Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.
TL;DR: There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure.
Abstract: The analysis of plasma kinetics of the sympathetic neurotransmitter norepinephrine can be used to estimate sympathetic nervous "activity" (integrated nerve firing rate) for the body as a whole and for individual organs. In 12 patients with cardiac failure (left ventricular ejection fraction 10% to 39%), the mean arterial plasma norepinephrine concentration was 557 +/- 68 pg/ml (mean +/- SE) compared with 211 +/- 21 pg/ml in 15 subjects without heart failure (p less than .002). The difference was due to both increased release of norepinephrine to plasma (indicating increased "total" sympathetic activity) and reduced clearance of norepinephrine from plasma. The increase in sympathetic activity did not involve all organs equally. Cardiac (32 +/- 9 vs 5 +/- 1 ng/min; p less than .002) and renal (202 +/- 45 vs 66 +/- 9 ng/min; p = .002) norepinephrine spillover were increased by 540% and 206%, respectively, but norepinephrine spillover from the lungs was normal. Adrenomedullary activity was also increased in the patients with heart failure, whose mean arterial plasma epinephrine concentration was 181 +/- 38 pg/ml compared with 71 +/- 12 pg/ml in control subjects (p less than .02). There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure. The finding of increased cardiorenal norepinephrine spillover has important pathophysiologic and therapeutic implications.
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The Heart Research Institute1, University of Erlangen-Nuremberg2, Saarland University3, Barts Health NHS Trust4, John Hunter Hospital5, Université catholique de Louvain6, University of Kiel7, University of Cologne8, Leipzig University9, Medical University of Vienna10, Complutense University of Madrid11, St. Vincent's Health System12, University of Duisburg-Essen13, Canterbury Hospital14, University of Zurich15, University of Glasgow16, Auckland City Hospital17, University of Freiburg18, Jagiellonian University19, Stanford University20, Harvard University21
TL;DR: Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients and should be continued, according to the authors.
2,200 citations
TL;DR: In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose- related reductions in mortality and hospitalization rate and was generally well tolerated.
Abstract: Background We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a “third-generation” β-blocking agent with vasodilator properties, in chronic heart failure. Methods and Results Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, ...
1,280 citations
TL;DR: This review examines the physiological foundations of sympathovagal balance, a model whose order (the number of parameters) is selected automatically to minimize Akaike’s information criterion statistic.
Abstract: Given the importance of the autonomic nervous system to cardiovascular health, it is not surprising that there is and has been great interest in measurements of human sympathetic and vagus nerve traffic as tools that might inform physiological and pathophysiological mechanisms. Pagani and coworkers1 advanced the provocative notion that the instantaneous balance between sympathetic and vagal nerve activities can be captured by a single number, obtained by dividing RR-interval spectral power centered at ≈0.1 Hz by spectral power centered at higher, primarily respiratory frequencies. This ratio, or sympathovagal balance, has been embraced with great enthusiasm2 because it offers new possibilities for understanding dynamic, critically important autonomic interrelations in humans by the use of totally noninvasive, unobtrusive means.3
The broad bases for this mathematical treatment are as follows: (1) 0.1-Hz RR intervals are importantly mediated by fluctuations of sympathetic nerve activity; (2) higher-frequency RR-interval rhythms are mediated almost exclusively by fluctuations of vagal-cardiac nerve activity; and (3) physiological interventions tend to provoke reciprocal changes of sympathetic and vagal neural outflows. Sympathovagal balance, the ratio of these periodicities, is taken to reflect the balance between the opposing neural mechanisms. This review examines the physiological foundations of sympathovagal balance.
The ECG is recorded with the subject in a steady state (when rhythms are stationary) for a period sufficiently long to define events occurring over frequencies of interest. RR-interval spectral power is calculated from this series of intervals with an autoregressive algorithm, which yields center frequencies and absolute power of component fluctuations, based on a model whose order (the number of parameters) is selected automatically to minimize Akaike’s information criterion statistic.4 (The statistical uncertainty and consequences of the automatic selection of the autoregressive model have not been defined fully; however, it is clear that the model order importantly determines both …
1,057 citations
TL;DR: This review describes how a treatment that began as a contraindication became an established treatment of chronic heart failure with β-adrenergic blocking agents.
Abstract: The medical treatment of chronic heart failure has undergone a remarkable transition in the past 10 years. The approach has changed from a short-term hemodynamic/pharmacological paradigm to a more long-term, reparative strategy that aims to favorably alter the biological properties of the failing heart.1 This is dramatically illustrated by the recent success in treating mild-to-moderate chronic heart failure with β-adrenergic blocking agents. This review describes how a treatment that began as a contraindication1 2 3 became an established treatment of chronic heart failure.
The failing human heart is adrenergically activated,4 5 6 which helps to maintain cardiac performance over the short term by increasing contractility and heart rate. In contrast, in the resting state there is no adrenergic support of normally functioning human left ventricles.6 Multiple lines of evidence7 8 9 indicate that it is the increase in cardiac adrenergic drive rather than an increase in circulating norepinephrine that is both initially supportive and then ultimately damaging to the failing human heart.
As shown in Table 1⇓, there are 3 adrenergic receptors (β1, β2, and α1) in human cardiac myocytes coupled to a positive inotropic response and cell growth.10 11 12 β-Adrenergic receptors are coupled via the “stimulatory” G protein Gs to the effector enzyme adenylyl cyclase, which converts the substrate MgATP to cAMP. cAMP is a positively inotropic and chronotropic second messenger and is strongly growth promoting. In nonfailing human left or right ventricles, the β1/β2 ratio is 70 to 80/30 to 20, but in failing human ventricles, 35% to 40% of the total number of β-receptors are β2 because of selective downregulation in the β1 subtype.10 11 α1 Receptors are coupled via a different G protein (G …
970 citations
TL;DR: The ratio of LF to HF (LF/HF) could be used to quantify the changing relationship between sympathetic and parasympathetic nerve activities (i.e., the sympatho-vagal balance) in both health and disease and it is vital to provide a critical assessment of the assumptions upon which this concept is based.
Abstract: Power spectral analysis of the beat-to-beat variations of heart rate or the heart period (R–R interval) has become widely used to quantify cardiac autonomic regulation (Appel et al., 1989; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Berntson et al., 1997; Denver et al., 2007; Thayler et al., 2010; Billman, 2011). This technique partitions the total variance (the “power”) of a continuous series of beats into its frequency components, typically identifying two or three main peaks: Very Low Frequency (VLF) <0.04 Hz, Low Frequency (LF), 0.04–0.15 Hz, and High Frequency (HF) 0.15–0.4 Hz. It should be noted that the HF peak is shifted to a higher range (typically 0.24–1.04 Hz) in infants and during exercise (Berntson et al., 1997). The HF peak is widely believed to reflect cardiac parasympathetic nerve activity while the LF, although more complex, is often assumed to have a dominant sympathetic component (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Berntson et al., 1997; Billman, 2011). Based upon these assumptions, Pagani and co-workers proposed that the ratio of LF to HF (LF/HF) could be used to quantify the changing relationship between sympathetic and parasympathetic nerve activities (i.e., the sympatho-vagal balance) (Pagani et al., 1984, 1986; Malliani et al., 1991) in both health and disease. However, this concept has been challenged (Kingwell et al., 1994; Koh et al., 1994; Hopf et al., 1995; Eckberg, 1997; Houle and Billman, 1999; Billman, 2011). Despite serious and largely under-appreciated limitations, the LF/HF ratio has gained wide acceptance as a tool to assess cardiovascular autonomic regulation where increases in LF/HF are assumed to reflect a shift to “sympathetic dominance” and decreases in this index correspond to a “parasympathetic dominance.” Therefore, it is vital to provide a critical assessment of the assumptions upon which this concept is based.
874 citations
Cites background from "Norepinephrine spillover to plasma ..."
...…(Hopf et al., 1995; Notarius and Floras, 2001; Jardine et al., 2002; Moak et al., www.frontiersin.org February 2013 | Volume 4 | Article 26 | 1 2007; Piccirillo et al., 2009), a condition known to increase cardiac sympathetic drive (Hasking et al., 1986; Saul et al., 1988; Watson et al., 2007)....
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References
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Book•
01 Jan 1956
TL;DR: This is the revision of the classic text in the field, adding two new chapters and thoroughly updating all others as discussed by the authors, and the original structure is retained, and the book continues to serve as a combined text/reference.
Abstract: This is the revision of the classic text in the field, adding two new chapters and thoroughly updating all others. The original structure is retained, and the book continues to serve as a combined text/reference.
35,552 citations
TL;DR: Measurements of Hemodynamics, plasma norepinephrine, and plasma renin activity in patients with moderate to severe congestive heart failure suggest that a single resting venous blood sample showing the plasma norenphrine concentration provides a better guide to prognosis than other commonly measured indexes of cardiac performance.
Abstract: Hemodynamics, plasma norepinephrine, and plasma renin activity were measured at supine rest in 106 patients (83 men and 23 women) with moderate to severe congestive heart failure. During follow-up lasting 1 to 62 months, 60 patients died (57 per cent); 47 per cent of the deaths were sudden, and 45 per cent were related to progressive heart failure. Statistically unrelated to the risk of mortality were cause of disease (60 patients had coronary disease, and 46 had cardiomyopathy), age (mean, 54.8 years), cardiac index (mean, 2.11 liters per minute per square meter of body-surface area), pulmonary wedge pressure (mean, 24.5 mm Hg), and mean arterial pressure (mean, 83.2 mm Hg). A multivariate analysis of the five significant univariate prognosticators--heart rate (mean, 84.4 beats per minute), plasma renin activity (mean, 15.4 ng per milliliter per hour), plasma norepinephrine (mean, 700 pg per milliliter), serum sodium (mean, 135.7 mmol per liter), and stroke-work index (mean, 21.0 g-meters per square meter)--found only plasma norepinephrine to be independently (P = 0.002) related to the subsequent risk of mortality. Norepinephrine was also higher in patients who died from progressive heart failure than in those who died suddenly. These data suggest that a single resting venous blood sample showing the plasma norepinephrine concentration provides a better guide to prognosis than other commonly measured indexes of cardiac performance.
3,065 citations
TL;DR: It is concluded that in failing human hearts a decrease in beta-receptor density leads to subsensitivity of the beta-adrenergic pathway and decreased beta-agonist-stimulated muscle contraction.
Abstract: To identify the role of the myocardial beta-adrenergic pathway in congestive heart failure, we examined beta-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in beta-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P less than 0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P less than 0.05). We conclude that in failing human hearts a decrease in beta-receptor density leads to subsensitivity of the beta-adrenergic pathway and decreased beta-agonist-stimulated muscle contraction. Regulation of beta-adrenergic receptors may be an important variable in cardiac failure.
2,268 citations
TL;DR: Modification of the original single isotope radioenzymatic assay of Passon and Peuler permits the direct and simultaneous analysis of norepinephrine, epinephrine and dopamine in plasma samples of 50 μl or less.
2,028 citations
TL;DR: It is demonstrated that the plasma norepinephrine concentration is directly related to the degree of left ventricular dysfunction in patients with congestive heart failure and suggested that beta adrenergic receptors are desensitized in these patients and that this desensitization contributes to the observed alterations in myocardial contractility.
Abstract: Resting plasma concentrations of norepinephrine, dopamine-beta-hydroxylase enzyme activity and peripheral blood lymphocyte beta adrenergic receptor sensitivity to isoproterenol as reflected in cyclic 3′,5′-adenosine monophosphate (cAMP) generation were studied in patients with congestive heart failure due to atherosclerotic heart disease or to congestive cardiomyopathy or hypertensive cardiovascular disease. Systolic time Intervals were also measured in nonhypertensive patients and correlated with the plasma norepinephrine concentration. Control patients were hospital employees without a previous history of heart disease or hypertension, and were matched for age to eliminate the effect of increasing age on the plasma norepinephrine concentration. The results of this study clearly demonstrate that the plasma norepinephrine concentration is directly related to the degree of left ventricular dysfunction in patients with congestive heart failure. When the systolic time intervals were correlated with the plasma norepinephrine levels, a significant prolongation of the preejection period was observed with progressively increasing plasma concentrations of norepinephrine. The reverse was true for the left ventricular ejection time, which demonstrated a significant Inverse relation with the plasma norepinephrine concentration. The ratio of the preejection period to the left ventricular ejection time, which is a reflection of left ventricular function, significantly increased with increasing levels of plasma norepinephrine. In addition, plasma lymphocytes from patients with the greatest degree of left ventricular dysfunction failed to generate normal amounts of cAMP after beta adrenergic receptor stimulation with isoproterenol. It Is suggested that beta adrenergic receptors are desensitized in these patients and that this desensitization contributes to the observed alterations in myocardial contractility.
896 citations
"Norepinephrine spillover to plasma ..." refers methods in this paper
...In this study, we have applied this technique to the study of congestive heart failure to determine (1) the extent to which the increased plasma levels of norepinephrine in patients reflect reduced clearance (rather than increased release) of norepinephrine and (2) whether sympathetic activity in patients with heart failure is uniformly increased or varies in different organs....
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