Morning surge of ventricular arrhythmias in a new arrhythmogenic canine model of chronic heart failure is associated with attenuation of time-of-day dependence of heart rate and autonomic adaptation, and reduced cardiac chaos.

Patients with chronic heart failure (CHF) exhibit a morning surge in ventricular arrhythmias, but the underlying cause remains unknown. The aim of this study was to determine if heart rate dynamics, autonomic input (assessed by heart rate variability (HRV)) and nonlinear dynamics as well as their abnormal time-of-day-dependent oscillations in a newly developed arrhythmogenic canine heart failure model are associated with a morning surge in ventricular arrhythmias. CHF was induced in dogs by aortic insufficiency & aortic constriction, and assessed by echocardiography. Holter monitoring was performed to study time-of-day-dependent variation in ventricular arrhythmias (PVCs, VT), traditional HRV measures, and nonlinear dynamics (including detrended fluctuations analysis α1 and α2 (DFAα1 & DFAα2), correlation dimension (CD), and Shannon entropy (SE)) at baseline, as well as 240 days (240 d) and 720 days (720 d) following CHF induction. LV fractional shortening was decreased at both 240 d and 720 d. Both PVCs and VT increased with CHF duration and showed a morning rise (2.5-fold & 1.8-fold increase at 6 AM-noon vs midnight-6 AM) during CHF. The morning rise in HR at baseline was significantly attenuated by 52% with development of CHF (at both 240 d & 720 d). Morning rise in the ratio of low frequency to high frequency (LF/HF) HRV at baseline was markedly attenuated with CHF. DFAα1, DFAα2, CD and SE all decreased with CHF by 31, 17, 34 and 7%, respectively. Time-of-day-dependent variations in LF/HF, CD, DFA α1 and SE, observed at baseline, were lost during CHF. Thus in this new arrhythmogenic canine CHF model, attenuated morning HR rise, blunted autonomic oscillation, decreased cardiac chaos and complexity of heart rate, as well as aberrant time-of-day-dependent variations in many of these parameters were associated with a morning surge of ventricular arrhythmias

Short-Acting β-Adrenergic Antagonist Esmolol Given at Reperfusion Improves Survival After Prolonged Ventricular Fibrillation

Background-High catecholamine concentrations are cytotoxic to cardiac myocytes. We hypothesized that myocardial interstitial catecholamine levels are greatly elevated immediately after long-duration ventricular fibrillation (VF), defibrillation, and reperfusion and that the short-acting β-antagonist esmolol administered at reperfusion would protect against this catecholamine surge and improve survival. Methods and Results-In part 1 of this study, catecholamines from myocardial interstitial fluid (ISF) and aortic and coronary sinus plasma were quantified by use of 3H-labeled radioenzymatic assay in 8 open-chest, anesthetized pigs. Eight minutes of electrically induced VF was followed by internal defibrillation and reperfusion. By 4 minutes of VF, ISF norepinephrine increased significantly, from 1.3±0.3 to 7.4±2.4 ng/mL. Epinephrine increased significantly, from 0.4±0.2 to 1.5±0.7 ng/mL. ISF norepinephrine and epinephrine peaked at 219.2±92.1 and 63.7±25.1 ng/mL after defibrillation and reperfusion and decreased significantly to 12.2±3.5 and 6.7±3.1 ng/mL 23 minutes after defibrillation. Transcardiac catecholamine changes were similar. In part 2, 8 minutes of VF was followed by external defibrillation in anesthetized, closed-chest pigs. Animals received 1.0 mg/kg esmolol (n=8) or saline (n=8) intravenously at the start of cardiopulmonary resuscitation (CPR). Advanced cardiac life support, including CPR and epinephrine, was delivered to both groups. Esmolol before reperfusion improved return of spontaneous circulation and 4-hour survival (7/8 versus 3/8 survivors, χ2 P\u3c0.05). Conclusions-Transcardiac and ISF norepinephrine and epinephrine levels are briefly massively elevated after 8 minutes of VF, defibrillation, and reperfusion. A short-acting β-antagonist administered immediately after defibrillation improves return of spontaneous circulation and 4-hour survival after this prolonged VF

CHF dogs developed LV dysfunction.

<p>(A) Histogram of LV fractional shortening (FS) at baseline, 240 days and 720 days after AC (* *, p<0.01 vs baseline). (B) 2D echocardiography demonstrates increased LV end-diastolic dimension (LVEDD) and LV end-systolic dimension (LVESD) in CHF dogs.</p

Detrended fluctuations analysis (DFA) α1 and α2.

<p>(A) Summarized data of average DFA α1 at baseline, 240 days and 720 days after AC. Mean DFA α1 was the average of every 3 hours. (B) Histogram of average 24-hour DFA α1 at baseline, 240 days and 720 days after AC (*, p<0.05 vs baseline; **, p<0.01 vs baseline). (C) Histogram of ΔDFA α1 at baseline, 240 days and 720 days after AC (*, p<0.05 vs baseline; # denote that DFA α1 is arrhythmic at 240d and 720d by rhythm analysis, i.e. exhibits loss of time-of-day dependence). ΔDFA α1 represents the increased average heart rate at 6 AM-noon vs midnight-6 AM, and was decreased with CHF. (D) Summarized data of average DFA α2 at baseline, 240 days and 720 days after AC. Mean DFA α2 is average of every 3 hours. (E) Histogram of average 24-hour DFA α2 at baseline, 240 days and 720 days after AC (* *, p<0.01 vs baseline). (F) Histogram of ΔDFA α2 at baseline, 240 days and 720 days after AC. ΔDFA α2 was decreased in CHF. ΔDFA α2 represents the change in DFA α2 at 6 AM-noon vs midnight-6 AM.</p