Arrhythmogenic potential of positive inotropic agents

The clinical use of positive inotropic agents has been associated with increased mortality, with proarrhythmia speculated to be a contributing factor. This study compares the arrhythmogenic potential of six positive inotropic agents representing different mechanistic classes: the β-adrenergic agonist dobutamine, the adenylyl cyclase activator forskolin, the phosphodiesterase-III inhibitor milrinone, the cardiac glycoside ouabain, and the sodium channel agonists DPI 201-106 and BDF 9148. These agents were studied in dogs with anterior myocardial infarction using lower and higher dose i. v. regimens targeted to elicit 20–40% and 70–90% increases in LV+dP/dt, respectively. Precipitation of new ventricular arrhythmia by programmed ventricular stimulation was observed in all treatment groups. Incidences of new arrhythmia were comparable in the lower dose regimens, ranging from 16.7% (3/18 animals with BDF 9148) to 31.6% (6/19 animals with DPI 201-106), and in the higher dose regimens, ranging from 10.0% (1/10 animals with milrinone) to 27.7% (5/18 animals with DPI 201-106). The overall incidence of new ventricular arrhythmia ranged from 27.3% (3/11 animals with ouabain) to 47.4% (9/19 animals with DPI 201-106). No differences were observed in underlying infarct size or time from infarction to electrophysiologic study between subgroups of animals in which new arrhythmias were precipitated vs. those remaining non-responsive in any treatment group. The positive inotropic agents tested displayed diverse total group effects on heart rate, electrocardiographic intervals including QTc and ventricular refractoriness. Within individual treatment comparisons revealed a general but not universal pattern of greater ventricular refractory period values in newly inducible vs. non-inducible subgroups in the DPI 201-106, BDF 9148 and ouabain (low and high dose); milrinone and dobutamine (high dose) treatment groups. These findings indicate that regardless of underlying cellular mechanisms of action, the six positive inotropic agents tested all displayed comparable proarrhythmic potentials unrelated to underlying infarct size and time from infarction. This observation suggests the general shared property of increased myocardial contractility, potentially adversely affecting myocardial oxygen balance, myocardial perfusion and electrical stability in the setting of previous myocardial infarction, to be a common underlying cause for arrhythmogenesis. Additionally, alterations in ventricular refractoriness and repolarization may contribute significantly to proarrhythmia with some positive inotropic interventions. Received: 20 July 1999, Returned for 1. revision: 16 September 1999, 1. Revision received: 26 October 1999, Returned for 2. revision: 24 November 1999, 2. Revision received: 22 December 1999, Accepted: 6 January 2000     

Implantable defibrillator event rates in patients with unexplained syncope and inducible sustained ventricular tachyarrhythmias: a comparison with patients known to have sustained ventricular tachycardia

OBJECTIVES

To assess the clinical significance of inducible ventricular tachyarrhythmias among patients with unexplained syncope.

BACKGROUND

Induction of sustained ventricular arrhythmias at electrophysiology study in patients with unexplained syncope and structural heart disease is usually assigned diagnostic significance. However, the true frequency of subsequent spontaneous ventricular tachyarrhythmias in the absence of antiarrhythmic medications is unknown.

METHODS

In a retrospective case-control study, the incidence of implantable cardiac defibrillator (ICD) therapies for sustained ventricular arrhythmias among patients with unexplained syncope or near syncope (syncope group, n = 22) was compared with that of a control group of patients (n = 32) with clinically documented sustained ventricular tachycardia (VT). Sustained ventricular arrhythmias were inducible in both groups and neither group received antiarrhythmic medications. All ICDs had stored electrograms or RR intervals. Clinical variables were similar between groups except that congestive cardiac failure was more common in the syncope group.

RESULTS

Kaplan-Meier analysis of the time to first appropriate ICD therapy for syncope and control groups produced overlapping curves (p = 0.9), with 57 ± 11% and 50 ± 9%, respectively, receiving ICD therapy by one year. In both groups, the induced arrhythmia was significantly faster than spontaneous arrhythmias, but the cycle lengths of induced and spontaneous arrhythmias were positively correlated (R = 0.6, p < 0.0001). During follow-up, three cardiac transplantations and seven deaths occurred in the syncope group, and two transplantations and five deaths occurred in the control group (36-month survival without transplant 52 ± 11% and 83 ± 7%, respectively, p = 0.03).

CONCLUSIONS

In patients with unexplained syncope, structural heart disease and inducible sustained ventricular arrhythmias, spontaneous sustained ventricular arrhythmias occur commonly and at a similar rate to patients with documented sustained VT. Thus, electrophysiologic testing in unexplained syncope can identify those at risk of potentially life-threatening tachyarrhythmias, and aggressive treatment of these patients is warranted.     

Small ventricular septal defects in adults

Aims To establish the frequency of complications in adults withsmall ventricular septal defects, which have not undergone surgery. Methods and Results One hundred and eighty-eight adults aged17–72 (mean, 29·2) years with a small ventricularseptal defect were studied. They were referred to a nationalcardiac centre (National Heart Hospital) and specialized grown-upcongenital heart unit. One hundred and thirty-eight were examinedin 1994–95. Fifty patients (26·6%) had additionalcardiovascular lesions, most commonly a bicuspid aortic valveand/or coarctation. Spontaneous closure occurred in 19 (10%)between the age of 17 and 45 (mean, 27) years. Twenty-one (11·2%)had infective endocarditis. Aortic regurgitation developed in37 (19·7%) patients; it was severe in nine. Atrial arrhythmias(supraventricular tachycardia or atrial fibrillation) occurredin 12 patients. In four patients, atrial fibrillation producedsevere right-sided congestion with a left ventricular to rightatrial shunt and haemodynamic features suggesting ‘restrictivecardiomyopathy’. Four patients had ventricular arrhythmia.Disproportionate left ventricular enlargement on echocardiographyand/or chest radiography was present in 26 (13·8%) withoutlesions to account for it. Conclusions Eighty nine patients (47%) aged 17–44 (mean,26·8) years had no complications through many years,while spontaneous closure occurred in 19 (10%) during adulthood.Forty-six (25%) had serious compli-cations: infective endocarditis(11%), progressive aortic regurgitation (5%), age-related symptomaticarrhythmias (8·5%) and atrial fibrillation the commonest.Accepting that there may be a referral bias for those with complications,the course of a small ventricular septal defect is not necessarilybenign during adult life.     

Segmental wall motion abnormalities alter vulnerability to ventricular ectopic beats associated with acute increases in aortic pressure in patients with underlying coronary artery disease

Objective—To evaluate whether patients with coronary artery disease are susceptible to pressure related ventricular arrhythmias, and if so to identify possible risk factors.
Design—Interventional study.
Methods—Metaraminol was given to 43 patients undergoing coronary arteriography for ischaemic heart disease to increase their aortic pressure, provided their systolic blood pressure was < 160 mm Hg and they were in sinus rhythm, without any ventricular ectopic activity (or with fewer than six ventricular ectopic beats a minute) during a five minute control period.
Results—During the metaraminol infusion, systolic aortic pressure rose from 131 (15) to 199 (12) mm Hg (mean (SD)). Ventricular ectopy appeared (or ventricular ectopic beats increased by > 100%) in 13/43 patients. Ventricular ectopy was not related to age, sex, presence of hypertension, history of myocardial infarction, use of β blockers, positive exercise test, number of vessels diseased, or heart rate change during metaraminol infusion. There was a strong relation between the appearance of ventricular arrhythmia and segmental wall motion abnormalities: 1/19 (5.3%, 95% confidence interval 0.1% to 26.0%) without abnormality; 2/12 (16.7%, 2.1% to 48.4%) with hypokinesia; and 10/12 (83.3%, 51.6% to 97.1%) with akinesia or dyskinesia, χ² = 22.7, p < 0.001). Ejection fraction was also a significant but not independent risk factor.
Conclusions—Patients with segmental wall motion abnormalities are predisposed to ventricular ectopic beats during an increase in systolic aortic pressure. This could be explained by associated electrophysiological inhomogeneity. The presence of mechanical inhomogeneity, as may occur in postinfarction akinesia or dyskinesia, may affect the aortic pressure above which ventricular arrhythmias appear.

Keywords: mechanoelectrical feedback;  segmental wall motion;  akinesia;  dyskinesia;  ventricular ectopic beats;  arrhythmias     

Acute and chronic effects of continuous positive airway pressure therapy on left ventricular systolic and diastolic function in patients with obstructive sleep apnea and congestive heart failure

BACKGROUND:

Obstructive sleep apnea (OSA) may contribute to the pathogenesis of congestive heart failure (CHF). Nocturnal continuous positive airway pressure (CPAP) therapy can alleviate OSA and may have a role in the treatment of CHF patients.

OBJECTIVES:

To investigate the acute and chronic effects of CPAP therapy on left ventricular systolic function, diastolic function and filling pressures in CHF patients with OSA.

METHODS:

Twelve patients with stable CHF (New York Heart Association II or III, radionuclide ejection fraction lower than 40%) underwent overnight polysomnography to detect OSA. In patients with OSA (n=7), echocardiography was performed at baseline (awake, before and during acute CPAP administration) and after 6.9±3.3 weeks of nocturnal CPAP therapy. Patients without OSA (n=5) did not receive CPAP therapy, but underwent a baseline and follow-up echocardiogram.

RESULTS:

In CHF patients with OSA, acute CPAP administration resulted in a decrease in stroke volume (44±15 mL versus 50±14 mL, P=0.002) and left ventricular ejection fraction ([LVEF] 34.8±5.0% versus 38.4±3.3%, P=0.006) compared with baseline, but no change in diastolic function or filling pressures (peak early diastolic mitral annular velocity [Ea]: 6.0±1.6 cm/s versus 6.3±1.6 cm/s, P not significant; peak early filling velocity to peak late filling velocity [E/A] ratio: 1.05±0.74 versus 1.00±0.67, P not significant; E/Ea ratio: 10.9±4.1 versus 11.3±4.1, P not significant). In contrast, chronic CPAP therapy resulted in a trend to an increase in stroke volume (59±19 mL versus 50±14 mL, P=0.07) and a significant increase in LVEF (43.4±4.8% versus 38.4±3.3%, P=0.01) compared with baseline, but no change in diastolic function or filling pressures (Ea: 6.2±1.2 cm/s versus 6.3±1.6 cm/s, P not significant; E/A ratio: 1.13±0.61 versus 1.00±0.67, P not significant; E/Ea ratio: 12.1±2.7 versus 11.3±4.1, P not significant). There was no change in left ventricular systolic function, diastolic function or filling pressures at follow-up in CHF patients without OSA.

CONCLUSIONS:

Acute CPAP administration decreased stroke volume and LVEF in stable CHF patients with OSA. In contrast, chronic CPAP therapy for seven weeks improved left ventricular systolic function, but did not affect diastolic function or filling pressures. The potential clinical implications of the discrepant effects of CPAP therapy on left ventricular systolic and diastolic function in CHF patients with OSA warrant further study.     

Intravenous streptokinase in acute myocardial infarction (I.S. A.M.): assessment of left ventricular function 1 and 7 months after infarction by radionuclide ventriculography

l.S.A.M. was a prospective, placebo-controlled, double-blindmulticentre trial of high-dose short-term intravenous streptokinasein acute myocardial infarction (AMI) within 6 h of the onsetof symptoms. Determination of left ventricular ejection fraction(LVEF) by radionuclide ventriculography was performed 1 and7 months after AMI in a subset of 192 patients at rest and,in 140 of them, also during exercise. Regional myocardial functionwas analysed in all 145 patients with neither a history of aprevious myocardial infarction nor revascularization proceduresor reinfarction within the 7-month follow-up period. One month after AMI, mean LVEF was higher in the streptokinasegroup in patients with anterior AMI (50±15% vs 42 ±16%,P = 0.013). This difference was more marked in the subgrouptreated within 3 h (53 ± 14% vs 42 ± 15%, P =0.004), whereas patients treated 3–6 h after the onsetof symptoms did not differ from respective controls (41 ±16%vs 41 ±18%). In patients with inferior A MI, the differencein mean LVEF was small (57±11% vs 55 ±12%, P =0.47). After anterior AMI benefit due to streptokinase therapywas preserved up to 7 months (52 ±14% vs 44 ±17%,P = 0.013). During exercise, the increase of mean LVEF was greaterin the streptokinase group at both dates, especially 7 monthsafter AMI (41 ±61% vs l.2±6.3%, P = 0.015). Instreptokinase-treated patients with anterior AMI, regional LVEFat rest was higher at both dates compared with controls, withinthe infarct zone as well as in remote myocardium. No treatment-controldifferences were demonstrable in patients with inferior AMI.During exercise, regional contractile reserve was better inthe streptokinase group within the infarct zone as well as inremote myocardium, irrespective of the site of infarction. Thus, intravenous streptokinase within 3 h after the onset ofA MI preserves global left ventricular function m anterior AMIover a period of at least 7 months. Intravenous streptokinaseimproves regional myocardial function within the infarct zoneas well as in remote areas. In inferior AMI investigation solelyat rest may underestimate the benefit of streptokinase therapy.     

Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature

BACKGROUND:

Although an autoimmune mechanism has been postulated for myocarditis and acute-onset inflammatory dilated cardiomyopathy (DCM), immunomodulatory treatment strategies are still under investigation.

METHODS AND RESULTS:

The clinical data of six patients with acute inflammatory DCM referred for evaluation for possible heart transplantation were reviewed. All patients were admitted with acute congestive heart failure and severely impaired left ventricular (LV) function and were treated with high-dose (2 g/kg) intravenous immunoglobulin (IVIG). The diagnosis of acute inflammatory DCM was based on recent onset of congestive heart failure (New York Heart Association functional class III or IV) with severely depressed LV ejection fraction ([LVEF] 30% or lower) occurring shortly after viral-like illness. All patients had inflammation on endomyocardial biopsy or elevated cardiac enzymes, as well as a normal coronary angiogram. All patients were in New York Heart Association class I or II at the time of hospital discharge. The mean LVEF improved from 21.7±7.5% at baseline to 50.3±8.6% at discharge (P=0.005). Four patients had complete recovery (LVEF 50% or higher) and two patients had partial LV recovery. Patients were followed for a median 13.2 months (range two to 24 months) and had a mean LVEF of 53±6% (P not significant versus LVEF at discharge).

CONCLUSIONS:

Therapy with intravenous high-dose IVIG may be a potentially useful treatment in selected patients if given early in the course of acute fulminant inflammatory DCM. A randomized, prospective trial is warranted to prove the real benefit of IVIG in this patient population.     

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??Objective To observe the changes of red cell distribution width ??RDW?? in children with heart failure secondary to dilated cardiomyopathy??DCM????and to explore the correlations between RDW and the common parameters of cardiac function. Methods Totally 68 children with heart failure secondary to DCM were enrolled. According to the modified Ross scoring system??the children were divided into 3 subgroups?? mild??moderate and severe heart failure subgroups. Fifty healthy children were selected as control group. RDW levels were compared among the groups. The correlation analysis was performed between RDW and plasma N-terminal brain natriuretic peptide ??NT-proBNP??as well as left ventricular ejection fraction??LVEF??. Results RDW levels in children with heart failure secondary to DCM were significantly higher than the control group ??P??0.01??.With increasing heart failure grade??NT-proBNP levels were elevated gradually and LVEF were decreased gradually ??both P??0.01????RDW levels had no significant difference among the heart failure groups??P??0.05??. RDM was not correlated with NT-proBNP or LVEF??r??0.144??r??-0.158??P??0.05??. Conclusion In children with DCM??RDW can be used as a new diagnostic marker of heart failure??but it can not reflect the severity of heart failure.     

Implantable Cardioverter-Defibrillators in Children and Adolescents With Brugada Syndrome

Background

Young patients presenting with symptomatic Brugada syndrome have very high risks for ventricular arrhythmias and should be carefully considered for implantable cardioverter-defibrillator (ICD) placement. However, this therapy is associated with high rates of inappropriate shocks and device-related complications.

New-Onset Atrial Fibrillation After PCI or CABG for Left Main Disease: The EXCEL Trial

Background

There is limited information on the incidence and prognostic impact of new-onset atrial fibrillation (NOAF) following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for left main coronary artery disease (LMCAD).