Reduced regional myocardial perfusion reserve is associated with impaired contractile performance in idiopathic dilated cardiomyopathy.

Background. In idiopathic dilated cardiomyopathy (IDC) an imbalance between myocardial oxygen consumption and supply has been postulated. Subclinical myocardial ischaemia may contribute to progressive deterioration of left ventricular function. The relation between regional myocardial perfusion reserve (MPR) and contractile performance was investigated.Methods. Patients with newly diagnosed IDC underwent positron emission tomography (PET) scanning using both (13)N-ammonia as a perfusion tracer (baseline and dypiridamole stress), and (18)F-fluorodeoxyglucose viability tracer and a dobutamine stress MRI. MPR (assessed by PET) as well as wall motion score (WMS, assessed by MRI) were evaluated in a 17-segment model.Results. Twenty-two patients were included (age 49+/-11 years; 15 males, LVEF 33+/-10%). With MRI, a total of 305 segments could be analysed. Wall motion abnormalities at rest were present in 127 (35.5%) segments and in 103 (29.9%) during dobutamine stress. Twenty-one segments deteriorated during stress and 43 improved. MPR was significantly higher in those segments that improved, compared with those that did not change or were impaired during stress (1.87+/-0.04 vs. 1.56+/- 0.07 p<0.01.)Conclusion. Signs of regional ischaemia were clearly present in IDC patients. Ischaemic regions displayed impaired contractility during stress. This suggests that impaired oxygen supply contributes to cardiac dysfunction in IDC. (Neth Heart J 2009;17:470-4.).

Influence of renal dysfunction on the pharmacokinetics of the selective Na+/H+ exchange inhibitor EMD 87 580 in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is a potential indication for the administration of EMD 87 580, a selective Na+/H+ exchange inhibitor. CHF is often accompanied by renal dysfunction, which is known to affect the pharmacokinetics of compounds predominately cleared by the kidneys. We examined the influence of renal dysfunction on the pharmacokinetics of EMD 87 580 in patients with CHF. METHODS: 21 patients with CHF and normal renal function (Group 1) and 9 patients with CHF and renal dysfunction (Group 2) received EMD 87 580 orally over 8 days. The mean creatinine clearance (CrCl) in Group 1 was 99.7 ml/min. 12 patients in this group were randomized to receive two doses of EMD 87 580 (7 patients 2 x 50 mg and 5 patients 2 x 100 mg). The 9 patients in Group 2 with renal dysfunction (mean CrCl = 49.5 ml/min) received 50 mg EMD 87 580 once daily. Plasma and urine samples were collected for pharmacokinetic assessment. RESULTS: In CHF patients with renal dysfunction EMD 87 580 clearance was reduced to approximately 50% compared to Group 1, i.e. 6.80 ml/min (4.89-11.60) vs. 12.73 ml/min (8.93-22.21), p < 0.05, for the 50 mg dose and 14.08 ml/min (9.96-18.10), p < 0.05, for the 100 mg dose. Consequently, plasma concentrations were increased in patients with renal dysfunction; AUC0-infinity 7,354 ng/ml x h (4,311-10,232) vs. 3,928 ng/ml x h (2,251-5,596, 50 mg dose, p < 0.05). A significant correlation was observed between EMD 87 580 plasma clearance and CrCl (r2 = 0.8062). CONCLUSION: In CHF patients with renal dysfunction EMD 87 580, clearance is reduced and plasma concentrations increased. Therefore, dose adjustments for EMD 87 580 are indicated in patients with CHF and renal dysfunction.

Autonomic and hemodynamic effects of a new selective dopamine agonist, CHF1035, in patients with chronic heart failure.

Dopamine agonists have been studied in chronic heart failure, but earlier reports with non-selective compounds demonstrated unfavourable long-term effects. CHF 1035 is an orally active, new selective dopamine agonist, primarily activating DA2- and alpha2 receptors, thereby inhibiting norepinephrine release, which may be beneficial in heart failure. We conducted a double-blind, placebo-controlled comparison of CHF 1035 (10 mg/day, n = 20) and placebo (n = 9) in patients with mild to moderate chronic heart failure (left ventricular ejection fraction <0.45). Patients were clinically stable on diuretics and angiotensin converting enzyme inhibitors. Both acute and chronic assessments were made, including plasma neurohormones and 24-hr Holter monitoring for heart rate variability analysis. CHF1035 was generally well tolerated during the study. After 10 days, there were no significant changes between the groups regarding heart rate and blood pressure. Compared to placebo, plasma norepinephrine levels decreased on CHF1035, both in the first 4 hours and after 10 days (p<0.05 between groups). Other neurohormones (natriuretic peptides, renin, aldosteron and endothelin) were not significantly affected. Heart rate variability parameters generally increased on CHF1035, but were unaffected by placebo (p < 0.05 between groups). Short-term treatment with the selective dopaminergic agonist CHF1035 is well tolerated, reduces plasma norepinephrine concentrations and increases heart rate variability in mild chronic heart failure.

Autonomic dysfunction in patients with mild heart failure and coronary artery disease and the effects of add-on beta-blockade.

AIM: Autonomic impairment is related to the incidence of sudden death in chronic heart failure (CHF). Our objective was to study autonomic profiles in patients with mild CHF due to coronary artery disease, and to investigate the value of add-on beta-blockade. METHODS AND RESULTS: Measures of autonomic function (plasma norepinephrine, heart rate [HR] variability, autonomic function testing), and exercise capacity, were compared between 24 patients with mild CHF, and 24 healthy controls. In this mechanistic study, we assessed the effect of 26 weeks metoprolol treatment in a double-blind, randomized, placebo-controlled design. All patients received metoprolol sustained release (200 mg; n=12) or placebo (n=12). Assessments were made at baseline and after 10 and 26 weeks' treatment. At baseline, norepinephrine levels were elevated, while HR variability parameters were decreased in patients vs. controls (both P<0.05). Autonomic function testing showed only small differences, although significant alterations were observed with deep breathing and head up tilting (both P<0.05). After 26 weeks', metoprolol did not affect exercise capacity or norepinephrine concentrations. In contrast, HR variability was markedly improved in metoprolol-treated patients vs. placebo-treated patients (P<0.05). In particular, a shift toward normal in the sympathovagal balance was observed (P<0.05). Autonomic function testing showed only small, and generally non-significant trends after metoprolol. CONCLUSIONS: Marked autonomic abnormalities are already present in mild CHF, which may be (partially) reversed by metoprolol. These observations support the reported reduction of sudden death by beta-blockade in patients with CHF.

Impairment of myocardial blood flow reserve in patients with asymptomatic left ventricular dysfunction: effects of ACE-inhibition with perindopril.

Myocardial blood flow (MBF) reserve is impaired in patients with symptomatic chronic heart failure. Whether this is already present in asymptomatic left ventricular (LV) dysfunction, and whether it is affected by angiotensin converting enzyme (ACE) inhibition, is unknown. We examined MBF in 20 patients with asymptomatic LV dysfunction and compared them to healthy volunteers. MBF (reserve) was assessed with positron emission tomography (PET) and N-13 ammonia at rest, during dipyridamole stress test (DST) and during cold pressor test (CPT). Further, in the LV-dysfunction group, we studied the effects of 3 months treatment with ACE inhibition with a second PET study. Patients were randomized double-blind to perindopril 4 mg daily or placebo. MBF at rest was similar in controls and patients. DST-induced MBF reserve, however, was decreased in patients vs. controls (1.71+/-0.2 vs. 2.62+/-0.5, respectively p < 0.05). Also CPT-induced MBF was lower in patients (1.14+/-0.06 vs. 1.23+/-0.03, p < 0.05). After 3 months double-blind treatment, CPT-induced MBF decreased in the placebo group (from 1.12+/-0.02 to 0.93+/-0.06), but was preserved in the perindopril group (from 1.16+/-0.08 to 1.14+/-0.08 shifts from baseline: -0.19+/-0.05 vs. -0.02+/-0.07 respectively p = 0.07). This was compatible with a trend to a smaller increase in coronary vascular resistance during CPT (1.23+/-0.08 vs. 1.03+/-0.06, placebo vs. perindopril, p = 0.06). In patients with asymptomatic LV dysfunction, MBF, both after vasodilation and after CPT, is already impaired. ACE inhibition with perindopril during this short-term treatment had no significant effects.

Hemodynamic effects of the new antiarrhythmic agent restacorin in patients with normal and decreased left ventricular function.

The hemodynamic and pharmacokinetic effects of the novel class 1c antiarrhythmic drug restacorin were investigated in two groups of patients. Group I consisted of 5 patients with normal left ventricular (LV) function, and group II consisted of 10 patients with mild heart failure [New York Heart Association (NYHA) II; mean LV ejection fraction 33 +/- 6%]. The study had an open label, baseline-controlled, single-dose design. Restacorin was infused in a total dosage of 1.2 mg/kg. In group I, the only significant change as compared with baseline findings was a 25% increase in right atrial pressure. In group II; cardiac output (CO), dP/dt, and stroke work index (SWI) decreased significantly (-18, -11, and -24%, respectively). In addition, a significant 32% increase was noted in pulmonary artery wedge pressure (PAWP), and a 27% increase occurred in systemic vascular resistance (SVR). No changes were observed in heart rate (HR) or mean arterial blood pressure (MAP). CO and SVR at baseline correlated with the average plasma concentrations (r = -0.65 and p = 0.009 and r = 0.56 and p = 0.028 respectively). Creatinine clearance was inversely correlated to the restacorin plasma concentration (r = -0.51, p = 0.05). The half-life (t1/2) elimination time of restacorin was 2.60 h for group I, and 4.06 h for group II. Clearance was 51.4 and 32.2 L.h-1, respectively. Restacorin appears to be well tolerated in patients with normal LV function. The drug is not recommended for use in patients with reduced LV function because of its moderate negative inotropic effect.

Flecainide: long-term effects in patients with sustained ventricular tachycardia or ventricular fibrillation.

Efficacy of flecainide was investigated in 50 patients with sustained ventricular tachycardia (n = 38) or ventricular fibrillation (n = 12) during a 4-week in-hospital and 1-year follow-up period. Furthermore, the predictive value of programmed electrical stimulation, Holter monitoring, and exercise testing on outcome of long-term treatment was studied. Etiology of the tachyarrhythmia was coronary artery disease in 37 patients and other etiologies in 13 patients. The success rate of flecainide after 1 year, based on intention to treat, was 54%. The success rate during the in-hospital phase was 84% (in six patients flecainide was discontinued because of tachyarrhythmia and in two because of side effects). Calculated after 4 weeks hospitalization, the success rate was 78% for patients with tachyarrhythmias based on coronary artery disease and 55% for patients with tachyarrhythmias based on other etiologies (11 patients showed recurrences and two patients severe side effects). Patients with tachyarrhythmias based on coronary artery disease showed a lower ejection fraction and earlier recurrence than patients with arrhythmias based on other etiologies. Proarrhythmic effects developed in six patients (12%). Electrophysiological evaluation was performed in 28 patients at baseline and after intravenous flecainide. Negative predictive value of the electrophysiological evaluation after intravenous flecainide for patients with inducible tachyarrhythmias at baseline (n = 21) was 40%. For Holter monitoring (n = 24) this value was 86%. Non-ischemia-related induction of tachycardia by exercise was present in two of 30 patients on flecainide; both patients showed recurrence of the tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter.

The efficacy and safety of flecainide were studied in the maintenance of sinus rhythm after electrical cardioversion for chronic atrial fibrillation or atrial flutter. Eighty-one patients were randomized to flecainide treatment or no treatment. Baseline characteristics of both groups were comparable. Compared to previous studies, patients could be classified as difficult-to-treat patients. Multiple regression analysis showed New York Heart Association class I for exercise tolerance (p = 0.0004) and flecainide treatment (p = 0.01) to be the main factors increasing the arrhythmia-free episode. However, Mantel-Cox lifetable analysis did not reveal significant differences between arrhythmia-free survival curves of both treatment groups. In the flecainide-treated group, 9% of patients experienced side effects, mostly related to negative dromotropic effects. The incidence of ventricular proarrhythmia in this group of patients was low. Thus, flecainide may be effective in postponing arrhythmia recurrence, even in difficult-to-treat patients. Caution should be excercised in treating patients with underlying conduction disturbances, sick sinus syndrome or characteristics favoring development of ventricular proarrhythmia.

Electrophysiological properties of isradipine (PN200-110) in humans.

Isradipine (PN 200-110) is a new dihydropyridine calcium-entry blocker with powerful vasodilating properties. Therapeutic concentrations do not affect myocardial contractility. However, in vitro studies have demonstrated at higher concentrations negative chronotropic action with only minor dromotropic influence. For this reason we studied the effect of intravenous isradipine (0.3 microgram/kg/min during 30 min) on sinus node and atrioventricular (AV) nodal function in 25 patients. Nine of these patients had normal sinus node function (group I), nine patients were treated with a beta blocker (group II), and seven patients had a sick sinus syndrome (group III). Mean supine arterial blood pressure decreased in all groups; however, in group I not significantly. Spontaneous sinus cycle length decreased significantly in all groups. In none of the patients effective refractory periods of atrium or ventricle were depressed. QRS duration was not significantly affected in any of the groups. There was only a slight, but significant, prolongation of the QTc of maximal 4% (except in group III). We concluded that isradipine has no depressant effect on sinus and AV nodal function in humans, not even in the presence of beta blockade or impaired sinus node function.

Cardiac electrophysiologic properties of intravenous isradipine in patients with sick sinus syndrome.

Isradipine is a new dihydrophyridine calcium antagonist with powerful vasodilating properties. Although therapeutic concentrations do not affect myocardial contractility in vivo, in vitro studies have demonstrated a negative chronotropic action with only minor dromotropic influence. In humans with normal sinus and atrioventricular node function, even in the presence of beta-blockade, such a negative chronotropic effect could not be proved. No data are available on the effects of isradipine on a compromised sinus node. Therefore, the effect of intravenous isradipine at 0.3 microgram/kg/minute for 30 minutes was studied in seven patients with the clinical signs of a sick sinus syndrome. Mean arterial blood pressure decreased from 126 +/- 21 to 113 +/- 15 mm Hg (p less than 0.05). Spontaneous sinus cycle length decreased from 969 +/- 22 to 843 +/- 161 msec (p less than 0.05). Changes in sinoatrial conduction time, sinus node recovery time, and corrected sinus node recovery time were not significant. Changes in atrioventricular node function, as reflected by the atrioventricular node functional refractory period, the atrial-His interval, the His-ventricle interval, and Wenckebach point were not significant. Also, effective refractory periods of atrium and ventricle, and QRS duration changed but not significantly. The QT interval decreased (419 +/- 45 to 405 +/- 44 msec; p less than 0.05), and there was a slight (not significant) increase of QTc interval (429 +/- 41 to 443 +/- 37 msec; not significant). It is concluded that isradipine in hemodynamically effective doses has no depressant effect on sinus and atrioventricular node function in patients with sick sinus syndrome.

Flecainide acetate in the treatment of supraventricular tachycardias: value of programmed electrical stimulation for long-term prognosis.

Twenty patients with recurrent symptomatic supraventricular tachycardia were studied to estimate the efficacy of flecainide in the long-term treatment of these arrhythmias and to evaluate the prognostic value of programmed electrophysiologic stimulation. All patients had their arrhythmia inducible at baseline evaluation. Nine patients had a Wolff-Parkinson-White (WPW) syndrome, five had a concealed bypass tract, and two had dual atrioventricular (AV) nodal pathways. In the remaining patients there was an intraatrial reentry circuit. Previous medication was no to five antiarrhythmic drugs (mean 2.4 drugs). At baseline, a circus movement tachycardia was induced in 12, AV nodal tachycardia was induced in two, atrial tachycardia was induced in three, atrial fibrillation was induced in five, and a flutter was induced in two patients. After flecainide, 2 mg/kg intravenously in 10 minutes, six patients no longer had their arrhythmia inducible. In the WPW patients, atrial fibrillation was no more inducible. In 65% of the patients there was no recurrence during a follow-up period of 11 +/- 10 months. None of the six patients who no longer had their arrhythmia inducible had a recurrence of the tachycardia over a period of up to 3 years. Seven of the other 14 patients (who still had their arrhythmia inducible) had a recurrence of the tachycardia. Positive and negative predictive values are 50% and 100%, respectively. We conclude that flecainide prevents recurrences of supraventricular tachycardias in 65% of patients with inducible supraventricular tachycardias during a mean follow-up of 11 months. Programmed electrical stimulation has a high negative predictive value in this setting. Flecainide is especially effective in preventing atrial fibrillation in patients with WPW syndrome.

Flecainide versus quinidine in the prevention of paroxysms of atrial fibrillation.

We compared the efficacy of flecainide versus quinidine in preventing paroxysms of atrial fibrillation in a randomized open crossover study. Twenty-six patients with weekly attacks of atrial fibrillation during the last 3 months, objectified by 24-h holter monitoring or 12-lead electrocardiogram (ECG) were treated for a period of 3 months with flecainide 100 mg b.i.d. or quinidine 500 mg b.i.d. Efficacy was assessed by 24-h holter monitoring and a questionnaire at the end of each month. Dosage was adjusted to flecainide 100 mg t.i.d. or quinidine 500 mg t.i.d. if patients still had symptomatic paroxysms of atrial fibrillation according to a questionnaire or on holter monitoring. In 46% of the patients, flecainide 100 mg b.i.d. caused total abolition of supraventricular tachycardia; after dose adjustment it caused 50% total abolition. For quinidine, the figures are 16% (p less than 0.05) and 32% (NS), respectively. Side effects occurred with flecainide only after dose adjustment (23%), but on quinidine they occurred before (8%) and after dose adjustment (20%). We conclude that flecainide suppresses paroxysms of atrial fibrillation significantly more often as compared with quinidine in the lower dosage regimen. Optimal treatment dosage of flecainide is 100 mg b.i.d. After quinidine dose adjustment, the difference in efficacy is no longer significant. However, side effects necessitating discontinuation of quinidine developed in 20% of the patients as compared to none in patients treated with flecainide 100 mg b.i.d.

Acute conversion of atrial fibrillation to sinus rhythm: clinical efficacy of flecainide acetate. Comparison of two regimens.

The efficacy and safety of oral (up to 400 mg in 3 h) and intravenous regimens (up to 150 mg in 10 min) of flecainide acetate were compared in the acute conversion of atrial fibrillation to sinus rhythm. Acute conversion was defined as conversion occurring within 5 h (oral) or within 30 min (intravenous regimen). Following classification in recent onset (duration less than 24 h) atrial fibrillation (n = 27) and chronic (greater than 24 h) atrial fibrillation (n = 13), patients were randomly assigned to one of the two regimens. In the group of patients with recent onset atrial fibrillation, 10 out of 14 (oral treatment) and 10 out of 13 (intravenous treatment) responded acutely. Approximately half of responding patients converted after the first oral dose or within the infusion time. In contrast, no patient with chronic atrial fibrillation showed conversion on flecainide. No serious adverse effects were encountered with the regimens used, not even in patients concomitantly using digitalis or verapamil. Thus, patients with recent onset atrial fibrillation can safely be converted to sinus rhythm using oral or intravenous regimens of flecainide.

Abnormal pharmacokinetics of flecainide in a "nonresponder".

Flecainide is well absorbed after oral administration. Following rapid infusion of flecainide, there is a short distribution phase. Plasma levels of flecainide are proportional to dose. Both QRS durations and flutter wave intervals are lengthened after flecainide administration. We report an abnormal pharmacokinetic response to oral as well as intravenous flecainide in a patient who was treated with flecainide for several episodes of atrial flutter. In contrast to the usual pattern, this patient did not show a significant increase in QRS duration, flutter wave interval, or plasma concentration. We could not explain this abnormal pharmacokinetic response, but excluded a rapid and complete renal clearance, an excessively high rate of metabolization, and an abnormal binding mechanism as possible mechanisms. We concluded that flecainide may produce abnormal pharmacokinetic mechanisms, preventing appearance of unbound substance in plasma, thereby preventing occurrence of electrophysiological effects.

Haemodynamic and antiarrhythmic effects of intravenous flecainide acetate in chronic congestive heart failure.

The objective of this study was to evaluate the haemodynamic and antiarrhythmic effects of flecainide acetate in patients with heart failure. Flecainide acetate, a class Ic antiarrhythmic agent, was given intravenously to 9 patients with congestive heart failure and frequent ventricular arrhythmias with nonsustained ventricular tachycardia. The drug (2 mg/kg) was infused slowly over 60 minutes. The maximum plasma level achieved was 218 (range 142-350) ng/ml. Six of the 9 patients experienced a 90% suppression of their arrhythmias for an average of 6.5 (range 2-15) hours. Pre-ejection period control (PEPc, 148.8 +/- 3.6 msec) increased to 157 msec and pre-ejection period/ejection time (PEP/ET) [control 0.449 +/- 0.027] to 0.516 (p less than 0.005), while the ejection time index (ETI) did not change. Cardiac index (control 2.4 +/- 0.36 L/min/m2) decreased by 11% (p less than 0.02), and pulmonary wedge pressure (control 13.4 +/- 2.4mm Hg) increased by 23% (p less than 0.05). Stroke work index, arterial pressure and vascular resistance did not change significantly. The parameters returned to control values on completion of the infusion. Flecainide acetate can be safely administered at the usual dose of 2 mg/kg to patients with congestive heart failure, provided that the infusion time is doubled. Antiarrhythmic efficacy under these conditions is good even at lower plasma concentrations.