Longitudinal analysis of echocardiographic and cardiac biomarker variables in dogs with atrial fibrillation: The optimal rate control in dogs with atrial fibrillation II study.

BACKGROUND: Rate control (RC; meanHRHolter ≤ 125 bpm) increases survival in dogs with atrial fibrillation (AF). The mechanisms remain unclear. HYPOTHESIS/OBJECTIVES: Investigate echocardiographic and biomarker differences between RC and non-RC (NRC) dogs. Determine if changes post-anti-arrhythmic drugs (AAD) predict successful RC in subsequent Holter monitoring. Evaluate if early vs late RC affects survival. ANIMALS: Fifty-two dogs with AF. METHODS: Holter-derived mean heart rate, echocardiographic and biomarker variables from dogs receiving AAD were analyzed prospectively at each re-evaluation and grouped into RC or NRC. The primary endpoint was successful RC. Between group comparisons of absolute values, magnitude of change from admission to re-evaluations and end of study were performed using Mann-Whitney tests or unpaired t-tests. Logistic regression explored variables associated with inability to achieve RC at subsequent visits. Kaplan-Meier survival analysis was used to compare survival time of early vs late RC. RESULTS: At visit 2, 11/52 dogs were RC; at visit 3, 14/52 were RC; and at visit 4, 4/52 were RC. At the end of study, 25/52 remained NRC. At visit 2, both groups had increased cardiac dimensions, but NRC dogs had larger dimensions; biomarkers did not differ. At the end of study, RC showed decreased cardiac dimensions and end-terminal pro-brain natriuretic peptide (NT-proBNP) compared with NRC. No variables were useful at predicting RC success in subsequent visits. Survival analysis found no differences between early vs late RC. CONCLUSIONS AND CLINICAL IMPORTANCE: The RC dogs had decreased cardiac dimensions and NT-proBNP, suggesting HR-mediated reverse-remodeling might benefit survival, even with delayed RC achievement. Pursuit of RC is crucial despite initial failures.

Optimal rate control in dogs with atrial fibrillation-ORCA study-Multicenter prospective observational study: Prognostic impact and predictors of rate control.

BACKGROUND: The optimal heart rate (HR) in dogs with atrial fibrillation (AF) is unknown. Impact of HR on survival needs elucidation. HYPOTHESIS/OBJECTIVES: Dogs with a 24 hours Holter-derived meanHR ≤125 beats per minute (bpm; rate controlled) survive longer than dogs with higher meanHR. We further aimed to determine which variables predict ability to achieving rate control. ANIMALS: Sixty dogs with AF. METHODS: Holter-derived meanHR, clinical, echocardiographic, and biomarker variables were analyzed prospectively. Survival was recorded from time of rate control, with all-cause mortality as primary endpoint. Cox proportional hazards analysis identified variables independently associated with survival; Kaplan-Meier survival analysis estimated the median survival time of dogs with meanHR ≤125 bpm vs >125 bpm. Logistic regression explored baseline variables associated with inability to achieve rate control. RESULTS: Structural heart disease was present in 56/60 dogs, 50/60 had congestive heart failure, and 45/60 died. Median time to all-cause death was 160 days (range, 88-303 days), dogs with meanHR >125 bpm (n = 27) lived 33 days (95% confidence interval [CI], 15-141 days), dogs with meanHR ≤125 bpm (n = 33) lived 608 days (95% CI, 155-880 days; P < .0001). Congenital heart disease and N-terminal pro-B-type natriuretic peptide were independently associated with higher risk of death (P < .01 and <.0001, respectively) whereas meanHR ≤125 bpm decreased the risk of death (P < .001). Increased left atrial size, increased C-reactive protein concentration and lower blood pressure at admission were associated with failure to achieve rate control. CONCLUSIONS AND CLINICAL IMPORTANCE: Rate control affects survival; an optimal target meanHR <125 bpm should be sought in dogs with AF. Baseline patient variables can help predict if rate control is achievable.

Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria.

Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A1 and M2 receptors coupled to inwardly rectifying GIRK/KIR3.1/3.4 channels, respectively. Unlike M2 receptors, bradycardia produced by A1 receptors activation predominates over negative inotropy. Such difference suggests that other ion currents may contribute to adenosine chronoselectivity. In isolated spontaneously beating rat atria, blockade of KCa2/SK channels with apamin and Cav1 (L-type) channels with nifedipine or verapamil, sensitized atria to the negative inotropic action of the A1 agonist, R-PIA, without affecting the nucleoside negative chronotropy. Patch-clamp experiments in the whole-cell configuration mode demonstrate that adenosine, via A1 receptors, activates the inwardly-rectifying GIRK/KIR3.1/KIR3.4 current resulting in hyperpolarization of atrial cardiomyocytes, which may slow down heart rate. Conversely, the nucleoside inactivates a small conductance Ca(2+)-activated KCa2/SK outward current, which eventually reduces the repolarizing force and thereby prolong action potentials duration and Ca(2+) influx into cardiomyocytes. Immunolocalization studies showed that differences in A1 receptors distribution between the sinoatrial node and surrounding cardiomyocytes do not afford a rationale for adenosine chronoselectivity. Immunolabelling of KIR3.1, KCa2.2, KCa2.3, and Cav1 was also observed throughout the right atrium. Functional data indicate that while both A1 and M2 receptors favor the opening of GIRK/KIR3.1/3.4 channels modulating atrial chronotropy, A1 receptors may additionally restrain KCa2/SK activation thereby compensating atrial inotropic depression by increasing the time available for Ca(2+) influx through Cav1 (L-type) channels.