Pedro Fernandez

Time to first shock and clinical outcome in patients receiving an automatic implantable cardioverter-defibrillator

The relation between time to first shock and clinical outcome was studied in 60 patients who received an automatic implantable cardioverter-defibrillator (AICD) from August 1983 through May 1988. The mean (+/- SD) patient age was 64 +/- 10 years, 82% were men and the mean ejection fraction was 33 +/- 13%. During follow-up, 38 patients (63%) had one or more shocks; there were no differences in age, gender distribution or ejection fraction at entry between the shock and no shock groups. Among 51 patients with coronary artery disease, 31 (61%) had one or more shocks, whereas all seven patients with cardiomyopathy had one or more shocks (p less than 0.05). Neither of the two patients with idiopathic ventricular fibrillation had shocks. Of the 13 deaths, 12 occurred during post-hospital follow-up and 1 during the index hospitalization. Of the four sudden post-hospital deaths, only one was due to tachyarrhythmia in the absence of acute myocardial infarction. All four sudden deaths and five of eight post-hospital nonsudden deaths occurred in patients who had had one or more appropriate shocks during follow-up. Eight of the nine first appropriate shocks among patients who subsequently died occurred within the first 3 months of follow-up, but the actual deaths were delayed to a mean of 14.1 +/- 13.9 months (p less than 0.05). The mean time to all deaths was 14.8 +/- 13.1 months. The ejection fraction was significantly lower among patients who died than among patients who survived (25 +/- 7% versus 35 +/- 14%, p less than 0.02), but it did not distinguish risk of first shocks.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of proarrhythmic effects of flecainide acetate and encainide hydrochloride by propranolol.

The use of membrane-active antiarrhythmic agents may be complicated by aggravation of existing arrhythmias or development of new drug-induced arrhythmias. Four patients, referred because of out-of-hospital cardiac arrest or symptomatic sustained ventricular tachycardia, were receiving class IC antiarrhythmic agents in an attempt to prevent inducibility of sustained ventricular tachycardia. New or worsening spontaneous arrhythmias developed while they were on flecainide acetate (n = 3) or encainide hydrochloride (n = 1) therapy. Spontaneous runs of rapid nonsustained and sustained ventricular tachycardia developed in two. Increased frequency of premature ventricular contractions and repetitive forms of ventricular ectopic activity developed in one, despite the fact that inducibility of sustained ventricular tachycardia had been prevented. Salvos and nonsustained ventricular tachycardia developed in the fourth patient. Propranolol had failed to prevent inducibility of sustained ventricular tachycardia during previous programmed stimulation studies in three of the four patients, but it reproducibly suppressed drug-induced arrhythmias that appeared only after administration of the IC agents in each patient. Suppression of the proarrhythmic effects by beta-adrenergic blockade suggests a possible interaction of these drugs with autonomic function in the genesis of the observed proarrhythmic effects. Direct pharmacologic control of proarrhythmic drug effects has not previously been reported.

Usefulness of the automatic implantable cardioverter defibrillator in improving survival of patients with severely depressed left ventricular function associated with coronary artery disease

Clinical outcome was analyzed among a group of 39 consecutive patients with coronary artery disease, left ventricular (LV) ejection fractions less than 30% and arrhythmias that required an automatic implantable cardioverter defibrillator (AICD) in an attempt to better define the role of the device in patients with severely depressed LV function. Twenty-nine (74%) were survivors of out-of-hospital cardiac arrest and 10 (26%) had ventricular tachycardia that was refractory to electrophysiologically guided antiarrhythmic therapy. The study group had the following demographic characteristics: 90% were men, mean age was 64 years (range 41 to 79) and mean LV ejection fraction was 21 +/- 4%. Concomitant pharmacotherapy included antiarrhythmic drugs 31 (79%), vasodilators in 22 (56%) and digoxin in 20 (51%). There was no statistical difference in baseline characteristics between survivors and nonsurvivors. Patients were followed for a mean of 24 months (range 2 to 72) from implantation. The difference between actuarial survival--77% at 1 year and 72% at 2 years--and projected survival without the AICD (patients who survive without appropriate device discharge)--30% at 1 year and 21% at 2 years--was significant (p less than 0.01 and less than 0.05 at 1 and 2 years, respectively). This study suggests that the AICD improves survival in patients with coronary artery disease despite severely depressed LV function.

The Automatic Implantable Cardioverter Defibrillator: Results, Observations, and Comments

The automatic implantable cardioverter‐defibrillator (AICD) is a device of proven efficacy in life‐threatening ventricular tachycardia and fibrillation. Initial experience with the AICD at the University of Miami consists of 21 patients with recurrent ventricular dysrhythmias for a total follow‐up of 3–35 months (mean 19). There were two deaths in the series, one nonarrhythmic and one arrhythmic, at the fifth and tenth postoperative months respectively. There were five complications requiring reoperation in three patients. Pacemakers were required in four patients with the AICD and resulted in interesting observations. Our data concur with previously published reports of improved survival in selected patients.

Subtype specific estrogen receptor action protects against changes in MMP-2 activation in mouse retinal pigmented epithelial cells

Eyes with age-related macular degeneration (AMD) demonstrate accumulation of specific deposits and extracellular matrix (ECM) molecules under the retinal pigment epithelium (RPE). AMD is about two times more prevalent in aging postmenopausal women. Therefore we studied whether 17beta-estradiol (E(2)) modulates the expression and activity of the trimolecular complex (MMP-2, TIMP-2 and MMP-14), molecules which are of major importance for ECM turnover in RPE. We used cell lines isolated from estrogen receptor knockout mice (ERKO) to determine which ER (estrogen receptor) subtype was important for ECM regulation in RPE cells. We found that mouse RPE sheets had higher baseline MMP-2 activity in the presence of ERbeta. This correlated with higher MMP-2 activity in RPE cell lines isolated from ERKOalpha mice. Exposure to E(2) increased MMP-2 activity in mouse RPE cell lines. In addition E(2) increased transcriptional activation of the MMP-2 promoter through a functional Sp1 site which required the presence of ERbeta, but not ERalpha. E(2) also maintained levels of pro MMP-2, and MMP-14 and TIMP-2 activity after oxidant injury. Since the direct effects of E(2) on MMP-2 transcriptional activation and the regulation of the trimolecular complex after oxidant-induced injury requires ERbeta, this receptor subtype may have a role as a potential therapeutic target to prevent changes in activation of MMP-2.

Estrogen receptor β protects against in vivo injury in RPE cells

Epidemiological data suggest that estrogen deficiency in postmenopausal women may contribute to the severity of AMD. We discovered that 17beta-estradiol (E2) was a crucial regulator of the severity of extracellular matrix turnover (ECM) dysregulation both in vivo and in vitro. We also found in vitro that the presence of estrogen receptor (ER)beta regulates MMP-2 activity. Therefore in an attempt to delineate the role of the ER subtypes, female estrogen receptor knockout (ERKO) mice were fed a high-fat diet, and the eyes were exposed to seven 5-second doses of nonphototoxic levels of blue-green light over 2 weeks. Three months after cessation of blue light treatment, transmission electron microscopy was performed to assess severity of deposits, Bruchs membrane changes, and choriocapillaris endothelial morphology. We found that changes in the trimolecular complex of pro-MMP-2, MMP-14 and TIMP-2 correlated with increased Bruchs membrane thickening or sub-retinal deposit formation (basal laminar deposits) in ERKObeta mice. In addition RPE isolated from ERKObeta mice had an increase in expression of total collagen and a decrease in MMP-2 activity. Finally we found that ERK an intermediate signaling molecule in the MMP pathway was activated in RPE isolated from ERKObeta mice. These data suggest that mice which lack ERbeta are more susceptible to in vivo injury associated with environmental light and high fat diet.

The implantable cardioverter-defibrillator: Clinical results

To evaluate the effectiveness of the automatic implantable cardioverter‐defibrillator (AICD), a 7‐year experience, from 1983–1990, was reviewed. A total of 111 patients received an AICD device. Their ages ranged between 8 and 83 years. Mean age was 63.9 years. There were 91 men and 20 women. Eighty of the patients received the AICD following an out‐of‐hospital cardiac arrest, white 32 were suffering from intermittent symptomatic ventricular tachycardia. The underlying etiology in 97 patients (87%) was ischemic coronary artery disease, in 11 patients (10%) dilated cardiomyopathy, and in 3 patients (3%) idiopathic ventricular fibrillation. Mean ejection fraction was 33.2%. Implantation of the AICD was performed via a left thoracotomy in 39 patients, median sternotomy in 49 patients and subxiphoidsubcostal approach in 23 patients. In‐hospital mortality occurred in one patient who suffered an acute myocardial infarction 4 hours postoperatively. Out‐of‐hospital mortality was observed in 19 patients. There were two arrhythmic deaths. Follow‐up was available for 107 patients. Mean follow‐up was 33.1 months. Sixty‐six patients (62%) had AICD shocks. The initial appropriate shocks occurred during the first postimplantation year in 91% of the patients. In 53 of the survivors, initial AICD shocks took place within 4.4 ± 4.7 months from implantation. Thirteen of the 20 patients who died had received appropriate AICD shocks. In these patients, the time between implantation and first shock was 2.7 ± 3.6 months whereas the time between implantation and death was 11.3 ± 10.3 months (NS). We conclude that the AICD is effective in converting ventricular tachyarrhythmias and prolongs survival.

Pharmacologic approaches to management of arrhythmias in patients with cardiomyopathy and heart failure

Interactions between disordered cardiac rhythm and abnormal cardiac hemodynamic function are well recognized. Demonstrations of this relationship include the relationship between prognostic significance of ventricular ectopy and left ventricular ejection fraction, impairment of ventricular function in association with loss of atrial systole in disease states, increased risk of potentially lethal arrhythmias in the myopathic ventricle, and the evolution of advanced grades of ventricular arrhythmias in acute heart failure. With the development of newer and more potent antiarrhythmic agents, in conjunction with drugs that can improve the failing circulation, it is now possible to clarify these interrelationships and perhaps develop new strategies for clinical management.

Future evaluation of antiarrhythmic therapy

The expansion of antiarrhythmic therapy beyond pharmacologic agents to include surgery, devices, and ablation procedures, plus the reaffirmation by the Cardiac Arrhythmia Suppression Trial (CAST) of the need for concurrent placebo-controlled trials to establish a mortality benefit, have resulted in the need to consider the requirements for evaluating therapy. Pharmacologic therapy may be used in three ways: (1) primary; (2) alternative; and (3) adjunctive. To accurately identify a mortality benefit from primary therapy, a placebo-controlled study is necessary. In contrast, control of symptoms may be identified without the same rigorous demands. Current data are limited by the absence of true negative controls for most interventions that claim a possible mortality benefit. Alternative therapy provides a choice between equally effective therapies, neither of which has necessarily been documented to have a mortality benefit. Adjunctive therapy is that which is used for control of symptoms, whereas another therapy is used to provide a presumed or proved mortality benefit. For any of these approaches, therapy must be further evaluated in terms of four modifying variables: (1) impact of therapy on the basis of both its efficacy and efficiency; (2) interpretation of outcome data based on analysis of competing risks; (3) measurement of efficacy in terms of extension of life; and (4) analysis of outcome as the equilibrium between antiarrhythmic benefit and proarrhythmic risk. With these approaches a rational analysis of the effect of therapy and its cost-based benefit can be achieved.

Symmetry, broken symmetry, and restored symmetry of apparent pure ventricular parasystole

Abstract Previous reports dealing with the dynamics of “pure” parasystole using mathematic and electronic (pacing-induced) models, respectively, showed that a number of predictions emerged naturally from mathematic analysis. 1,2 Therefore, it appeared of interest to determine whether they would also apply to a series of patients with clinical (apparently) “pure” ventricular parasystole who were monitored for relatively long periods of time. In contrast to previous studies, Glass et al 1 had the ingenious idea of analyzing the number of sinus beats interposed between 2 consecutive manifest parasytolic beats. They observed that, with the rates being practically constant, a detailed mathematic description could be made using 2 parameters: the ratio of ectopic cycle length to sinus cycle length and the ratio of ventricular refractory period to sinus cycle length. From a correlation of these parameters 3 basic rules emerged: (1) There are at most 3 different values for the number of sinus beats in between parasystolic beats. (2) Only 1 of these values is odd. (3) The sum of the 2 lesser values is 1 less than the larger value.