Plasma Neurohormones Research Articles

Neurohormonal Activation and Renal Chloride Avidity in Acute Heart Failure: Clinical Evidence Supporting the “Chloride Theory”

Introduction: Heart failure (HF) progression according to changes in the serum chloride concentration ([sCl−]) was recently proposed as the “chloride (Cl) theory” for HF pathophysiology. The present study examined the association of neurohormones and renal Cl avidity to determine their contribution to acute HF and their involvement to the “Cl theory.” Methods: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) were analyzed. Blood and urine samples were obtained before decongestive therapy. Clinical tests included peripheral blood, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), and plasma neurohormones. Results: In the 29 patients, urinary Cl concentrations ([uCl−]) inversely correlated with log (plasma renin activity [PRA]) (r = −0.64, p = 0.0002) and log (plasma aldosterone concentration) (r = −0.50, p = 0.006). The [sCl−]‒[uCl−] difference positively correlated with log PRA (r = 0.63, p = 0.0002) and log (plasma aldosterone concentration) (r = 0.49, p = 0.008). Patients were divided into 2 groups according to the [sCl−]‒[uCl−] difference, an excretion (low renal Cl avidity) group and an absorption (high renal Cl avidity) group. Compared with the excretion group (−77 to ‒5 mEq/L; n = 14), the absorption group (1–84 mEq/L; n = 15) exhibited greater renal impairment (serum creatinine; 1.45 ± 0.63 vs. 1.00 ± 0.38 mg/d, p = 0.029) and cardiac burden (log BNP; 2.99 ± 0.3 vs. 2.66 ± 0.32 pg/mL, p = 0.008), higher log PRA (0.20 ± 0.58 vs. −0.25 ± 0.35 ng/mL/h, p = 0.018), and lower fractional urinary Cl excretion (1.34 ± 1.3 vs. 5.33 ± 4.1%, p < 0.001). Conclusion: Renal Cl avidity differs in acute HF, i.e., excretion (low renal Cl avidity) versus absorption (high renal Cl avidity) types, involving renin-aldosterone-angiotensin activity as the underlying mechanism, which provides the neurohormonal background for the “Cl theory.” A version of this study was presented in part at the annual international scientific assembly (ACC.23) of the American College of Cardiology, March 4–6, 2023.

Estimation of Plasma Renin Activity on the Basis of Serum and Urinary Chloride Concentrations versus Sodium Concentrations

Introduction: The present study examined the possible estimation of plasma renin activity (PRA) by serum and urinary concentrations of chloride versus sodium in acute and chronic heart failure (HF). Methods: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) and 26 patients with recovery of HF after decongestive therapy (50% men; 81.2 ± 12 years) were analyzed. Blood and urine samples were obtained immediately before decongestive therapy in acute HF patients. Clinical tests included peripheral blood tests, serum and spot urinary electrolytes, and plasma neurohormones. Sodium- or chloride-related indices included serum ([sNa⁺] or [sCl⁻]) and urinary ([uNa⁺] or [uCl⁻]) concentrations, their differences, and their ratio. Linear regression analysis was used for correlation coefficients. Results: PRA levels higher than the normal range were detected in only 5 (17%) of 29 patients with acute HF, but in as many as 11 (42%) of 26 patients with chronic HF. In the 29 patients with acute HF, all the chloride- and sodium-related indices except for [sNa⁺] were correlated with PRA: the [sCl⁻]/[uCl⁻] ratio was best correlated with PRA (R² = 0.84, p < 0.0001) followed by the [sNa⁺]/[uNa⁺] ratio (R² = 0.64, p < 0.0001). In the 26 patients with chronic HF, however, both the [sCl⁻] (R² = 0.36, p = 0.001) and [sNa⁺] (R² = 0.22, p = 0.016) were only weakly correlated with PRA. Conclusion: In acute HF, chloride-related indices derived from serum and urinary concentrations were firmly associated with PRA or better than sodium-related indices. In chronic HF, either chloride- or sodium-related indices were not firmly associated with PRA, presumably due to influence of cardiovascular medication.

Arginine Vasopressin as an Important Mediator of Fluctuations in the Serum Creatinine Concentration Under Decongestion Treatment in Heart Failure Patients.

Background: The mechanism underlying serum creatinine (SCr) fluctuations in heart failure (HF) patients remains unclear. This study examined mediators of SCr fluctuations under diuretic treatment in HF patients.Methods and Results: Data from 26 HF patients were analyzed. Clinical tests included measurement of peripheral blood, blood urea nitrogen, SCr, serum and urinary electrolytes, B-type natriuretic peptide (BNP), and plasma neurohormones. Among the 26 patients recovering from worsening HF, changes in SCr were negatively correlated with changes in serum Cl, and positively correlated with changes in plasma arginine vasopressin (AVP). According to the median change in SCr, patients were divided into high (range 0.16–0.79 mg/dL; n=13) and low (range −0.35 to 0.14 mg/dL; n=13) change groups. Plasma AVP concentrations after treatment decreased in the low SCr change group and increased in the high SCr change group (−1.28±2.8 vs. 2.14±4.4 pg/mL, respectively; P=0.027). In both groups, there was no change in plasma volume, plasma BNP and norepinephrine concentrations decreased, and plasma renin activity increased after treatment. Multivariate logistic regression analysis showed a tendency towards an independent association between an increase in SCr and an increase or no change in the plasma AVP after decongestion (odds ratio 4.44; 95% confidence interval 0.81–24.3; P=0.086).Conclusions: Plasma AVP appears to be a physiologically important mediator of SCr fluctuations under decongestion treatment in HF patients.

Plasma Renin Activity after Diuretic Treatment in Patients with Stable Heart Failure: With Special Reference to its Association with Electrolyte Chloride

A recent study reported an intimate association between urinary chloride (Cl) and plasma renin activity (PRA) in acute heart failure (HF) status, reflecting normal functioning of the ‘tubulo-glomerular feedback’ mechanism. Whether the ‘tubuloglomerular feedback’ mechanism functions normally in stable HF status, however, is unclear. This study examined whether the ‘tubulo-glomerular feedback’ mechanism functions normally under resolution of worsening HF after decongestive therapy. Data from 26 patients with acute HF and its recovery after decongestive therapy were analyzed. Clinical tests included measurement of peripheral blood tests, serum and spot urinary electrolytes, plasma neurohormones, and fractional urinary excretions of electrolytes. In a total of 26 patients, PRA increased after acute HF treatment (from 1.64±2.0 to 5.48±6.1 ng/ mL/h, p=0.002). Changes in the serum logPRA and urinary Cl concentration from worsening to its recovery tended to be inversely correlated (R2 =0.12, p=0.085) and logPRA and the serum Cl concentration at recovery were inversely correlated (R2 =0.23, p=0.01). When divided into 2 groups (n=13 in each) according to the median PRA, the group with greater PRA changes showed a larger decrease in the urinary Cl concentration (from 110±44 to 72.8±38, p=0.03). The group with higher PRA at recovery showed a lower serum Cl concentration than the group with lower PRA at recovery (102±6.5 vs 107±4.2 mEq/L, p=0.04). In conclusion, the association between PRA and the serum/urinary Cl concentration is blunted in stable HF under-decongestive therapy, possibly due to the physiologic status under full cardiovascular medication compared with that in acute HF status.

Clinical Significance of Spot Urinary Chloride Concentration Measurements in Patients with Acute Heart Failure: Investigation on the Basis of the ‘TubuloGlomerular Feedback’ Mechanism

Urinary chloride (Cl) is the key electrolyte for regulating renin secretion at the macula densa under the ‘tubulo-glomerular feedback’. Whether or not Cl filtrated into the urinary tubules actually associates with plasma renin activity (PRA) in clinical heart failure (HF) remains unclear. Data from 29 patients with acute worsening HF (48% men; 80.3±12 years) were analyzed. Blood and urine samples were immediately obtained before decongestive therapy after the patients rested in a supine position for 20-min. Clinical tests included peripheral blood tests, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), plasma neurohormones, and fractional urinary electrolyte excretion. In the 29 patients, urinary Cl concentrations inversely correlated with logarithmically transformed PRA (R2 =0.41, p=0.0002). The correlation was weaker in worsening chronic HF patients (R2 =0.32, p=0.01) compared with de novo HF patients (R2 =0.70, p=0.0026). Patients were divided into 2 groups according to the median urinary Cl concentration, a low group and a high group. Compared with the high group (100~184 mEq/L; n=14), the low group (4~95 mEq/L; n=15) exhibited more renal (serum creatinine; 1.45±0.63 vs 1.00±0.38 mg/d, p=0.029) and cardiac (log BNP; 2.99±0.3 vs 2.66±0.32 pg/mL, p=0.008 p=0.008) impairment, and higher PRA (3.42±4.7 vs 0.73±0.46 ng/mL/h, p=0.049), and lower fractional excretion of urinary Cl (1.34±1.3 vs 5.33±4.1%, p&lt;0.0001). The present study provides clinical data on the possible functioning of urinary Cl involved in the mechanism of ‘tubulo-glomerular feedback’, and thus advances our understanding of the clinical meanings of the significance of urinary Cl concentration measurement.

Clinical Significance of Spot Urinary Chloride Concentration Measurements in Patients with Acute Heart Failure: Investigation on the Basis of the ‘TubuloGlomerular Feedback’ Mechanism

Urinary chloride (Cl) is the key electrolyte for regulating renin secretion at the macula densa under the ‘tubulo-glomerular feedback’. Whether or not Cl filtrated into the urinary tubules actually associates with plasma renin activity (PRA) in clinical heart failure (HF) remains unclear. Data from 29 patients with acute worsening HF (48% men; 80.3±12 years) were analyzed. Blood and urine samples were immediately obtained before decongestive therapy after the patients rested in a supine position for 20-min. Clinical tests included peripheral blood tests, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), plasma neurohormones, and fractional urinary electrolyte excretion. In the 29 patients, urinary Cl concentrations inversely correlated with logarithmically transformed PRA (R2 =0.41, p=0.0002). The correlation was weaker in worsening chronic HF patients (R2 =0.32, p=0.01) compared with de novo HF patients (R2 =0.70, p=0.0026). Patients were divided into 2 groups according to the median urinary Cl concentration, a low group and a high group. Compared with the high group (100~184 mEq/L; n=14), the low group (4~95 mEq/L; n=15) exhibited more renal (serum creatinine; 1.45±0.63 vs 1.00±0.38 mg/d, p=0.029) and cardiac (log BNP; 2.99±0.3 vs 2.66±0.32 pg/mL, p=0.008 p=0.008) impairment, and higher PRA (3.42±4.7 vs 0.73±0.46 ng/mL/h, p=0.049), and lower fractional excretion of urinary Cl (1.34±1.3 vs 5.33±4.1%, p&lt;0.0001). The present study provides clinical data on the possible functioning of urinary Cl involved in the mechanism of ‘tubulo-glomerular feedback’, and thus advances our understanding of the clinical meanings of the significance of urinary Cl concentration measurement.

Neurohormonal profile of patients with heart failure and diabetes.

Background. Neurohormonal activation is generally recognised to play an important role in the pathophysiology, prognosis and treatment of chronic heart failure (HF). While the number of patients with diabetes increases, little if anything is known about neurohormonal activation in HF patients with diabetes. Methods. The study population consisted of 371 patients with advanced HF who were enrolled in a multicentre survival trial. Ten different plasma neurohormones were measured (noradrenaline, adrenaline, dopamine, aldosterone, renin, endothelin, atrial natriuretic peptide [ANP], N-terminal (pro)ANP, brain natriuretic peptide [BNP] and N-terminal (pro)BNP. Comparisons were made between patients with diabetes (n=81) and those without (n=290). Results. At baseline, the two groups were comparable regarding age (mean 68 years), left ventricular ejection fraction (23%), severity and aetiology of HF, while body weight was higher in those with diabetes (77.4 vs. 74.2 kg, p=0.04). Most plasma neurohormones were similar between groups, but patients with diabetes had higher values of BNP (94 vs. 47 pmol/l, p=0.03), while a similar trend was observed for N-terminal (pro)BNP (750 vs. 554 pmol/l, p=0.10). During almost five years of follow-up, 51/81 patients with diabetes died (63%), as compared with 144 of 290 non-diabetic patients (50%) who died (p=0.046). Natriuretic peptides and noradrenaline were the most powerful predictors of mortality in both diabetic and non-diabetic HF patients. Conclusion. HF patients with diabetes have higher (N-terminal (pro)) BNP levels than non-diabetic patients, while other neurohormones are generally similar. Natriuretic peptides are also good prognostic markers in diabetic HF patients. (Neth Heart J 2010;18:190-6.).

Size and function of the atria

Size and function of the atria

Neurohormonal Profile of a Novel Chimeric Natriuretic Peptide, CD-NP, as Compared to C-Type Natriuretic Peptide, in the Normal Dog

Background: CD-NP is a novel Mayo-designed chimeric natriuretic peptide (NP) that was synthesized by combining the 22-amino-acid (AA) residues of human C-type natriuretic peptide (CNP) with the 15-AA C-terminus of Dendroaspis NP. In this investigation, we sought to evaluate the effects of CD-NP, as compared to CNP, on plasma neurohormone levels and natriuretic peptide (NP) immunoreactivities (IR). We hypothesized that CD-NP would inhibit the renin-angiotensin-aldosterone system (RAAS) and would enhance endogenous NP levels. Methods: Normal anesthetized dogs received CD-NP 50 ng/kg/min i.v. (n = 10) or an equimolar dose of CNP (29.3 ng/kg/min i.v., n = 6) for 75 min. Four clearances were performed: pre-infusion (I), 30 min and 60 min of infusion (I), post-I. Plasma neurohormones and natriuretic peptide IR were quantified by radioimmunoassays. Comparisons were made within group versus pre-I (mean ± SEM, P < 0.05∗, < 0.01†) and between groups (P < 0.05‡, < 0.001§). Results: CD-NP significantly suppressed plasma renin activity (PRA, 6.1 ± 1.4 to 1.8 ± .7† to 1.1 ± .4† to 7.0 ± 1.6 ng/ml/hr), whereas CNP tended to suppress PRA (3.9 ± 2.1 to 2.4 ± 1.0 to 3.4 ± 0.9 to 4.3 ± 1.3 ng/ml/hr). CD-NP significantly decreased angiotensin II (Ang II, 16.6 ± 3.0 to 7.5 ± 1.8† to 4.4 ± .7† to 14.7 ± 2.8 pg/ml), whereas CNP tended to decrease Ang II (16.4 ± 6.2 to 9.0 ± 1.6 to 14.1 ± 3.1 to 19.3 ± 6.7 pg/ml). CD-NP tended to reduce plasma aldosterone (21.6 ± 5.0 to 18.2 ± 5.5 to 14.3 ± 4.7 to 18.6 ± 6.4 ng/dl) whereas no decrease was observed with CNP (18.7 ± 5.8 to 27.3 ± 3.4 to 26.7 ± 3.7 to 27.8 ± 3.9 ng/dl). Plasma BNP IR in CD-NP-treated versus CNP-treated dogs were 23.7 ± 5.0 to 26.5 ± 2.5 to 40.0 ± 4.1†§ to 29.7 ± 4.2§ pg/ml; 9.8 ± 2.9 to 17.1 ± 1.6† to 17.2 ± 2.2† to 7.5 ± 0.8 pg/ml, respectively. Plasma CNP IR, an estimate of both CD-NP and CNP levels, were significantly increased in both groups (CD-NP 8.7 ± 3.3 to 808 ± 100†‡ to 897 ± 159†‡ to 17.3 ± 1.7 pg/ml; CNP 7.7 ± 3.1 to 413 ± 140∗ to 436 ± 165† to 7.9 ± 3.4 pg/ml). Conclusion: The novel chimeric natriuretic peptide, CD-NP, possesses RAAS-inhibiting properties, and significantly augments endogenous BNP levels to a greater extent as compared to CNP. The greater increase in CNP with CD-NP strongly supports a longer half-life for CD-NP versus CNP. These greater neurohumoral changes in response to CD-NP compared to native CNP support potentially important biological properties for this novel chimeric peptide in the treatment of cardiorenal diseases.

Role of nitric oxide deficiency and its detection as a risk factor in pre-hypertension

Systemic inhibition of nitric oxide (NO) synthesis raises blood pressure, and endothelial dysfunction with reduced NO bioactivity is a precursor of atherosclerosis. Pre-hypertensive blood pressures place patients at increased risk for cardiovascular morbid events. Whether NO deficiency contributes to this increased risk has not been explored. Constitutive NO release was inhibited by infusion of the substituted arginine NG-nitro-L-arginine-methyl ester (L-NAME) in 10 normal volunteers. Hemodynamics, radial artery pulse contour analysis, brachial artery ultrasound, and aortic pulse wave velocity were monitored as well as plasma neurohormone levels. A modest rise in blood pressure within the normotensive range (113/65 to 124/77 mm Hg, P < .01) was accompanied by a rise in estimated systemic vascular resistance (1193 to 1514 dyne-sec-cm-5, P < .001). Pulse contour analysis revealed a fall to abnormal levels in systemic small artery elasticity (diastolic decay) (9.8 to 6.4 ml/mm Hg, P < .001) and a less consistent but significant increase in the second pressure peak in systole ( P < .05). Large artery elasticity index, brachial artery caliber, and brachial artery compliance were unchanged. Flow-mediated brachial artery dilation was blunted slightly (5.29% to 4.47%, P = .06), and aortic pulse wave velocity increased slightly but significantly (8.25 to 8.98 m/s, P = .04), probably as a result of the rise in pressure. The magnitude of effect of L-NAME on small artery elasticity (−31.2% ± 18.4%) was significantly greater and more consistent than its effect on other vascular measurements. Circulating neurohormonal vasoconstrictor levels fell or were unchanged after L-NAME, and a significant reduction in plasma norepinephrine was closely inversely correlated with the rise in blood pressure. Nitroglycerin infusion in 4 additional subjects produced selective relaxation in small arteries, whereas norepinephrine constricted both small and large arteries. A hemodynamic state consistent with pre-hypertension was induced by NO synthase inhibition in normal volunteers. Reduction in small artery compliance was a sensitive marker for this induced endothelial dysfunction and may serve as a useful marker for pre-hypertensive patients at risk for cardiovascular morbid events.

Proteomics in cardiovascular surgery

Proteomics describes, analogous to the term genomics, the study of the complete set of proteins present in a cell, organ, or organism at a given time. The genome tells us what could theoretically happen, whereas the proteome tells us what does happen. Therefore, a genomic-centered view of biologic processes is incomplete and does not describe what happens at the protein level. Proteomics is a relatively new methodology and is rapidly changing because of extensive advances in the underlying techniques. The core technologies of proteomics are 2-dimensional gel electrophoresis, liquid chromatography, and mass spectrometry. Proteomic approaches might help to close the gap between traditional pathophysiologic and more recent genomic studies, assisting our basic understanding of cardiovascular disease. The application of proteomics in cardiovascular medicine holds great promise. The analysis of tissue and plasma/serum specimens has the potential to provide unique information on the patient. Proteomics might therefore influence daily clinical practice, providing tools for diagnosis, defining the disease state, assessing of individual risk profiles, examining and/or screening of healthy relatives of patients, monitoring the course of the disease, determining the outcome, and setting up individual therapeutic strategies. Currently available clinical applications of proteomics are limited and focus mainly on cardiovascular biomarkers of chronic heart failure and myocardial ischemia. Larger clinical studies are required to test whether proteomics may have promising applications for clinical medicine. Cardiovascular surgeons should be aware of this increasingly pertinent and challenging field of science.

Aging Adversely Affects Postinfarction Inflammatory Response and Early Left Ventricular Remodeling after Reperfused Acute Anterior Myocardial Infarction

Background and Aims: We have demonstrated that an increased peak serum C-reactive protein (CRP) level after acute myocardial infarction (AMI) was a major predictor of left ventricular (LV) remodeling. We sought to clarify the effect of aging on the postinfarction inflammatory response and LV remodeling. Methods: We studied 102 patients who underwent primary angioplasty for a first anterior Q-wave AMI. Serum CRP levels, plasma neurohormones and interleukin-6 (IL-6) levels, and LV volume by left ventriculography were serially measured. Patients were divided into two groups according to their age (≧70 years, n = 33; <70 years, n = 69). Results: There was no difference in use of cardiovascular drugs and coronary angiographic findings. Older patients had a greater increase in LV end-diastolic volume during 2 weeks after AMI (p = 0.0007) and a higher peak CRP level (12.4 ± 7.3 vs. 5.5 ± 4.2 mg/dl, p < 0.0001), although peak CK level was comparable between the two groups. Plasma atrial natriuretic peptide, brain natriuretic peptide and IL-6 levels were higher in older patients at 2 weeks and 6 months after AMI. Conclusions: Augmented and prolonged activation of the inflammatory system after AMI was observed in older patients, in association with exaggerated LV remodeling. Aging may adversely affect LV remodeling through modification of the inflammatory response after AMI.

Plasma Neurohormone Levels Correlate With Left Ventricular Functional and Morphological Improvement in LVAD Patients

Plasma Neurohormone Levels Correlate With Left Ventricular Functional and Morphological Improvement in LVAD Patients

Increased circulating big endothelin-1, endothelin-1 and atrial natriuretic peptide in infants and children with heart failure secondary to congenital heart disease

In order to characterize the changes of five neurohormones in pediatric patients with varying degrees of congestive heart failure (CHF) secondary to congenital heart disease (CHD), we measured plasma neurohormone levels by using radioimmunoassay or high-performance liquid chromatography in 81 subjects including 13 normal children and 68 pediatric patients with CHD. Patients with CHF ( n=27) had elevated levels of big endothelin-1 (big ET-1) (29.5±1.6 vs. 18.1±2.1 pg/ml, p<0.001), endothelin-1 (ET-1) (17.9±1.7 vs. 7.8±1.7 pg/ml, p<0.001) and norepinephrine (505.6±65.6 vs. 219.6±23.3 pg/ml, p<0.01) as compared with healthy control subjects ( n=13). Plasma norepinephrine levels (505.6±65.6 vs. 230.0±8.0 pg/ml, p<0.001) and atrial natriuretic peptide (35.5±4.2 vs. 7.6±0.6 pg/ml, p<0.001) in the 27 patients with CHF were significantly higher than in the 41 patients without CHF. There was also a highly significant stepwise increase in big ET-1, atrial natriuretic peptide and norepinephrine according to the severity of heart failure. Our results suggest that increased circulating neurohormonal activity in CHD relates to the presence and clinical severity of heart failure in children. Plasma levels of big ET-1 and ET-1 were not only significant markers of CHF but also correlated well with the severity of CHF in CHD with left-to-right shunt.

278 Carvedilol improves ejection fraction and reduces heart rate in non-hypertensive patients with heart failure, with no modification of ambulatory blood pressure and plasma neurohormones

278 Carvedilol improves ejection fraction and reduces heart rate in non-hypertensive patients with heart failure, with no modification of ambulatory blood pressure and plasma neurohormones

Impaired Endothelium-Dependent Forearm Vasodilation in Idiopathic Dilated Cardiomyopathy Is Related to Severe Left Ventricular Dysfunction and Elevated Serum Tumor Necrosis Factor Levels

Endothelial dysfunction has been found in patients with idiopathic dilated cardiomyopathy (IDC), but its mechanism remains unknown. Our aim was to investigate whether forearm endothelium-dependent vasoreactivity correlates with cardiac disease severity or neurohormonal activation. We studied 23 patients with IDC and 10 healthy sex- and age-matched controls using brachial artery ultrasound to assess flow-mediated dilation (FMD) and nitroglycerin-induced vasodilation (NIV). In the IDC group, we determined plasma neurohormone and cytokine levels at the same time. FMD was significantly less in the IDC group compared with the control group [--0.06 (2.8)% vs 4.4 (4.6)%, respectively; P<.01], whereas NIV was similar in both groups [15.0 (6.4)% vs 14.0 (7.4)%, respectively; P=NS]. FMD was significantly less in patients with poorer left ventricular (LV) function and more severe LV dilatation, and in those with a higher tumor necrosis factor-alpha (TNF-alpha) level. NIV was similar in all patient subgroups. There was a significant inverse correlation between the TNF-alpha plasma level and FMD (r=-0.75; P<.01). No correlation was found between the plasma levels of other neurohormones and FMD. FMD, but not NIV, was impaired in patients with IDC compared with control subjects. In patients, there were significant associations between FMD impairment and the severity of LV dilatation, the severity of LV systolic dysfunction, and the plasma TNF-alpha level. The strongest correlation was observed between TNF-alpha plasma level and FMD. These data suggest that TNF-alpha may be implicated in endothelial dysfunction in patients with IDC.

Plasma neurohormone levels correlate with left ventricular functional and morphological improvement in LVAD patients 1

Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) have been shown to be markers of left ventricular (LV) function. To determine the feasibility of using serial assays of these neurohormones in the assessment of cardiac status in the left ventricular assist device (LVAD) setting, we examined the relationship between LV function, myocardial morphology, and plasma levels of these hormones in LVAD recipients. Plasma BNP and ET-1 levels were serially assayed in 19 end-stage congestive heart failure (CHF) patients before and after LVAD implantation with various devices (i.e., MicroMed DeBakeyVAD/DVAD, Novacor/NVAD, TCI Heartmate/TCI, Thoratec/TVAD). Echocardiography performed correspondingly at the time points of the hormonal assays and immunohistochemical collagen staining of left ventricular tissue samples, derived from six non-failing hearts as well as from LVAD patients at the time of device insertion and removal, were then contrasted. Patients were grouped according to device used and etiology of heart disease (ischemic or dilated cardiomyopathy, ICM/DCM). LVAD therapy significantly improved LV ejection fraction (EF%: 21 +/- 3.8% to 28.11 +/- 3.57%), cardiac output (CO: 3.49 +/- 1.3 to 7.3 +/- 0.2 l/m), and left ventricular end-diastolic diameter (LVEDD: 6.68 +/- 0.92 versus 4.79 +/- 1.54 cm, P < 0.0001) in all patients. Absolute BNP and ET-1 plasma levels remained significantly lower in all patients after LVAD implantation (both P < 0.001). The NVAD group exhibited the most BNP reduction and EF% increase (P < 0.0004 and P < 0.038, respectively). Average collagen levels were reduced in all patients (P < 0.0005). Among the devices, the NVAD group demonstrated the most evident change (P < 0.0036), while there was comparable reduction in the DCM and ICM groups (both P < 0.03). In general, postoperative BNP and ET-1 trends exhibited a notable parallelism with both manifesting bi-phasic tendencies and an inverse proportionality to corresponding EF% measurements. Device selection appears to influence the cardiac morphological and neurohormonal expressive tendencies exhibited by recipients. Plasma BNP and ET-1 levels correlate with both LV function and myocardial morphological improvement. Alterations in the levels of these hormones during LVAD support may be real-time indicators of prevailing myocardial autocrine/paracrine activity and as such may be of potential use in future algorithms of cardiac assessment and therapeutic decision-making with regard to transplant urgency and/or possible device explantation.

Impaired renal function in patients with ischemic and nonischemic chronic heart failure: association with neurohormonal activation and survival

Background Renal dysfunction is a strong predictor of mortality in chronic heart failure (CHF). Most patients with CHF have atherosclerotic vascular disease, and several authors have suggested that impaired renal function is only a marker of advanced atherosclerosis. We compared renal function in patients with ischemic and nonischemic CHF and examined associations with prognosis and extent of neurohormonal activation. Methods In a large survival study (1906 patients), patients with documented coronary artery disease (CAD, n = 995), were compared with patients with idiopathic dilated cardiomyopathy (IDC, n = 429). In a smaller substudy, plasma neurohormones were determined in 270 patients and 37 patients (CAD and IDC, respectively). All patients had advanced CHF (New York Heart Association functional class III–IV). At baseline, the mean patient age was 64 ± 10 years, and the mean left ventricular ejection fraction was 0.26 ± 0.08. The baseline glomerular filtration rate was calculated with the Cockcroft-Gault equation (GFRc). Results GFRc was a strong predictor for mortality in both groups on multivariate analysis. The relative risk was 3.04 for patients with IDC ( P ≤.01, for the lowest quartile ≤53 mL/min), and the relative risk for patients with CAD was 1.81 ( P = .01 for the lowest quartile ≤42 mL/min). Plasma neurohormones showed a relation with GFRc in both groups. Conclusions GFRc is related to survival and plasma neurohormones in both patient groups. In patients with IDC, this association appears to be at least as strong as in patients with CAD.

Clinical Use of Markers of Neurohormonal Activation in Heart Failure

Chronic heart failure secondary to ventricular dysfunction is characterized by neurohormonal activation, reflected mainly as increased sympathetic and renin-angiotensin system activation. Increased plasma levels of several neurohormones have been associated with increased morbidity and mortality. Neurohormone activation is part of the mechanism of compensation that is activated to maintain hemodynamic stability when heart output is reduced. Despite the initial benefits of this mechanism, neurohormone activation has been shown to contribute to progressive impairment of ventricular function and symptoms of heart failure, such that the greater the degree of activation, the worse the prognosis.Despite their important implications for prognosis, plasma neurohormone levels are not measured in clinical practice as part of the clinical evaluation of patients with heart failure. Medical treatment with ACE inhibitors and beta blockers, by lowering the plasma levels of some neurohormones, reduces their prognostic usefulness in establishing risk. Thus, no ideal biomarker is yet available that is stable and easy to measure, and that accurately established risk in patients with heart failure. Such a marker should also have an acceptable cost/benefit ratio.

NT-proBNP in heart failure: therapy decisions and monitoring.

With increasing cardiac dysfunction, a complex neurohormonal response results in increasing circulating levels of an array of plasma hormones. Increments in plasma levels of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) and their amino-terminal congeners are more closely related to cardiac structure and function and to cardiovascular prognosis than changes in other plasma neurohormones. Reports suggest that changes in plasma BNP levels in the course of treatment of acutely decompensated heart failure provide a more powerful prognostic indicator of the likelihood of survival or recurrent decompensation than symptomatic assessment. This observation requires a randomised controlled trial in which changes in peptide levels determine aggression and duration of in-patient therapy in order to establish whether this indicator can improve results from management of acute in-patient heart failure. Plasma BNP or NT-proBNP is a powerful independent predictor of mortality and morbidity in long-term follow-up of heart failure cohorts. In addition, it appears likely to be a good predictor of beneficial response to the addition of beta blockade to anti-heart failure pharmacotherapy. Finally, adjustment of therapy for heart failure according to serial measurements of NT-proBNP promises to improve outcomes in comparison with adjusting therapy according to unassisted clinical acumen.