Determinants of survival in sudden cardiac arrest manifesting with pulseless electrical activity.

OBJECTIVE: The proportion of sudden cardiac arrests (SCA) manifesting with pulseless electrical activity (PEA) has increased significantly, and the survival rate remains lower than ventricular fibrillation (VF). However, a subgroup of PEA-SCA cases does survive and may yield key predictors of improved outcomes when compared to non-survivors. We aimed to identify key predictors of survival from PEA-SCA. METHODS: Our study sample is drawn from two ongoing community-based, prospective studies of out-of-hospital SCA: Oregon SUDS from the Portland, OR metro area (Pop. approx. 1 million; 2002-2017) and Ventura PRESTO from Ventura County, CA (Pop. approx. 850,000, 2015-2021). For the present sub-study, we included SCA cases with PEA as the presenting rhythm where emergency medical services (EMS) personnel attempted resuscitation. RESULTS: We identified 1,704 PEA-SCA cases, of which 173 (10.2%) were survivors and 1,531 (89.8%) non-survivors. Patients whose PEA-SCA occurred in a healthcare unit (16.9%) or public location (18.1%) had higher survival than those whose PEA-SCA occurred at home (9.3%) or in a care facility (5.7%). Young age, witness status, PEA-SCA location and pre-existing COPD/asthma were independent predictors of survival. Among witnessed cases the survival rate was 10% even if EMS response time was >10 minutes. CONCLUSIONS: Key determinants for survival from PEA-SCA were young age, witnessed status, public location and pre-existing COPD/asthma. Survival outcomes in witnessed PEA cases were better than expected, even with delayed EMS response.

Sudden cardiac death with apparently normal heart.

BACKGROUND: Mechanisms of sudden cardiac death (SCD) in subjects with apparently normal hearts are poorly understood. In survivors, clinical investigations may not establish normal cardiac structure with certainty. Large autopsy series may provide a unique opportunity to confirm structural normalcy of the heart before reviewing a patient's clinical history. METHODS AND RESULTS: We identified and reexamined structurally normal hearts from a 13-year series of archived hearts of patients who had sudden cardiac death. Subsequently, for each patient with a structurally normal heart, a detailed review of the circumstances of death as well as clinical history was performed. Of 270 archived SCD hearts identified, 190 were male and 80 female (mean age 42 years); 256 (95%) had evidence of structural abnormalities and 14 (5%) were structurally normal. In the group with structurally normal hearts (mean age 35 years), SCD was the first manifestation of disease in 7 (50%) of the 14 cases. In 6 cases, substances were identified in serum at postmortem examination without evidence of drug overdose; 2 of these chemicals have known associations with SCD. On analysis of ECGs, preexcitation was found in 2 cases. Comorbid conditions identified were seizure disorder and obesity (2 cases each). In 6 cases, there were no identifiable conditions associated with SCD. CONCLUSIONS: In 50% of cases of SCD with structurally normal hearts, sudden death was the first manifestation of disease. An approach combining archived heart examinations with detailed review of the clinical history was effective in elucidating potential SCD mechanisms in 57% of cases.

Epidemiology and natural history of atrial fibrillation: clinical implications.

With a substantial impact on morbidity and mortality, the growing "epidemic" of atrial fibrillation (AF) intersects with a number of conditions, including aging, thromboembolism, hemorrhage, hypertension and left ventricular dysfunction. Currently, the epidemiology and natural history of AF govern all aspects of its clinical management. The ongoing global investigative efforts toward understanding AF are also driven by epidemiologic findings. New developments, by affecting the natural history of the disease, could eventually alter the nature of decision making in patients with AF. The crucial issue of rate versus rhythm control awaits completion of the AF Follow-up Investigation of Rhythm Management trial. The processes of electrical and structural remodeling that perpetuate AF appear to be reversible. In the era of functional genomics, the molecular basis of this ubiquitous arrhythmia is in the process of being defined. Unraveling the molecular genetics of AF might provide new insights into the structural and electrical phenotypes resulting from genetic mutations and, as such, new approaches to treatment of this arrhythmia at the ion channel and cellular levels. Thus, current adverse trends are superimposed on a background of a rapidly developing knowledge base and potentially exciting new therapeutic options. Consequently, an understanding of the epidemiology and natural history of AF is crucial to the future allocation of resources and the utilization of an expanding range of therapies aimed at reducing the impact of this disease on a changing patient population.

Altered response to ibutilide in a heart failure model.

OBJECTIVE: Despite the frequent use of anti-arrhythmic drugs in the general population, the electrophysiologic effects of these agents have not been elucidated in congestive heart failure (CHF). METHODS: To examine the impact of left ventricular dysfunction on actions of type III anti-arrhythmic drugs, we evaluated the actions of ibutilide in a canine model of pacing-induced dilated cardiomyopathy. Following ablation of the atrioventricular node, effects on action potential duration at 90% (APD(90)) were compared in vivo, between eight CHF animals and seven controls. Monophasic action potential recordings were obtained from right and left ventricular endocardium/epicardium during and after three doses of ibutilide (0. 01, 0.02 and 0.05 mg/kg), at pacing cycle lengths of 300-1000 ms. RESULTS: APD(90) prolongation with ibutilide (0.01 mg/kg) was significantly greater in CHF vs. controls (P=0.0026, ANOVA). However, plasma ibutilide levels at this dose, were not significantly different between the two groups. In CHF, maximal effects were observed at the lowest dose, whereas effects were gradual and dose-dependent in controls. With ibutilide administration (0.01 mg/kg), an increased dispersion of left-right ventricular APD(90) was observed in CHF, but not in controls (P=0.03). A trend was observed, for increased incidence of non-sustained polymorphic ventricular tachycardia in CHF. CONCLUSIONS: In the presence of CHF, the actions of ibutilide are altered significantly. These findings may reflect altered tissue effects, as a consequence of myocardial electrical remodeling in CHF.

Electrophysiologic characteristics of diverse accessory pathway locations of antidromic reciprocating tachycardia.

This study assessed antidromic reciprocating tachycardia (ART) in patients with paraseptal accessory pathways (APs). Previous clinical experience suggests that paraseptal APs are unable to serve as the anterograde limb during ART. Based on the reentry wavelength concept, we hypothesized that anatomic location of a paraseptal AP may not preclude occurrence of ART. If wavelength criteria were met due to prolonged conduction time retrogradely in the atrioventricular node or anterogradely in the AP, ART may be sustained. All patients who had ART in the electrophysiologic laboratory at our institution (1991 to 1998) were studied. Based on fluoroscopically guided electrophysiologic mapping and radiofrequency ablation, AP location was classified as paraseptal, posterior, or lateral. Conduction time and refractoriness measurements were made for all components of the ART circuit. Of 24 patients with ART, 5 (21%) had ART utilizing a paraseptal AP. Anterograde conduction time through the AP and retrograde atrioventricular nodal conduction time were significantly longer in patients with paraseptal versus lateral pathways. Isoproterenol was required for ART induction in 38% of patients with a posterior AP, 36% with lateral AP location, but not in patients with a paraseptal AP. There were no significant differences in tachycardia cycle length or refractoriness of anterograde and/or retrograde components of the macroreentry circuit between the 3 pathway locations. Thus, ART can occur in patients with a paraseptal AP. Slower anterograde pathway conduction, or retrograde atrioventricular nodal conduction renders the wavelength critical for completion of the antidromic re-entrant circuit.

Early changes in gene expression that influence the course of primary glomerular disease.

Serial changes in glomerular capillary loop gene expression were used to uncover mechanisms contributing to primary glomerular disease in rat models of passive Heymann nephritis and puromycin nephrosis. Before the onset of proteinuria, podocyte protein-tyrosine phosphatase (GLEPP1) expression was transiently decreased in the nephrosis model, whereas the immune costimulatory molecule B7.1 was stimulated in both models. To relate these changes to the development of proteinuria, the time of onset and intensity of proteinuria were altered. When the models were induced simultaneously, proteinuria and anasarca occurred earlier with the collapse of glomerular capillary loops. Upregulation of B7.1 with the downregulation of GLEPP1, Wilms' tumor gene (WT1), megalin, and vascular endothelial growth factor started early and persisted through the course of disease. In the puromycin and the combined models, changes in GLEPP1 expression were corticosteroid-sensitive, whereas B7.1, WT1, vascular endothelial growth factor, and most slit diaphragm genes involved later in the combined model, except podocin, were corticosteroid-resistant. There was a very early increase in the nuclear expression of podocyte transcription factors ZHX2 and ZHX1 that may be linked to the changes in gene expression in the combined proteinuric model. Our studies suggest that an early and persistent change in mostly steroid-resistant glomerular gene expression is the hallmark of severe and progressive glomerular disease.

Mechanisms and management of renal dysfunction in heart failure.

The syndrome of congestive heart failure is characterized by activation of many neurohormonal systems with vasoconstrictor and vasodilator actions. Data suggest that the stimulus that evokes this response is a threat to the arterial blood pressure. The long-term consequences of this response on the kidney are retention of sodium and water. Strategies designed to reverse the effects of these neurohormones on the kidney have so far had limited success.

Amplified effects of d,l-sotalol in canine dilated cardiomyopathy.

Despite the presence of well-described cardiac repolarization abnormalities in heart failure, d,l-sotalol effects on cardiac repolarization have not been evaluated in animal models of CHF. The authors hypothesized that the d,l-sotalol effects on cardiac repolarization are altered in canine dilated cardiomyopathy when compared to controls. Effects of d,l-sotalol were compared in seven dogs with tachycardia induced cardiomyopathy (CHF) and six control animals. In an open-chest model, contact monophasic action potential recordings were obtained from RV and LV endocardium/epicardium during and after two doses of d,l-sotalol (1 mg/kg and 3 mg/kg, each over 20 minutes). Effects of d,l-sotalol on action potential duration at 90% repolarization (APD90) were examined at pacing cycle lengths of 300-1,000 ms. Plasma d,l-sotalol levels were measured at baseline, 10, and 40 minutes following each dose. Prolongation of APD90 by d,l-sotalol, was significantly exaggerated in CHF animals versus controls (P < 0.05, ANOVA). These differences were magnified at slow heart rates (P < 0.05, ANOVA). There were no significant differences in plasma d,l-sotalol levels between the two groups. Effects of d,l-sotalol on cardiac repolarization are exaggerated in CHF without significant alterations in plasma drug levels. While using d,l-sotalol in heart failure, independent additional effects due to ventricular electrical remodeling may be a consideration.

Endocardial activation during ventricular fibrillation in normal and failing canine hearts.

Because congestive heart failure (CHF) promotes ventricular fibrillation (VF), we compared VF in seven dogs with CHF induced by combined myocardial infarction and rapid ventricular pacing to VF in six normal dogs. A noncontact, multielectrode array balloon catheter provided full-surface real-time left ventricular (LV) endocardial electrograms and a dynamic color-coded display of endocardial activation projected onto a three-dimensional model of the LV. Fast Fourier transform (FFT) analysis of virtual electrograms showed no difference in peak or centroid frequency in CHF dogs compared with normals. The average number of simultaneous noncontiguous wavefronts present during VF was higher in normals (2.4 +/- 1.0 at 10 s of VF) than in CHF dogs (1.3 +/- 1.0, P < 0.005) and decreased in both over time. The wavefront "turnover" rate, estimated using FFT of the noncontiguous wavefront data, did not differ between normals and CHF and did not change over 5 min of VF. Thus the fundamental frequency characteristics of VF are unaltered by CHF, but dilated abnormal ventricles sustain fewer active wavefronts than do normal ventricles.

First evidence of premature ventricular complex-induced cardiomyopathy: a potentially reversible cause of heart failure.

Tachycardia-induced cardiomyopathy is a well-recognized and reversible condition, but left ventricular dysfunction due to frequent isolated premature ventricular complexes (PVCs) has not been reported. We observed resolution of dilated cardiomyopathy in a patient after a focal source of PVCs was eliminated by radiofrequency ablation. In a subset of patients with heart failure, PVC-induced cardiomyopathy may be a potentially reversible cause of left ventricular dysfunction.

Catheter tip orientation affects radiofrequency ablation lesion size in the canine left ventricle.

While some factors influencing size of RF lesions in ventricular tissue have been characterized, the effects of catheter electrode-endocardial surface orientation on lesion generation have not been investigated. Therefore, the effects of parallel versus perpendicular catheter electrode-endocardial surface orientation on dimensions of RF lesion produced with 4-, 6-, 8-, 10-, and 12-mm distal electrode lengths were studied in 20 closed-chested dogs. Orientation was established by biplane fluoroscopy and confirmed by intracardiac echocardiography for the majority of energy deliveries (71%). RF voltage was titrated to maintain constant catheter electrode temperature of 75 degrees C for 60 seconds. In the perpendicular orientation, lesion size did not change significantly with increasing electrode lengths. There was a statistically significant interaction between electrode orientation and maximum lesion length (analysis of variance [ANOVA] P = 0.04], lesion width (ANOVA P = 0.01), lesion area (ANOVA P = 0.02), and estimated lesion volume (ANOVA P < 0.005) over all electrode lengths. With parallel tip-tissue orientation, lesion size was a function of increasing electrode length. For 4-, 6-, 8-, 10-, and 12-mm electrodes, maximum lesion surface areas were 95 +/- 38, 97 +/- 38, 119 +/- 29, 147 +/- 52, and 147 +/- 67 mm2, respectively. For electrode lengths 8, 10, and 12 mm, estimated lesion volumes were significantly greater with parallel orientation (P < 0.05 for all). Thus, ventricular lesion size is dependent on catheter electrode length, but only when the catheter is oriented parallel to the endocardial surface. This information may be helpful in increasing lesion dimensions for RF ablation of ventricular tachycardias.

Isolated myocyte contractile function is normal in postinfarct remodeled rat heart with systolic dysfunction.

BACKGROUND: Postinfarction ventricular remodeling is associated with lengthening and contractile dysfunction of the remote noninfarcted myocardium. Mechanisms underlying this phenomenon remain unclear. METHODS AND RESULTS: We studied serial changes in global left ventricular (LV) structure and function in infarcted (1, 2, 4, and 6 weeks after myocardial infarction) and sham-operated rat hearts and correlated them with structural and functional changes in myocytes isolated from the remote LV myocardium in the same hearts. Rats with myocardial infarction developed significant remodeling. The heart weight-to-body weight ratios were increased. LV volumes at filling pressure of 10 mm Hg were higher (305+/-28 versus 215+/-12 microL, P<.01). This was accompanied by global LV dysfunction (in vivo LV end-diastolic pressure, 4+/-1 versus 23+/-1.6 mm Hg; Langendorff LV developed pressure, 105+/-4 versus 62+/-9 mm Hg, P<.001 for both). Myocytes isolated from these hearts showed significant structural remodeling (LV myocytes, 24% longer and 15% wider; right ventricular myocytes, 38% longer and 31% wider, all P<.05). LV myocyte length correlated with changes in LV volume (r=.79) and function (LV developed pressure, r=-.81). However, LV myocytes from the same hearts showed normal contractile function and intracellular Ca2+ transients at baseline and during inotropic stimulation with increasing extracellular Ca2+ (1 to 6 mmol/L). The shortening-frequency relationship was also similar in myocytes from sham and myocardial infarction rats. CONCLUSIONS: Postinfarct LV remodeling occurs predominantly by myocyte lengthening rather than by myocyte slippage. However, contractile function of the unloaded myocytes from the remote noninfarcted LV myocardium of the remodeled heart is normal. Therefore, myocyte contractile abnormalities may not contribute to global dysfunction of the remodeled heart. Reduced myocyte mass and nonmyocyte factors like increased wall stress, altered LV geometry, and changes in the myocardial interstitium may be more important in the genesis of postinfarct LV dysfunction in this model.

Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema.

BACKGROUND: High-altitude pulmonary edema (HAPE) is characterized by pulmonary hypertension, increased pulmonary capillary permeability, and hypoxemia. Treatment is limited to descent to lower altitude and administration of oxygen. METHODS AND RESULTS: We studied the acute effects of inhaled nitric oxide (NO), 50% oxygen, and a mixture of NO plus 50% oxygen on hemodynamics and gas exchange in 14 patients with HAPE. Each gas mixture was given in random order for 30 minutes followed by 30 minutes washout with room air. All patients had severe HAPE as judged by Lake Louise score (6.4+/-0.7), PaO2 (35+/-3. 1 mm Hg), and alveolar to arterial oxygen tension difference (AaDO2) (26+/-3 mm Hg). NO had a selective effect on the pulmonary vasculature and did not alter systemic hemodynamics. Compared with room air, pulmonary vascular resistance fell 36% with NO (P<0.001), 23% with oxygen (P<0.001 versus air, P<0.05 versus NO alone), and 54% with NO plus 50% oxygen (P<0.001 versus air, P<0.005 versus oxygen and versus NO). NO alone improved PaO2 (+14%) and AaDO2 (-31%). Compared with 50% oxygen alone, NO plus 50% oxygen had a greater effect on AaDO2 (-18%) and PaO2 (+21%). CONCLUSIONS: Inhaled NO may have a therapeutic role in the management of HAPE. The combined use of inhaled NO and oxygen has additive effects on pulmonary hemodynamics and even greater effects on gas exchange. These findings indicate that oxygen and NO may act on separate but interactive mechanisms in the pulmonary vasculature.

Intra-atrial conduction block along the mitral valve annulus during accessory pathway ablation: evidence for a left atrial "isthmus".

INTRODUCTION: We observed a change in the atrial activation sequence during radiofrequency (RF) energy application in patients undergoing left accessory pathway (AP) ablation. This occurred without damage to the AP and in the absence of a second AP or alternative arrhythmia mechanism. We hypothesized that block in a left atrial "isthmus" of tissue between the mitral annulus and a left inferior pulmonary vein was responsible for these findings. METHODS AND RESULTS: Electrophysiologic studies of 159 patients who underwent RF ablation of a left free-wall AP from 1995 to 1999 were reviewed. All studies with intra-atrial conduction block resulting from RF energy delivery were identified. Fluoroscopic catheter positions were reviewed. Intra-atrial conduction block was observed following RF delivery in 11 cases (6.9%). This was evidenced by a sudden change in retrograde left atrial activation sequence despite persistent and unaffected pathway conduction. In six patients, reversal of eccentric atrial excitation during orthodromic reciprocating tachycardia falsely suggested the presence of a second (septal) AP. A multipolar coronary sinus catheter in two patients directly demonstrated conduction block along the mitral annulus during tachycardia. CONCLUSION: An isthmus of conductive tissue is present in the low lateral left atrium of some individuals. Awareness of this structure may avoid misinterpretation of the electrogram during left AP ablation and may be useful in future therapies of atypical atrial flutter and fibrillation.