Henze M, Tiniakov R, Samarel A, Holmes E, Scrogin K. Chronic fluoxetine reduces autonomic control of cardiac rhythms in rats with congestive heart failure. Am J Physiol Heart Circ Physiol 304: H444 -H454, 2013. First published December 7, 2012 doi:10.1152/ajpheart.00763.2012.-Up to 40% of patients with heart failure develop depression, and depression is an independent risk factor for cardiovascular mortality in this patient population. Consequently, increasing numbers of patients with heart failure are treated with antidepressants. Selective serotonin reuptake inhibitors are typically the antidepressant of choice since this drug class has limited cardiovascular toxicity. However, little is known about the effects of selective serotonin reuptake inhibitors on autonomic cardiac regulation in congestive heart failure (CHF). Here, indexes of cardiac autonomic control were evaluated before and during chronic fluoxetine (FLX) treatment (20 mg·kg Ϫ1 ·day Ϫ1 , 5 wk) in rats that developed CHF after coronary artery ligation. FLX reduced the lowfrequency (LF) component of heart rate variability (HRV; P Ͻ 0.01) as well as the sympathetic contribution to LF HRV (P Ͻ 0.01) in both CHF and sham-operated rats. Both FLX and CHF reduced highfrequency HRV (P Ͻ 0.01). Spontaneous baroreflex gain was decreased in CHF rats 8 wk after ligation (P Ͻ 0.01). Cross-spectral coherence between the interbeat interval and mean arterial pressure was reduced in the LF domain 3 wk after ligation in CHF rats (P Ͻ 0.01) and was further reduced after chronic FLX treatment (P Ͻ 0.01). Plasma catecholamines and LF blood pressure variability were not affected by FLX. Chronotropic responses to both efferent vagal nerve stimulation and isoproterenol administration were reduced in CHF rats and by FLX (P Ͻ 0.01), whereas inotropic responses to isoproterenol were reduced only in CHF rats (P Ͻ 0.01). These data indicate that chronic FLX reduces the responsiveness to autonomic output controlling cardiac rhythm and may further compromise autonomic regulation of cardiac function in CHF.heart rate variability; selective serotonin reuptake inhibitor IT IS NOW WELL RECOGNIZED that patients who experience a myocardial infarction and subsequently develop congestive heart failure (CHF) have a high risk (up to 40%) of developing mood and anxiety disorders (13). Moreover, a diagnosis of depression is associated with increased morbidity and mortality in CHF patients. Individuals diagnosed with depression or anxiety disorders without underlying cardiovascular disease at the time of diagnosis also have a greater risk of dying of cardiovascular disease than do individuals without depression (54). As a consequence, increasing numbers of cardiovascular patients are being treated with antidepressant drugs. The most common antidepressant drugs used for the treatment of cardiovascular patients are the selective serotonin reuptake inhibitors (SSRIs) due to their relatively limited cardiovascular toxicity (43). However, little is known about how SSRIs influence cardiac autonom...