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Increased Muscarinic Receptors Impair Beta Adrenergic Response in Failing Human Heart
S14 Journal of Cardiac Failure Vol. 18 No. 8S August 2012 Methods: From 2006 to 2011, 87 consecutive ADHF patients who underwent UF at our center were identified. Patients with ventricular assist device and with heart transplantation were excluded. Selection of UF as the treatment method was the choice of the attending cardiologist. All patients had a trial of loop diuretics. WRF was defined as creatinine rising $0.3 mg/dl from baseline. Results: Patients were 67618 years old. After UF therapy, 28 (32%) patients met the criteria for WRF; their creatinine worsened from 1.860.8 to 3.461.7 (p!0.0001). In comparison to the rest of 59 patients, their creatinine was improved from 2.160.9 to 1.660.8 (p50.048). WRF patients were more likely to be female (p!0.0001), have non-ischemic cardiomyopathy (p!0.0001), and have relatively preserved left ventricular ejection fraction (0.4260.19 vs. 0.3660.18; p50.047) compared to those without WRF. Other characteristics including age (p50.24), baseline creatinine (p50.31), pulmonary arterial pressure (p50.22) and dilatation of the inferior vena cava (p50.65) were comparable in both groups. Interestingly, patients with WRF tended to have normal or mild right ventricular dysfunction (79% vs. 44%; p!0.0001) and trace to mild tricuspid regurgitation (79%vs. 44%; p!0.0001). During 90 days after discharged, patients whose renal function worsened also had a higher incidence of readmission (57% vs. 46%) and death (42% vs. 25%) (p!0.0001 for all). Conclusions: In patients with ADHF undergoing UF, worsening of the renal function identified a group of patients with extremely high mortality and morbidity. Surprisingly, WRF was more prevalent in patients with relatively preserved left and right systolic function, suggesting that optimal unloading strategy in this condition is far to be completely elucidated.
041 Non-Invasive Hemodynamic Measurements for Acute Decompensated Heart Failure Marcelo E. Ochiai, Marcelo V. Lima, Euler O. Brancalhao, Raphael S. Puig, Kelly N. Viera, Juliano N. Cardoso, Antonio P. Barretto; Cotoxo Hospital, Heart Institute(INCOR), University of Sao Paulo, SP, Brazil
042 Increased Muscarinic Receptors Impair Beta Adrenergic Response in Failing Human Heart Wendy E. Sweet, Matthew T. Baumann, Jessica A. French, Christine S. Moravec; Kaufman Center for Heart Failure, Cleveland Clinic, Cleveland, OH Dysregulation of the sympathetic nervous system is a defining feature of human heart failure, but the role of parasympathetic nervous system alterations has been less well studied. We have reported that total muscarinic (M) receptor density, measured by radioligand binding, is significantly increased in the failing human heart (F) as compared to the non-failing human heart (NF). M receptors on cardiac myocytes predominantly activate Gi, causing inhibition of adenylyl cyclase. We hypothesized that increased M receptor density in F is accompanied by increased functional consequences for cardiac muscle. We studied human left ventricular trabecular muscle contractility in F and NF hearts at 37 C and 1.0Hz stimulation, as previously described. We measured the inotropic response to a single dose (10 6M) of the beta adrenergic agonist, isoproterenol (ISO) after a standard dose-response curve to the muscarinic agonist, acetylcholine (ACh). Paired muscles from each heart were used as vehicle controls (Ctrl). No differences were found in developed tension (DT) in response to ACh pre-treatment in F and NF hearts. As shown below, in NF Ctrl muscles, ISO increased DT by 191% and ACh pre-treatment decreased this effect to 109% (p ! 0.001). In F Ctrl muscles, ISO increased DT by 128% and ACh pre-treatment decreased this effect to 48% (p ! 0.001). The effect of ACh pre-treatment on the ISO response was significantly greater on F than NF muscles (p ! 0.01). Although it is well established that ISO causes less of a response in F vs NF muscles, our study is the first to show greater inhibition of the ISO response in F muscles, correlating with the demonstrated increase in M receptor density. Future work is aimed at understanding the temporal relationship between M receptor up-regulation and beta adrenergic receptor down-regulation in human heart failure.
Background: Hemodynamic invasive monitoring has been proved without benefit in management of decompesated heart failure. However non-invasive hemodynamic modelflow method has not been assessed in management of decompesated severe heart failure. The objective of this study was to compare the non-invasive modelflow method of hemodynamic monitoring with the thermodilution pulmonary artery catheter method in hospitalized patients by decompensated severe heart failure. Methods: Hospitalized patients for acute decompensated heart failure were included. The patients had ejection fraction ! 0.45, in use of inotropes for low cardiac output and underwent to invasive pulmonary artery catheterization to hemodynamic measurement. Simultaneously non-invasive modelflow method hemodynamic (NexfinÔ, Bmeye) was done for each patient. For same patient hemodynamic measurements in different day were considered separate. The data were analyzed by Bland-Altman agreement method and correlation Pearson or Spearman method. P ! 0.05 was significant. Results: Twenty eight patients were included and 47 simultaneous hemodynamic measurements were done. For cardiac index, the correlation coefficient was 0.281 (P50.05) and for indexed systemic vascular resistance was 0.104 (P50.48). the Bland-Altman plot show the agreement between the methods. Conclusion: In decompensated severe heart failure with current use of inotropes non-invasive hemodynamic modelflow method measurement was in agreement with invasive measurement. The non-invasive modelflow method could be useful for heart failure management.
043 Phrenic Nerve Stimulation Improves Circulatory Delay in Patients With Heart Failure and Central Sleep Apnea William T. Abraham1, Olaf Oldenburg2, Piotr Ponikowski3, Alan Schwartz4, Bradley Bart5, Danuta Czarnecka6, Dariusz Michalkiewicz7, Ayesha Hasan1, David Bourn8; 1 The Ohio State University, Columbus, OH; 2Ruhr-University of Bochum, Bad Oeynhausen, Germany; 34th Militry Hospital, Medical University, Wroclaw, Poland; 4Johns Hopkins University, Bayview, MD; 5Hennepin County Medical Center, Minneapolis, MN; 6Jagiellonian University Medical College, Krackow, Poland; 7Military Medical Institute, Warsaw, Poland; 8Respicardia, Inc, Minnetonka, MN Background: Central sleep apnea (CSA) is a common comorbidity occurring in up to 40% of patients with heart failure. It is associated with increased mortality in patients with heart failure (HF). A novel therapy which treats CSA by stimulating the phrenic nerve has shown potential in mitigating CSA by controlling breathing patterns. Circulatory delay (CD) has been correlated in previous studies to cardiac output and is defined as the time elapsed from the end of an apnea to the subsequent nadir of oxygen saturation as measured by pulse oximetry. The goal of this study is to determine the acute effect of phrenic nerve stimulation on CD and thus cardiac output. Methods: As part of an international acute feasibility study, patients underwent transvenous placement of a lead (Respicardia, Inc.) into either the left pericardiophrenic or the brachiocephalic vein for stimulation of the left or right phrenic nerve. Patients had predominantly CSA and were studied for two consecutive nights, a control night and a therapy night. CD was measured as the first measurable movement of airflow to the nadir of the oxygen desaturation following a central apneic event. Results: Sixteen patients (age 58.6 6 11.7) New York Heart Association Class
041 Non-Invasive Hemodynamic Measurements for Acute Decompensated Heart Failure Marcelo E. Ochiai, Marcelo V. Lima, Euler O. Brancalhao, Raphael S. Puig, Kelly N. Viera, Juliano N. Cardoso, Antonio P. Barretto; Cotoxo Hospital, Heart Institute(INCOR), University of Sao Paulo, SP, Brazil
042 Increased Muscarinic Receptors Impair Beta Adrenergic Response in Failing Human Heart Wendy E. Sweet, Matthew T. Baumann, Jessica A. French, Christine S. Moravec; Kaufman Center for Heart Failure, Cleveland Clinic, Cleveland, OH Dysregulation of the sympathetic nervous system is a defining feature of human heart failure, but the role of parasympathetic nervous system alterations has been less well studied. We have reported that total muscarinic (M) receptor density, measured by radioligand binding, is significantly increased in the failing human heart (F) as compared to the non-failing human heart (NF). M receptors on cardiac myocytes predominantly activate Gi, causing inhibition of adenylyl cyclase. We hypothesized that increased M receptor density in F is accompanied by increased functional consequences for cardiac muscle. We studied human left ventricular trabecular muscle contractility in F and NF hearts at 37 C and 1.0Hz stimulation, as previously described. We measured the inotropic response to a single dose (10 6M) of the beta adrenergic agonist, isoproterenol (ISO) after a standard dose-response curve to the muscarinic agonist, acetylcholine (ACh). Paired muscles from each heart were used as vehicle controls (Ctrl). No differences were found in developed tension (DT) in response to ACh pre-treatment in F and NF hearts. As shown below, in NF Ctrl muscles, ISO increased DT by 191% and ACh pre-treatment decreased this effect to 109% (p ! 0.001). In F Ctrl muscles, ISO increased DT by 128% and ACh pre-treatment decreased this effect to 48% (p ! 0.001). The effect of ACh pre-treatment on the ISO response was significantly greater on F than NF muscles (p ! 0.01). Although it is well established that ISO causes less of a response in F vs NF muscles, our study is the first to show greater inhibition of the ISO response in F muscles, correlating with the demonstrated increase in M receptor density. Future work is aimed at understanding the temporal relationship between M receptor up-regulation and beta adrenergic receptor down-regulation in human heart failure.
Background: Hemodynamic invasive monitoring has been proved without benefit in management of decompesated heart failure. However non-invasive hemodynamic modelflow method has not been assessed in management of decompesated severe heart failure. The objective of this study was to compare the non-invasive modelflow method of hemodynamic monitoring with the thermodilution pulmonary artery catheter method in hospitalized patients by decompensated severe heart failure. Methods: Hospitalized patients for acute decompensated heart failure were included. The patients had ejection fraction ! 0.45, in use of inotropes for low cardiac output and underwent to invasive pulmonary artery catheterization to hemodynamic measurement. Simultaneously non-invasive modelflow method hemodynamic (NexfinÔ, Bmeye) was done for each patient. For same patient hemodynamic measurements in different day were considered separate. The data were analyzed by Bland-Altman agreement method and correlation Pearson or Spearman method. P ! 0.05 was significant. Results: Twenty eight patients were included and 47 simultaneous hemodynamic measurements were done. For cardiac index, the correlation coefficient was 0.281 (P50.05) and for indexed systemic vascular resistance was 0.104 (P50.48). the Bland-Altman plot show the agreement between the methods. Conclusion: In decompensated severe heart failure with current use of inotropes non-invasive hemodynamic modelflow method measurement was in agreement with invasive measurement. The non-invasive modelflow method could be useful for heart failure management.
043 Phrenic Nerve Stimulation Improves Circulatory Delay in Patients With Heart Failure and Central Sleep Apnea William T. Abraham1, Olaf Oldenburg2, Piotr Ponikowski3, Alan Schwartz4, Bradley Bart5, Danuta Czarnecka6, Dariusz Michalkiewicz7, Ayesha Hasan1, David Bourn8; 1 The Ohio State University, Columbus, OH; 2Ruhr-University of Bochum, Bad Oeynhausen, Germany; 34th Militry Hospital, Medical University, Wroclaw, Poland; 4Johns Hopkins University, Bayview, MD; 5Hennepin County Medical Center, Minneapolis, MN; 6Jagiellonian University Medical College, Krackow, Poland; 7Military Medical Institute, Warsaw, Poland; 8Respicardia, Inc, Minnetonka, MN Background: Central sleep apnea (CSA) is a common comorbidity occurring in up to 40% of patients with heart failure. It is associated with increased mortality in patients with heart failure (HF). A novel therapy which treats CSA by stimulating the phrenic nerve has shown potential in mitigating CSA by controlling breathing patterns. Circulatory delay (CD) has been correlated in previous studies to cardiac output and is defined as the time elapsed from the end of an apnea to the subsequent nadir of oxygen saturation as measured by pulse oximetry. The goal of this study is to determine the acute effect of phrenic nerve stimulation on CD and thus cardiac output. Methods: As part of an international acute feasibility study, patients underwent transvenous placement of a lead (Respicardia, Inc.) into either the left pericardiophrenic or the brachiocephalic vein for stimulation of the left or right phrenic nerve. Patients had predominantly CSA and were studied for two consecutive nights, a control night and a therapy night. CD was measured as the first measurable movement of airflow to the nadir of the oxygen desaturation following a central apneic event. Results: Sixteen patients (age 58.6 6 11.7) New York Heart Association Class