (from 41.4 +/- 4.6 to 39.5 +/- 4.3 kg/m2, -4.6%, p<0.0001) and heart rate (from 77.8 +/- 8.6 to 73.6 +/- 8.7 b/min, p=0.0003). Significant changes in the autonomic profile were observed both in the time and frequency domain (SD of RR interval, SDRR: +16.1%; mean squared successive difference: (MSSD) +16.7%; percentage of RR intervals differing more than 50 msec from the preceding one, pNN50: +31.8%; low frequency oscillation, LF: +17.1%; high frequency oscillation, HF: +/- 18.2%). In conclusion, this study demonstrates that a short-term, integrated body weight reduction program is able to favorably modify the autonomic profile in a population of normotensive, severely obese subjects. The reduction of heart rate and the increase in parasympathetic activity may consistently contribute to a reduction of the risk of cardiovascular morbidity and of sudden cardiac death, still high in this patients' group.

Characterization of the non-linear rate-dependency of QT interval in humans.

AIMS: Repolarization has rate-dependent and rate-independent components. A function considering such components separately was validated in canine Purkinje fibres and applied to the QT/RR relation in humans. METHODS AND RESULTS: Action potential duration (APD) was measured in Purkinje fibres during steady-state pacing at different cycle lengths (CL) and after prolonged quiescence (APD(0)). The APD/CL relationship was expressed by this function: APD=APD(max)(*)CL(S)/(CL(50)(S)+CL(S)), where APD(max) (APD extrapolated at infinite CL) is a rate-independent measure of repolarization, CL(50) (CL at which 50% of APD(max) is achieved) and S evaluates the rate dependency of APD. The same function was used to fit the QT/RR relation in 46 normal subjects (20 males, 26 females) and in 7 amiodarone-treated subjects undergoing a bicycle stress test. RR and QT (V(5)) were measured at the end of each load step; QT(c) (Bazett's formula) was obtained at rest. The APD/CL and QT/RR relations were equally well expressed by the function with high correlation coefficients (R>or=0.90). In Purkinje fibres, APD(max) was 461+/-37 ms, CL(50) was 394+/-54 ms and S was 0.98+/-0.11. APD(max) and APD(0) correlated (R=0.96) and were similar. The corresponding values in humans were: QT(max) 432+/-63 ms, RR(50) 345+/-60 ms and S 2.6+/-0.8. While QT(c) and QT(max) were longer in females, RR(50) and S were similar between genders. Amiodarone increased QT(c), QT(max) and RR(50) and decreased S. In QT(max) and QT(c) distributions generated by pooling data from treated and untreated subjects, 86% of treated subjects were correctly identified by QT(max) and 28% by QT(c). CONCLUSIONS: Canine and human repolarization showed a saturating dependency on cycle length, described by the proposed function. Gender and amiodarone independently affected QT(max), RR(50) and S: therefore they might reflect specific ionic mechanisms. Finally, QT(max) identified drug-induced repolarization abnormalities in individual subjects better than QT(c).

Different baseline sympathovagal balance and cardiac autonomic responsiveness in ischemic and non-ischemic congestive heart failure.

BACKGROUND: A profound autonomic unbalance is present in heart failure: its correlation with the etiology of the disease has never been investigated. AIMS: We characterized the sympatho-vagal balance and autonomic responsiveness of 42 patients (21 with ischemic heart failure, 21 with idiopathic dilated cardiomyopathy). Patients had comparable NYHA class, ejection fraction, exercise pVO(2), exercise ventilatory response, incidence of beta-blocking treatment. None showed periodic breathing or nocturnal arterial desaturation. METHODS: Heart rate variability was assessed in the time and frequency domain during: (1) 10 min of quiet supine resting and free breathing; (2) 10 min of regular breathing at a frequency of 20 acts/min (=parasympathetic stimulus); and (3) 10 min of active standing (=sympathetic stimulus). The ratio of the low- to high-frequency components of each autospectrum obtained in the frequency domain (LF/HF) was used as an index of sympathovagal balance. RESULTS: Patients with ischemic heart failure had a greater baseline sympathetic activation (higher LF/HF) than those with idiopathic dilated cardiomyopathy, maintaining some parasympathetic responsiveness as well (reduced LF/HF with regular breathing). CONCLUSIONS: There is a distinct autonomic control according to the etiology of heart failure, a finding that may help understanding its pathophysiology, and could be useful in the clinical management of patients.

Long-term lifestyle changes maintain the autonomic modulation induced by rehabilitation after myocardial infarction.

The altered autonomic balance observed after myocardial infarction is shifted toward a higher parasympathetic tone by rehabilitation. This effect persists after 1 year, however we observed a discrete variability in the long-term sympathovagal balance among patients. We postulated that such variability derives from the disparate adherence of patients to lifestyle prescriptions regarding exercise continuance and smoking avoidance. To test this hypothesis, we reviewed the data of 40 patients, who completed with a favourable autonomic modulation the initial rehabilitation phase after myocardial infarction and underwent the annual follow-up. One year after infarction, 23 patients complied to the advice about regular exercise and smoking avoidance (adherent, Group 1); 17 did not (non-adherent, Group 2). Groups were similar for age, site of infarction, left ventricular function, stress test duration and therapy. The ratio LF/HF, derived from the power spectral density of RR intervals variability, was used as an index of the sympathovagal balance. It was obtained from 15 min of ECG at rest, assessed 1 month after MI (baseline), and repeated 3 months (rehabilitation) and 1 year (follow-up) afterwards. Rehabilitation increased parasympathetic tone in all patients, reducing LF/HF by 33%. At follow-up, this potentially favourable autonomic profile persisted only in Group 1 patients. In conclusion, after a first myocardial infarction, the persistence of the potentially beneficial effect of rehabilitation on the sympathovagal balance depends on the compliance to the lifestyle changes proposed during the initial phase.

Markers of electrical instability in hypertensive patients with and without ventricular arrhythmias. Are they useful in identifying patients with different risk profiles?

BACKGROUND: Markers of electrical instability of the ventricular myocardium, namely abnormal repolarization and late potentials, are frequently observed in patients with hypertension when both ventricular arrhythmias and left ventricular hypertrophy are present. This information cannot be extrapolated to the population of hypertensive patients with ventricular arrhythmias but without left ventricular hypertrophy. OBJECTIVE: To evaluate QT duration, QT dispersion and the incidence of ventricular late potentials in patients with essential hypertension, already on anti-hypertensive therapy, both with and without non-sustained ventricular arrhythmia. DESIGN: The study population consisted of 49 patients with essential hypertension who were compared to 89 control normotensive subjects both with and without frequent (> 30 per h) ventricular ectopic beats (VPBs). Patients were divided into four groups: (1) hypertensive patients without VPBs (H, n = 19), (2) hypertensive patients with VPBs (HA, n = 30), (3) normotensive subjects without VPBs (C, n = 28), and (4) normotensive subjects with VPBs (CA, n=61). METHODS: Echocardiographic parameters, QT interval, QT dispersion and signal-averaged ECG were evaluated without withdrawing anti-hypertensive drugs. RESULTS: In no case was left ventricular hypertrophy documented. The number of VPBs during 24 h Holter recording (median 11 343 versus 7617) and the incidence of repetitive VPBs (37 versus 46% of patients) were similar in the two groups of patients (HA versus CA). Signal-averaged ECG parameters were normal and not different between the four groups. QT interval was longer in hypertensive patients compared to controls irrespective of the presence of VPBs. QT dispersion was slightly greater in subjects with VPBs, both hypertensive and normotensive, compared to subjects without arrhythmias. CONCLUSIONS: In patients with hypertension well-controlled by drug therapy and without left ventricular hypertrophy, frequent VPBs are not associated with markers indicating an electrophysiological substrate for re-entrant arrhythmias. However, QT prolongation suggests the persistence of a higher risk of cardiovascular mortality that is independent of the presence of VPBs.

Role of the input/output relation of sinoatrial myocytes in cholinergic modulation of heart rate variability.

INTRODUCTION: Modulation of sinus rate may be viewed as the transduction of an input signal (receptor stimulation) into an output signal (cycle length [CL]) by the sinus node. This study analyzes the input/output (I/O) relation of sinoatrial pacemaking elements and tests its impact on cholinergic modulation of heart rate variability. METHODS AND RESULTS: Spontaneous activity of isolated rabbit sinoatrial myocytes was recorded by patch clamp techniques. CL and all the action potential parameters determining CL were automatically measured from >100 consecutive cycles. Acetylcholine (ACh, 5 to 50 nM) increased CL by decreasing diastolic depolarization rate (DDR) only. This was associated with a substantial increase in the coefficient of variation of CL and minor changes in the coefficient of variation of other parameters. A simple function relating CL to action potential parameters accurately described CL response to ACh (I/O relation). Numerical simulations based on this I/O relation showed that ACh-induced depression of DDR might, by its own, increase CL variability. CONCLUSION: Time-domain measurements of CL variability may not necessarily reflect variability of the neural input to the sinoatrial node, but also may be affected by its tonic level. Properties of the I/O relation of sinoatrial myocytes may fully account for the dependency of CL variability on mean heart rate, previously described in humans. Any condition depressing DDR may enhance CL variability, independent of changes in the pattern of neural activity.

Relationship between baseline sympatho-vagal balance and the autonomic response to cardiac rehabilitation after a first uncomplicated myocardial infarction.

BACKGROUND: After a first uncomplicated myocardial infarction, cardiac rehabilitation increases the parasympathetic tone, in a direction linked to a reduced risk of sudden cardiac death. This change in sympatho-vagal balance may be related to other clinical variables. The aim of this study was to define the factors implicated in determining the autonomic response to cardiovascular rehabilitation after myocardial infarction. METHODS: In 55 patients (39-80 years) we evaluated the modulation of the autonomic profile induced by 8 weeks of rehabilitation: we analyzed the changes in pNN50 derived from time-domain analysis (deltapNN50) and in the low frequency/high frequency (LF/HF) ratio derived from autoregressive power spectral analysis (deltaLF/HF). A control group of 15 patients not undergoing rehabilitation was also studied. Variables considered at 4 weeks postinfarction and related to deltapNN50 and deltaLF/HF ratio were: age, site of myocardial infarction, previous thrombolysis, ejection fraction, stress test duration, baseline LF/HF ratio. RESULTS: Patients not undergoing rehabilitation did not change their autonomic profile. On the contrary, rehabilitation induced a higher vagal tone (pNN50 from 6.5 +/- 1.5 to 16.2 +/- 3.1; LF/HF ratio from 8.3 +/- 5.2 to 5.1 +/- 2.9, p < 0.05). Eleven patients (20%) had baseline LF/HF ratio exceeding the mean value by 1.5 SD (19.4 +/- 1.4): in this subgroup, pNN50 was very low. In these patients, rehabilitation increased pNN50 and decreased LF/HF ratio. Indeed, both deltapNN50 and deltaLF/HF ratio were significantly related to their baseline values (p < 0.001), even considering thrombolysis, site of myocardial infarction, age, and beta-blocker therapy. CONCLUSIONS: After a first uncomplicated myocardial infarction, sympatho-vagal balance may be very disturbed in some patients, despite a preserved ventricular function, good exercise capability and beta-blockers. These patients should be encouraged to undergo rehabilitation, since the significant improvement in the parasympathetic tone may protect them against subsequent arrhythmic events.

Increased left ventricular dimensions in patients with frequent nonsustained ventricular arrhythmia and no evidence of underlying heart disease.

INTRODUCTION: To test the hypothesis that frequent nonsustained ventricular premature beats (VPBs) in patients without underlying heart disease are the first marker of mild systolic dysfunction of the left ventricle, we evaluated whether a subclinical abnormality of left ventricular function and/or an intraventricular conduction defect was present at the first clinical documentation of the arrhythmia. METHODS AND RESULTS: We compared 57 patients (mean age 46 +/- 14 years) with > 30 VPBs/hour and no heart disease (A) to 32 healthy volunteers (mean age 42 +/- 12 years) without arrhythmia (B). Left ventricular echocardiographic parameters and signal-averaged ECG were evaluated. Filtered QRS duration (98 +/- 10 msec in A vs 98 +/- 7 msec in B) was similar in the two groups. End-diastolic left ventricular diameter (EDLVD) was 50 +/- 6 mm in A versus 47 +/- 3 mm in B (P < 0.005); 15 patients (26%) and none of the controls had EDLVD > or = 55 mm (P < 0.005). Filtered QRS interval was longer in the subgroup of patients (n = 15) with increased EDLVD (> or = 55 mm) compared with the subgroup (n = 42) with EDLVD < 55 mm (106 +/- 9 msec vs 95 +/- 9 msec; P < 0.001) and was related to greater left ventricular mass. CONCLUSION: We documented a subclinical but significant increase of left ventricular dimensions that suggests that frequent VPBs may be an initial marker of mild systolic dysfunction of the left ventricle. However, an effect of VPBs per se in modifying left ventricular dimensions cannot be excluded.

Effects of cardiac rehabilitation and beta-blocker therapy on heart rate variability after first acute myocardial infarction.

After acute myocardial infarction (AMI), rehabilitation with physical training increases parasympathetic tone. It is unknown whether such a favorable effect of exercise on the sympathovagal balance interacts with effects of other widespread therapies, such as beta blockers. In 53 patients after a first, uncomplicated AMI, we studied the combined short- and long-term influence on heart rate variability (HRV) of rehabilitation and beta blockade. Patients were divided into 3 groups: group 1 (n = 19) underwent rehabilitation with physical training; group 2 (n = 20) was taking beta blockers and underwent rehabilitation; group 3 (n = 14) was taking beta blockers and did not enter the rehabilitation program for logistic reasons. Patients were similar as to age, site of infarction, ejection fraction, left ventricular diameter, and baseline stress test duration. Measures of HRV (obtained from a 15-minute resting electrocardiogram) were the standard deviation of the mean RR interval (RRSD), the mean squared successive differences (MSSD), the percent of RR intervals differing >50 ms from the preceding one (pNN50), the low-(LF) and high-(HF) frequency components of the autoregressive power spectrum of the RR intervals and their ratio (LF/HF). Four weeks after AMI, there was less sympathetic predominance in groups 2 and 3 (i.e., patients taking beta blockers [p <0.05]). Rehabilitation modified HRV in groups 1 and 2 (p <0.05), with signs of increased parasympathetic tone (group 1: MSSD +25%, pNN50 +69%, LF/HF -40%; group 2: MSSD +41%, pNN50 +48%, LF/HF -39%). These changes persisted in the long term. In group 3, HRV was unchanged over time. Hence, after AMI, the effects of rehabilitation and beta blockers on HRV are not redundant: their association induces a more favorable sympathovagal balance, accelerating the recovery of a normal autonomic profile.

Adults with childhood-onset growth hormone deficiency: effects of growth hormone treatment on cardiac structure.

OBJECTIVES: To evaluate the effects of growth hormone deficiency (GHD) and of growth hormone (GH) therapy on cardiac structure in adults with childhood-onset GHD. SETTING: Out-patient clinic in the Italian Institute for Auxology, Milan. SUBJECTS: Eight adults with childhood-onset GHD and eight healthy controls, matched for sex, age, exercise and body mass index. INTERVENTIONS: Recombinant GH (Saizen Serono, Italy), administered in a conventional dose of 0.5 IU kg-1 week-1 for 6 months. MAIN OUTCOME MEASURES: Cardiac structure parameters, evaluated by two-dimensional, M-mode and Doppler echocardiograms, and stress test, by means of a modified Bruce protocol with a bicycle ergometer, were determined before and after 6 months GH therapy. RESULTS: Before treatment, mean (+/- SE) intraventricular septal thickness (IVST: 7.1 +/- 0.2 mm), LV posterior wall thickness (LVPT: 5.2 +/- 0.1 mm), LV mass (LVM: 94.6 +/- 5.0 g), LV mass index (LVM/body surface area, LVMI: 65.1 +/- 3.0 g m-2) and left ventricular end-diastolic diameter (LVED: 41.4 +/- 0.6 mm) of patients were significantly lower (P < 0.01) than in controls, whilst LV end-systolic diameter (LVES) of patients (25.5 +/- 0.7 mm) was similar to controls (27.5 +/- 0.7). GH treatment significantly (P < 0.01) increased LVPT (6.8 +/- 0.2 mm), LVM (111.6 +/- 4.6 g) and LVMI (80.5 +/- 3.5 g m-2); no significant changes were observed in LVED, LVES and IVST values. The stress test showed a significant improvement of cardiac performance, as demonstrated by the reduction of blood pressure x heart rate product at the same workload (basal: 32,722.5 +/- 897.4 vs. after: 25,574.6 +/- 439.7). CONCLUSIONS: GH plays a role in the maintenance of a normal cardiac structure in adulthood. The present study suggests that GH treatment might be able to improve the cardiac structure of patients with childhood-onset GHD.

Muscarinic effects on action potential duration and its rate dependence in canine Purkinje fibers.

Studies of the autonomic influence on action potential duration (APD) in the ventricles show direct effects of muscarinic stimulation on epicardial, but not endocardial, APD and conflicting results regarding direct vagal effects on the conduction system. In canine Purkinje fibers, we analyzed the action of the M2 agonist oxotremorine (OXO, 0.1 microM) on APD and on its cycle length (CL) dependence. Fibers were impaled with glass microelectrodes and superfused with Tyrode's solution. APD90 was measured after 3 minutes of drive at CL between 0.3 and 5 seconds. The best fit for the APD/CL relationship at steady state was a hyperbole: APD = APDmax*CL/(CL+CL50), where APDmax (APD at infinite CL) is a rate independent measure of APD, and CL50 (CL at which 50% APDmax is reached) is an index of the rate dependence of APD. In five fibers, OXO reduced APD at all CL (P < 0.05), APDmax was also reduced to 377 +/- 41 ms from 447 +/- 34 ms (P < 0.05), while CL50 was unchanged (405 +/- 46 ms from 437 +/- 28 ms). No effects of OXO on APD and APDmax were seen in two fibers obtained from dogs pretreated with pertussis toxin (PTX). In conclusion, stimulation of M2 receptors in intact, and not PTX treated, Purkinje fibers affects APD but not its CL dependence. This may reflect the activation of a rate independent, background current through a GTP binding protein-linked pathway, such as, IK,ACh. These data differ from those obtained in endocardial and epicardial muscle, stressing the regional differences in vagal modulation of ventricular electrophysiological properties.

Short and long term effects of exercise training on the tonic autonomic modulation of heart rate variability after myocardial infarction.

We studied the effects of cardiac rehabilitation on the sympathovagal control of heart rate variability in 30 patients after a first, uncomplicated myocardial infarction. Twenty-two patients completed 8 weeks of endurance training (trained), while eight decided not to engage in the rehabilitation programme for logistical reasons, and were taken as untrained controls. Age, site of infarction, ejection fraction, ventricular diameter and stress test duration were similar in the two groups at baseline. Heart rate variability was evaluated 4 weeks after infarction before starting rehabilitation, and repeated 8 weeks and one year later in both trained and untrained patients. Measures of heart rate variability, obtained from both time- and frequency-domain analysis of a 15 min ECG recording in resting conditions, were as follows: mean RR interval and its standard deviation (RRSD), the mean square successive differences (MSSD), the percent of RR intervals differing > 50 ms from the preceding RR (pNN50), the low and high frequency components of the autoregressive power spectrum of the RR intervals and their ratio (LF/HF). At baseline, heart rate variability was similar in trained and untrained patients. In the short term (8 weeks after infarction), training increased RRSD by 25% (P < 0.01), MSSD by 69% (P < 0.01), pNN50 by 120% (P < 0.01), and reduced LF/HF ratio by 30% (P < 0.01). The effects persisted after one year in trained patients. In untrained patients, the autonomic control of heart rate variability did not change 8 weeks after myocardial infarction and was only slightly modified by time. Thus, exercise training, performed for 8 weeks after a myocardial infarction, modifies the sympathovagal control of heart rate variability toward a persistent increase in parasympathetic tone, known to be associated with a better prognosis. This may partly account for the favourable outcome of patients who undergo rehabilitation.

Effects on atrial repolarization of the interaction between K+ channel blockers and muscarinic receptor stimulation.

We have tested, in guinea pig atria, how muscarinic stimulation by oxotremorine (Oxo) modifies the effects on action potential duration (APD) of two iK blockers: d-sotalol (5 microM) and ambasilide (1 microM). APD was prolonged by d-sotalol (+34.8 +/- 2.9%) and ambasilide (+54.2 +/- 5.5%). Simultaneous superfusion with Oxo 0.5 microM markedly shortened APD; this effect was larger in the presence of d-sotalol than in the presence of ambasilide (-69 +/- 2% vs. -37.4 +/- 5%; P < .05). Moreover ambasilide, but not d-sotalol, antagonized APD shortening induced by Oxo. The basis for such a difference between the two drugs was studied in patch-clamp experiments on isolated rabbit atrial and sinoatrial myocytes. Besides blocking iK (half-effective concentration: EC50 = 2 microM), ambasilide almost completely inhibited iKACh (-86 +/- 2% at 10 microM; EC50 = 1.6 microM), which was minimally affected by d-sotalol. Ambasilide 2 microM increased 10-fold the acetylcholine (ACh) required for 50% iKACh activation, and reduced maximally activated iKACh by 18.8 +/- 6.3%. When iKACh was activated through a receptor-independent mechanism, 10 microM ambasilide reduced this current by only 18.7 +/- 1.4% of its control value. Moreover, ambasilide, although not affecting the current i(f), in basal conditions, reversed its inhibition by ACh. Thus, 1) the effect of K+ channel blockers on atrial APD may be blunted by ACh; ambasilide effects are less sensitive to ACh than those of d-sotalol; 2) ambasilide, but not d-sotalol, inhibits iKACh; this probably occurs largely, although not exclusively, through muscarinic receptor antagonism. Inhibition of iKACh may account for the persistence of the effects of this drug on atrial APD despite muscarinic stimulation.

Modulation of the electrical restitution of canine Purkinje fibers by local anesthetic drugs: a study with flecainide and propafenone.

Some antiarrhythmic drugs that depress conduction also influence action potential duration (APD). This could modify the time course of changes in the APD of premature stimuli (electrical restitution) and affect dispersion of repolarization and homogeneity of refractoriness. The effects of two potent local anesthetic drugs, i.e., flecainide and propafenone, on electrical restitution were studied in canine Purkinje fibers, superfused with Tyrode's solution and impaled with glass microelectrodes. APD was measured at 90% repolarization (APD90): fibers were stimulated for 3 minutes at cycle lengths (CLs) between 350 msec and 1.5 seconds, and kept quiescent for 5 minutes in between. For each run we calculated the percent ratio of the second APD (APD test = APDt) to the first APD after quiescence (APDo) (APDt/APDo x 100). The ratio was correlated with the CL of the run (i.e., the coupling interval between APDo and APDt = CI) by the monoexponential function APDt/APDo x 100 = 100-exp(-tau/CI), whose time constant tau indicates the speed of electrical restitution. At 1 microM, flecainide decreased tau by 26% +/- 4% (to 310 +/- 41 msec from 245 +/- 30 msec, n = 6, P < 0.05), while propafenone did not change it. Thus, unlike propafenone, flecainide slows the process of electrical restitution in Purkinje fibers. This may derive from the drug's action on currents other than Na current (i.e., IK), relevant to the duration of action potential. In a reentrant circuit, despite similar effects on conduction, APD and refractoriness of the first beat would be differently modulated by flecainide and propafenone.

Diverse electrophysiologic effects of propafenone and flecainide in canine Purkinje fibers: implications for antiarrhythmic drug classification.

Propafenone and flecainide are assigned to class Ic of the Campbell-Vaughan Williams classification because of their effects on ventricular muscle. The authors compared the use-dependent local anesthetic properties and the effects on repolarization of these drugs (1 and 5 microM) in Purkinje fibers. A reduction in maximum upstroke velocity was used as an index of the local anesthetic action. The rate dependency of the drug's effects on repolarization was evaluated by analyzing the relationship between action potential duration during steady-state stimulation and cycle length (CL). Tonic block was higher for propafenone (n = 10) than for flecainide (n = 7) at both concentrations tested (19 +/- 3% vs. 4 +/- 1% at 1 microM; 59 +/- 10% vs. 24 +/- 4% at 5 microM). Use-dependent block onset and dissipation were significantly slower for flecainide than for propafenone (e.g., at 1 microM and CL = 500 ms, time constant of block onset = 31 +/- 6 vs. 9 +/- 1 beats; time constant of recovery from block = 7.7 +/- 0.2 vs. 2.8 +/- 0.2 sec; P < .05). Steady-state block measured at each CL was compared with that predicted by a theoretical model of use dependency. Predictions approximated the experimentally results only for flecainide. At 1 microM, propafenone shortened action potential duration at all rates; flecainide had biphasic effects. At 5 microM, the effect of flecainide was similar to that of 1 microM propafenone. Thus, in Purkinje fibers, the kinetics of use-dependent local anesthetic effects and the effects on repolarization discriminate flecainide from propafenone.

Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome.

OBJECTIVES: We evaluated the diagnostic and prognostic value of morphologic abnormalities of the T wave (mainly notched or biphasic T waves) in patients affected by the idiopathic long QT syndrome. BACKGROUND: In the long QT syndrome, these abnormalities in T wave morphology are often observed and are of uncertain significance. METHODS: The T wave abnormalities in the electrocardiogram (ECG) of 53 patients with the long QT syndrome and 53 control subjects of similar age and gender were analyzed, and their association with major cardiac events was defined. RESULTS: Notched or biphasic T waves were defined according to morphologic criteria. They were present in 33 (62%) of 53 patients with the long QT syndrome and in 8 (15%) of 53 control subjects (p < 0.001). Moreover, among patients with the long QT syndrome they were much more frequent in symptomatic (history of syncope or cardiac arrest) than in asymptomatic subjects (30 [81%] of 37 vs. 3 [19%] of 16, p < 0.001). The same distribution was observed within families with the long QT syndrome, in which symptomatic members had more pronounced T wave abnormalities than did their asymptomatic siblings or parents. In symptomatic patients, the occurrence of T wave abnormalities was independent of the length of repolarization (corrected QT). These T wave abnormalities were associated with the presence of a specific pattern of abnormal left ventricular wall motion. CONCLUSIONS: This study has quantified an ECG pattern typical of the long QT syndrome and provides the first evidence that morphologic analysis of T wave abnormalities may contribute to the diagnosis of the long QT syndrome and the identification of patients at higher risk for syncope or cardiac arrest.