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A number of pathologic processes contribute to the elevation in cardiac filling pressures in heart failure (HF), including myocardial dysfunction and primary volume overload. In this review, we discuss the important role of the venous system and the concepts of stressed blood volume and unstressed blood volume. We review how regulation of venous tone modifies the distribution of blood between these 2 functional compartments, the physical distribution of blood between the pulmonary and systemic circulations, and how these relate to the hemodynamic abnormalities observed in HF. Finally, we review recently applied methods for estimating stressed blood volume and how they are being applied to the results of clinical studies to provide new insights into resting and exercise hemodynamics and therapeutics for HF., Competing Interests: Funding Support and Author Disclosures Dr Fudim was supported by the National Heart, Lung, and Blood Institute (NHLBI) (NHLBI K23HL151744), the American Heart Association (grant number 20IPA35310955), Mario Family Award, Duke Chair’s Award, Translating Duke Health Award, Bayer, and BTG Specialty Pharmaceuticals; and has received consulting fees from AxonTherapies, Bodyport, CVRx, Daxor, Edwards LifeSciences, NXT Biomedical, Zoll, and Viscardia. Dr Borlaug has received research funding from the National Institutes of health/NHLBI (R01 HL128526, U01 HL125205), AstraZeneca, Corvia, Medtronic, Mesoblast, GlaxoSmithKline, and TENAX; and has served on the Advisory Board/as a consultant for Merck, Novartis, Lilly, and Novo Nordisk. Dr Shah has consulted for AxonTherapies. Dr Rich is the chief medical officer of Tenax. Dr Burkhoff has received institutional grants from Abiomed, Ancora, and Fire 1; and has received consulting fees from PVLoops LLC and Axon Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Implantation of an interatrial shunt device (IASD) in patients with heart failure (HF) reduces left atrial hypertension by shunting oxygenated blood to the right heart and lungs. The attendant increases in pulmonary blood flow (Qp) and oxygen content may alter pulmonary vascular function, while left-to-right shunting might compromise systemic perfusion., Objectives: The authors hypothesized that IASD would improve indexes of pulmonary artery (PA) function at rest and during exercise in HF patients without reducing systemic blood flow (Qs)., Methods: This is a pooled analysis from 2 trials assessing the effects of the IASD on resting and exercise hemodynamics in HF patients (n = 79) with EF ≥40% with baseline and repeated hemodynamic evaluation between 1 and 6 months. Patients with pulmonary vascular resistance (PVR) >4 WU or right ventricular dysfunction were excluded., Results: Qp and PA oxygen content increased by 27% and 7% following IASD. These changes were associated with salutary effects on pulmonary vascular function (17% reduction in PVR, 12% reduction in PA elastance [pulmonary Ea], and 24% increase in PA compliance). Qp increased during exercise to a greater extent following IASD compared with baseline, which was associated with reductions in exercise PVR and pulmonary Ea. Patients with increases in PA compliance following IASD experienced greater improvements in supine exercise duration. There was no reduction in Qs following IASD at rest or during exercise., Conclusions: Implantation of an IASD improves pulmonary vascular function at rest and during exercise in selected patients with HF and EF ≥40%, without compromising systemic perfusion. Further study is warranted to identify underlying mechanisms and long-term pulmonary hemodynamic effects of IASD. (REDUCE LAP-HF Trial [REDUCE LAP-HF]; NCT01913613; and REDUCE LAP-HF Randomized Trial I [REDUCE LAP-HF I]; NCT02600234)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) frequently co-exist despite adequate rate control. Existing randomized studies of AF and LVSD of varying etiologies have reported modest benefits with a rhythm control strategy., Objectives: The goal of this study was to determine whether catheter ablation (CA) for AF could improve LVSD compared with medical rate control (MRC) where the etiology of the LVSD was unexplained, apart from the presence of AF., Methods: This multicenter, randomized clinical trial enrolled patients with persistent AF and idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤45%). After optimization of rate control, patients underwent cardiac magnetic resonance (CMR) to assess LVEF and late gadolinium enhancement, indicative of ventricular fibrosis, before randomization to either CA or ongoing MRC. CA included pulmonary vein isolation and posterior wall isolation. AF burden post-CA was assessed by using an implanted loop recorder, and adequacy of MRC was assessed by using serial Holter monitoring. The primary endpoint was change in LVEF on repeat CMR at 6 months., Results: A total of 301 patients were screened; 68 patients were enrolled between November 2013 and October 2016 and randomized with 33 in each arm (accounting for 2 dropouts). The average AF burden post-CA was 1.6 ± 5.0% at 6 months. In the intention-to-treat analysis, absolute LVEF improved by 18 ± 13% in the CA group compared with 4.4 ± 13% in the MRC group (p < 0.0001) and normalized (LVEF ≥50%) in 58% versus 9% (p = 0.0002). In those undergoing CA, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7%; p = 0.0069) and normalization at 6 months (73% vs. 29%; p = 0.0093)., Conclusions: AF is an underappreciated reversible cause of LVSD in this population despite adequate rate control. The restoration of sinus rhythm with CA results in significant improvements in ventricular function, particularly in the absence of ventricular fibrosis on CMR. This outcome challenges the current treatment paradigm that rate control is the appropriate strategy in patients with AF and LVSD. (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction [CAMERA-MRI]; ACTRN12613000880741)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to use cardiac magnetic resonance (CMR) imaging and invasive left ventricular (LV) pressure-volume (PV) measurements to explore the relationship between diffuse myocardial fibrosis and indexes of diastolic performance in a cohort of cardiac transplant recipients., Background: The precise mechanism of LV diastolic dysfunction in the presence of myocardial fibrosis has not previously been established., Methods: We performed CMR with T1 mapping and obtained invasive LV PV measurements via a conductance catheter in 20 cardiac transplant recipients at the time of clinically-indicated coronary angiography., Results: Both post-contrast myocardial T1 time and extracellular volume fraction correlated with β, the load-independent passive LV stiffness constant (r = -0.71, p = 0.001, and r = 0.58, p = 0.04, respectively). After multivariate analysis, post-contrast myocardial T1 time remained the only independent predictor of β. No significant associations were observed between myocardial T1 time and τ, the active LV relaxation constant, or other load-dependent parameters of diastolic function., Conclusions: Diffuse myocardial fibrosis, assessed by post-contrast myocardial T1 time, correlates with invasively-demonstrated LV stiffness in cardiac transplant recipients. In patients with increased diffuse myocardial fibrosis, abnormal passive ventricular stiffness is therefore likely to be a major contributor to diastolic dysfunction., (Copyright © 2014. Published by Elsevier Inc.)

Adjuvant radiation therapy in the management of early stage breast cancer, Hodgkin's disease, and to a lesser extent other thoracic malignancies has led to a significant improvement in disease-specific survival. Cardiovascular disease is now the most common nonmalignancy cause of death in radiation-treated cancer survivors, most often occurring decades after treatment. The spectrum of radiation-induced cardiac disease is broad, potentially involving any component of the heart. The relative risk of coronary artery disease, congestive heart failure, valvular heart disease, pericardial disease, conduction abnormalities, and sudden cardiac death is particularly increased. Over the years contemporary techniques have been introduced to reduce cardiac morbidity and mortality in radiation-treated cancer survivors; however, the long-term effects on the heart still remain unclear, mandating longer follow-up. Awareness and early identification of potential cardiac complications is crucial in cancer survivors, with the management often being quite complex. This review examines the epidemiology of radiation-induced cardiac disease together with its pathophysiology and explores the available treatment strategies and the potential utility of various screening strategies for affected cancer survivors., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to evaluate diffuse myocardial fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF)., Background: Diffuse myocardial fibrosis is a hallmark of cardiomyopathy. Unlike replacement fibrosis, it is not visualized on delayed-enhancement cardiac magnetic resonance (CMR) imaging, but may be quantified with contrast-enhanced T(1) mapping methods. In atrial fibrillation (AF), it may be induced by arrhythmia or reflect pre-existing cardiomyopathy., Methods: Ninety subjects underwent CMR using a clinical 1.5-T scanner: 23 controls, 40 paroxysmal AF patients, and 27 persistent AF patients. Cardiac morphology and function was evaluated from CMR cine imaging. A histologically validated T(1) mapping sequence was used to calculate post-contrast T(1) relaxation time (T(1) time) of the LV myocardium as an index of diffuse myocardial fibrosis., Results: Age was similar across controls, paroxysmal AF patients, and persistent AF patients (54 ± 12 years, 58 ± 9 years, and 56 ± 10 years, p = NS). Persistent AF patients had larger indexed left atrium volume (55 ± 18 ml vs. 41 ± 12 ml and 47 ± 14 ml) and lower ejection fraction (54 ± 10% vs. 65 ± 6% and 61 ± 8%) than controls and paroxysmal AF patients (p < 0.05). Post-contrast ventricular T(1) time differed across all groups (controls, 535 ± 86 ms; paroxysmal AF, 427 ± 95 ms; persistent AF, 360 ± 84 ms; p < 0.001). Univariate predictors of post-contrast ventricular T(1) time included age, sex, AF category, ejection fraction, LV mass, congestive heart failure, and body mass index. After multivariate analysis, age, AF category, and ejection fraction remained independent predictors., Conclusions: Post-contrast ventricular T(1) mapping identifies diffuse LV fibrosis in patients with AF and provides new insights into the association between AF and adverse ventricular remodeling., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the potential pathophysiological link between anemia and disease severity, and adverse outcome in heart failure (HF)., Background: Anemia frequently accompanies advanced HF; however, the pathophysiological mechanism responsible for the association between anemia and more severe HF remains uncertain. We hypothesized that a depletion of myocardial iron content may provide the biological link., Methods: Complementary clinical and basic studies were performed. Hemodynamic, biochemical, and echocardiographic investigations were performed in 9 healthy controls and 25 patients with advanced HF (left ventricular ejection fraction: 23 ± 10%). Tissue iron content and type 1 transferrin receptor (Tfr1) expression were assessed in human myocardial tissue, and the regulation of Tfr1 expression was studied in isolated cardiomyocytes., Results: HF patients displayed evidence of iron deficiency as measured by lower serum iron (p < 0.05) and transferrin saturation (TFS) (p < 0.05). When subclassified according to the presence of anemia, TFS was lower in anemic compared with nonanemic HF patients, whereas TFS in nonanemic HF patients was intermediate. In association, myocardial iron content was reduced in HF versus non-HF samples (0.49 ± 0.07 μg/g vs. 0.58 ± 0.09 μg/g, p < 0.05), and there was a significant reduction (p < 0.05) in the myocardial mRNA expression of Tfr1, which plays a key role in cellular iron transport. In the context of HF, catecholamines and aldosterone both down-regulated Tfr1 expression in isolated cardiomyocytes., Conclusions: This study suggests the presence of iron depletion in the failing human heart, providing a potential link for the association between anemia and adverse prognosis in HF., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to evaluate the association between regional myocardial fibrosis and ventricular arrhythmias in patients with cardiomyopathy., Background: Patients with heart failure are at risk of sudden cardiac death (SCD). Current guidelines recommend implantable cardioverter-defibrillator (ICD) devices for a subgroup based on impaired left ventricular function. A significant proportion of devices never discharge, hence a more accurate method for targeting those at risk is desirable., Methods: We prospectively enrolled 103 patients meeting criteria for ICD implantation for primary prevention of SCD. Cardiac magnetic resonance imaging was performed before device implantation. Regional fibrosis was identified with late gadolinium enhancement (LGE)., Results: Median follow-up was 573 days (interquartile range: 379 to 863 days). The LGE identified regional fibrosis in 31 of 61 (51%) patients with nonischemic cardiomyopathy (NICM) and in all 42 patients with ischemic cardiomyopathy (ICM). There was a 29% (9 of 31) discharge rate in the NICM group with LGE compared with a 14% (6 of 42) discharge rate in the ICM group (p = NS). There were no ICD discharges in the NICM group without LGE, which was significantly lower than the rate observed in both the ICM patients (p = 0.04) and the NICM patients with LGE (p < 0.01). Left ventricular ejection fraction was similar in patients with and without device therapy (24 ± 12% vs. 26 ± 8%, p = NS) and those with or without LGE (25 ± 9% vs. 26 ± 9%, p = NS)., Conclusions: Patients with advanced cardiomyopathy and myocardial fibrosis demonstrated by LGE on cardiac magnetic resonance imaging have a high likelihood of appropriate ICD therapy. Correspondingly, absence of LGE may indicate a lower risk for malignant ventricular arrhythmias., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to invasively investigate the hemodynamic response to exercise in patients with heart failure with normal ejection fraction (HFNEF) and to evaluate the ability of the peak early diastolic transmitral velocity to peak early diastolic annular velocity ratio (E/e') to reflect exercise hemodynamics., Background: There is little information regarding the hemodynamic response to exercise in HFNEF., Methods: Patients with HFNEF (n = 14) and asymptomatic controls (n = 8) underwent right-side heart catheterization at rest and during supine cycle ergometer exercise and echocardiography with measurement of resting and peak exercise E/e'., Results: Resting pulmonary capillary wedge pressure (PCWP) (10 +/- 4 mm Hg vs. 10 +/- 4 mm Hg; p = 0.94) was similar in HFNEF patients and controls, but stroke volume index (SVI) (p = 0.02) was lower, and systemic vascular resistance index (SVRI) (p = 0.01) was higher in patients. Patients stopped exercise at lower work rate (0.63 +/- 0.29 W/kg vs. 1.13 +/- 0.49 W/kg; p = 0.006). Although peak exercise PCWP was similar in both groups (23 +/- 6 mm Hg vs. 20 +/- 7 mm Hg; p = 0.31), the peak PCWP/work rate ratio was higher in patients compared with controls (46 +/- 31 mm Hg/W/kg vs. 20 +/- 9 mm Hg/W/kg; p = 0.03). Peak exercise SVI (p = 0.001) was lower and SVRI was higher (p = 0.01) in patients. Resting E/e' was modestly elevated in patients (13.2 +/- 4.1 vs. 9.5 +/- 3.4; p = 0.04). Peak exercise E/e' did not differ between the groups (11.1 +/- 3.4 vs. 9.4 +/- 3.4; p = 0.28)., Conclusions: The HFNEF patients achieved a similar peak exercise PCWP to that of asymptomatic controls, at a much lower workload. This occurs at a lower SVI and in the setting of higher SVRI. The E/e' does not reflect the hemodynamic changes during exercise in HFNEF patients., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

It is estimated that approximately 50% of the heart failure population has a normal left ventricular ejection fraction, a complex broadly referred to as heart failure with normal left ventricular ejection fraction (HFNEF). While these patients have been considered in epidemiologic studies and clinical trials to represent a single pool of patients, limited more detailed studies indicate that HFNEF patients are a very heterogeneous group, with a number of key pathophysiologic mechanisms. This review summarizes and critically analyzes available data on the pathophysiology of HFNEF, placing it into context with a recently developed diagnostic algorithm. We evaluate the utility of commonly applied echocardiographic measures and biomarkers and integrate mechanistic observations into potential future therapeutic directions.

Objectives: The purpose of this study was to investigate a noninvasive method for quantifying diffuse myocardial fibrosis with cardiac magnetic resonance imaging (CMRI)., Background: Diffuse myocardial fibrosis is a fundamental process in pathologic remodeling in cardiomyopathy and is postulated to cause increased cardiac stiffness and poor clinical outcomes. Although regional fibrosis is easily imaged with cardiac magnetic resonance, there is currently no noninvasive method for quantifying diffuse myocardial fibrosis., Methods: We performed CMRI on 45 subjects (25 patients with heart failure, 20 control patients), on a clinical 1.5-T CMRI scanner. A prototype T(1) mapping sequence was used to calculate the post-contrast myocardial T(1) time as an index of diffuse fibrosis; regional fibrosis was identified by delayed contrast enhancement. Regional and global systolic function was assessed by cine CMRI in standard short- and long-axis planes, with echocardiography used to evaluate diastology. An additional 9 subjects underwent CMRI and endomyocardial biopsy for histologic correlation., Results: Post-contrast myocardial T(1) times correlated histologically with fibrosis (R = -0.7, p = 0.03) and were shorter in heart failure subjects than controls (383 +/- 17 ms vs. 564 +/- 23 ms, p < 0.0001). The T(1) time of heart failure myocardium was shorter than that in controls even when excluding areas of regional fibrosis (429 +/- 22 ms vs. 564 +/- 23 ms, p < 0.0001). The post-contrast myocardial T(1) time shortened as diastolic function worsened (562 +/- 24 ms in normal diastolic function vs. 423 +/- 33 ms in impaired diastolic function vs. 368 +/- 20 ms in restrictive function, p < 0.001)., Conclusions: Contrast-enhanced CMRI T(1) mapping identifies changes in myocardial T(1) times in heart failure, which appear to reflect diffuse fibrosis.

Objectives: The purpose of this study was to develop a clinically applicable high-efficiency percutaneous means of therapeutic gene delivery to the failing heart., Background: Substantial advances in the understanding of the cellular and molecular basis of heart failure (HF) have recently fostered interest in the potential utility of gene and cell therapy as novel therapeutic approaches. However, successful clinical translation is currently limited by the lack of safe, efficient, and selective delivery systems., Methods: We developed a novel percutaneous closed-loop recirculatory system that provides homogeneous myocardial delivery for gene transfer in the failing large animal heart. After 4 weeks' rapid pacing in adult sheep to induce HF, the animals were randomly allocated to receive either adenovirus expressing a pseudophosphorylated mutant (AdS16E) of phospholamban (PLN) or Ad-beta-galactosidase (AdLacZ)., Results: Two weeks after gene delivery, in the presence of continued pacing, left ventricular (LV) ejection fraction had significantly improved in the AdS16E-treated animals (27 +/- 3% to 50 +/- 4%; p < 0.001), whereas a further decline occurred in the AdLacZ group (34 +/- 4% to 27 +/- 3%; p < 0.05). In conjunction, AdS16E delivery resulted in significant reductions in LV filling pressures and end-diastolic diameter (both p < 0.05). In conjunction, AdS16E-treated animals showed significant improvement in the expression of PLN and Ca2+-adenosine triphosphatase activity. In separate animals, recirculating AdLacZ delivery was shown to achieve superior myocardial gene expression in contrast to intracoronary delivery and was associated with lower systemic expression., Conclusions: We report the development of a novel closed-loop system for cardiac gene therapy. Using this approach delivery of AdS16E reversed HF progression in a large animal HF model.

Objectives: In the present study, we aimed to evaluate the effect of adrenergic receptor polymorphisms on the response of myocardium to measured levels of cardiac adrenergic drive, and to evaluate whether polymorphisms of presynaptic adrenoceptors modified the rate of cardiac and systemic release of norepinephrine., Background: Heightened sympathetic activity plays an important pathophysiologic role in congestive heart failure (CHF). Recently several functionally relevant polymorphisms of the alpha(2)-, beta(1)-, and beta(2)-adrenoceptors have been identified, and specific genotypes have been associated with the incidence or clinical severity of CHF. These adrenoceptors are known to be located both pre-synaptically (alpha(2) and beta(2)) and post-synaptically (beta(1) and beta(2)), raising the possibility that their association with clinical measures in CHF could be mediated either by modulation of the cardiac response to a given level of adrenergic drive or by altering norepinephrine release from sympathetic nerve terminals., Methods: We determined the beta(1)-, beta(2)-, and alpha(2C)-adrenoceptor genotype in 60 patients with severe CHF in conjunction with measurement of cardiac and systemic sympathetic activity using the radiotracer norepinephrine spillover method., Results: We showed a strong relationship (r = 0.67, p < 0.001) between heart rate and the level of cardiac adrenergic drive, and heart rate for a given level of cardiac adrenergic drive was substantially greater in patients with the Arg/Arg16 beta(2)-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the beta(1)-adrenoceptor. The genotype of the alpha(2C)- and beta(2)-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves., Conclusions: For the first time, we show that beta(2)-adrenoceptor polymorphisms significantly influence the relationship between heart rate and cardiac adrenergic drive in CHF, but do not affect the rate of norepinephrine release from sympathetic nerve terminals.

Objectives: The aim of this study was to investigate the role of peripheral presynaptic alpha-2 adrenergic receptors in modulating norepinephrine (NE) release in congestive heart failure (CHF)., Background: Activation of the sympathetic nervous system is a hallmark of CHF. Clonidine, an imidazoline and adrenergic agonist with high selectivity for the alpha-2 adrenoceptor, has been shown to reduce generalized sympathetic activity in heart failure after parenteral administration. If it could be shown that peripheral presynaptic alpha-2 adrenoceptors are inhibitory to NE release, then they could be targeted for future therapy, and as a corollary, potentially circumvent unwanted side effects arising from stimulation of alpha-2 adrenoceptors in the brain. Additionally, it could be concluded that these receptors form the basis for an auto-inhibitory feedback to further NE release., Methods: Fifteen healthy volunteers and 10 patients with heart failure received intra-arterial clonidine via the brachial artery (0.05 microg and 0.48 microg/100 ml forearm/min). Radio-tracer techniques were employed for studying NE kinetics., Results: Intra-arterial clonidine caused a dose-dependent decrease in forearm spillover of NE in healthy individuals (low dose, high dose: 26%, 49%: p < 0.05, p < 0.001, respectively). In the patient group, no decrease in forearm spillover was demonstrated after local administration. The difference in response between the two groups was statistically significant (p = 0.004)., Conclusions: Peripheral sympathoneural alpha-2 adrenoceptors are functionally important in inhibiting NE release in the healthy human. In heart failure, this function is lost. This finding offers further insights into the mechanisms responsible for high circulating levels of NE in patients with heart failure. In addition, it suggests that selective targeting of peripheral presynaptic alpha-2 adrenoceptors will not achieve sympathoinhibition in heart failure.

Objectives: We sought to assess the effects of brain natriuretic peptide (BNP) on systemic and regional sympathetic nervous activity (SNA) in both patients with congestive heart failure (CHF) and healthy control subjects., Background: Although the response of SNA to atrial natriuretic peptide (ANP) has been well documented, the response of SNA to BNP is largely unknown., Methods: We assessed cardiac and whole-body SNA using the norepinephrine (NE) tracer dilution method before and after infusion of two doses of BNP (3 and 15 ng/kg body weight per min) in 11 patients with stable CHF (ejection fraction 24 +/- 2%) and 12 age-matched healthy control subjects. In addition, renal SNA and hemodynamic variables were assessed at baseline and after the higher BNP dose., Results: Low dose BNP did not change blood pressure or whole-body NE spillover, but reduced cardiac NE spillover in both groups by 32 +/- 13 pmol/min (p < 0.05). In both groups, high dose BNP reduced pulmonary capillary pressure by 5 +/- 1 mm Hg (p < 0.001) and mean arterial pressure by 6 +/- 3 mm Hg (p < 0.05), without a concomitant increase in whole-body NE spillover; however, cardiac NE spillover returned to baseline levels. Renal NE spillover remained virtually unchanged in healthy control subjects (501 +/- 120 to 564 +/- 115 pmol/min), but was reduced in patients with CHF (976 +/- 133 to 656 +/- 127 pmol/min, p < 0.01)., Conclusions: Our results demonstrate a sympathoinhibitory effect of BNP. Cardiac sympathetic inhibition was observed at BNP concentrations within the physiologic range, whereas high dose BNP, when arterial and filling pressures fell and reflex sympathetic stimulation was expected, systemic and cardiac SNA equated to baseline values. There was inhibition of renal SNA in patients with CHF, but not in healthy control subjects. Whether this effect is specific to BNP or related to reduced filling pressure remains to be determined.

Objectives: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure., Background: Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect., Methods: To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity., Results: Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart., Conclusions: These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.

Objectives: The present study was designed to identify the hemodynamic factor or factors that reflexly contribute to activation of the cardiac sympathetic nerves in patients with severe congestive heart failure (CHF)., Background: We and others have previously shown that activation of the sympathetic nervous system is a key feature of CHF in humans. Furthermore, the degree of sympathetic activation shows marked regional heterogeneity and is most pronounced in the heart. Recent studies have shown a significant positive relation between pulmonary artery pressure and the magnitude of cardiac sympathetic activation. Of particular importance, the degree of cardiac sympathoexcitation has also been shown to be strongly associated with mortality in CHF., Methods: We assessed total systemic and cardiac sympathetic activity (norepinephrine [NE] spillover method) in nine patients with severe CHF and significantly elevated pulmonary artery pressure (mean [+/-SEM] pulmonary artery pressure 46 +/- 3 mm Hg) at rest and during a titrated infusion of sodium nitroprusside (SNP)., Results: SNP infusion significantly reduced mean arterial blood pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. During SNP infusion, the total body NE spillover rate (NESR) increased (from 7.9 +/- 1.7 to 11.2 +/- 3.1 nmol/min, p < 0.01), whereas the cardiac NESR decreased (from 522 +/- 86 to 409 +/- 71 pmol/min, p < 0.05). The ratio of cardiac/total NE spillover was also substantially reduced (from 7.8 +/- 1.3 to 4.9 +/- 0.9%, p < 0.001)., Conclusions: There is a directionally opposite change in whole-body (increase) and cardiac (reduction) sympathetic nervous activity during SNP infusion, most likely due to unloading of arterial baroreceptors and specific cardiopulmonary baroreceptors, respectively, in severe CHF. These observations support the concept of a positive feedback relation between pulmonary artery pressure/filling pressure and cardiac sympathetic tone in CHF and serve to reinforce the importance of vasodilator therapy in this condition.

Objectives: We sought to examine the efficacy of dietary supplementation of L-arginine on endothelium-dependent vasodilation in patients with congestive heart failure., Background: Endothelial dysfunction, as evidenced by a diminished response to such vasodilators as acetylcholine, is well defined in patients with heart failure. These responses are improved by intraarterial infusion with L-arginine. Because L-arginine is a semi-essential amino acid, we investigated the effects of dietary L-arginine on endothelium-dependent vasodilation in these patients., Methods: Twenty patients with heart failure (New York Heart Association functional class III/IV, mean [+/- SE] age 51.3 +/- 1.7 years) and seven healthy control subjects (mean age 52.6 +/- 3.3 years) were studied. All patients continued taking their usual treatment. Responses to acetylcholine and sodium nitroprusside were determined using forearm plethysmography. Patients with heart failure received either L-arginine (20 g/day every day for 28 days) or placebo (vehicle syrup in equal amounts) in a double-blind protocol. The calculated power of the study was between 62% and 80% to detect a 30% to 40% change in area under the dose-response (forearm vascular resistance) curve., Results: Responses to acetylcholine, but not to sodium nitroprusside, were significantly attenuated in patients with heart failure compared with control subjects (mean area under curve [AUC], control subjects vs. patients with heart failure: 1,125.4 +/- 164.5 vs. 617.3 +/- 116.6 U, p < 0.05, by Student t test). A significant increase in urea and aspartate transaminase levels in patients receiving active L-arginine treatment was observed. Responses to acetylcholine (AUC; before vs. after L-arginine: 641.5 +/- 126.7 vs. 695.9 +/- 151.9 U) and sodium nitroprusside were not affected by either L-arginine or placebo., Conclusions: Endothelial dysfunction was apparent in patients with heart failure despite rigorous vasoactive treatment. Oral administration with L-arginine was ineffective in influencing endothelial function in these patients.

Objectives: In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias, we prospectively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure., Background: Despite recent therapeutic advances, patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias. It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive, potentially contributing to subsequent adverse events., Methods: Sixty patients with moderate to severe heart failure (left ventricular ejection fraction 18.9 +/- 0.9% [mean +/- SE]) were studied prospectively. In addition to the compilation of a hemodynamic, biochemical and electrocardiographic profile for each patient, whole-body and cardiac sympathetic activity were determined by isotope dilution. The relation of these variables to outcome was determined by Cox proportional hazards analysis., Results: The mean follow-up period of the study group was 7 +/- 1 months (range 1 to 24) with a 12-month actuarial survival of 75%. Deaths (14 in all) were accounted for either by sudden death or progressive heart failure in equal numbers. The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects (402 +/- 37 vs. 105 +/- 19 pmol/min, p < 0.01), although the values for heart failure ranged widely from normal to 10 times normal. By univariate Cox proportional hazards analysis, pulmonary capillary wedge pressure (p < 0.01), mean pulmonary artery pressure (p < 0.001), serum sodium levels (p < 0.01) and cardiac norepinephrine spill-over rate (p < 0.001) were identified as significant prognostic markers. In a multivariate analysis, cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker (p = 0.0006) of those evaluated in this study., Conclusions: These results suggest that activation of the sympathetic nervous system in patients with heart failure, specifically the cardiac sympathetic nerves, may contribute to the poor prognosis associated with severe heart failure. The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure.

Objectives: The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to investigate the influence of the cause of heart failure, hemodynamic variables and central nervous system catecholamine release on cardiac sympathetic tone., Background: Although heart failure is generally accompanied by sympathoexcitation, the integrity of cardiac sympathetic nerve function in heart failure remains controversial, particularly in relation to nerve firing activity and to the capacity of sympathetic nerves to recapture norepinephrine. Additionally, the location of the afferent and central neural pathways implicated in heart failure-induced sympathoexcitation remains unclear., Methods: Radiotracer techniques were applied in 41 patients with severe heart failure and 15 healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic indexes of cardiac performance were measured in the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was measured to study the central noradrenergic control of sympathetic outflow., Results: Sympathoexcitation was evident in the heart failure group, reflected by a 62% increase (p < 0.001) in total body and a 277% increase (p < 0.001) in cardiac norepinephrine spillover rates. These changes were accompanied by significant increases in the cardiac spillover of the norepinephrine precursor dihydroxyphenylalanine, the sympathetic cotransmitter neuropeptide Y and the extraneuronal metabolite 3-methoxy-4-hydroxyphenylglycol. The level of cardiac sympathetic activity was significantly correlated (r = 0.59, p < 0.001) with the mean pulmonary artery pressure. An increase in the spillover of dihydroxyphenylalanine and 3-methoxy-4-hydroxyphenylglycol from the brain was present, suggesting activation of central noradrenergic neurons., Conclusions: Cardiac sympathetic activation is present in severe heart failure, bearing a close relation with pulmonary artery pressures, independent of heart failure etiology. Activation of noradrenergic neurons in the brain is also present and may be the underlying central nervous mechanism of the sympathoexcitation observed in heart failure.