Plasma Somatostatin in Advanced Heart Failure: Association with Cardiac Filling Pressures and Outcome.

BACKGROUND: Somatostatin inhibits intestinal motility and hormonal secretion and is a potent arterial vasoconstrictor of the splanchnic blood flow. It is unknown if somatostatin concentrations are associated with central hemodynamic measurements in patients with advanced heart failure (HF). METHODS: A prospective study of HF patients with a left ventricular ejection fraction (LVEF) <45% referred to right heart catheterization (RHC) for evaluation for heart transplantation (HTX) or left ventricular assist device (LVAD). RESULTS: Fifty-three patients were included with mean LVEF 18 ± 8% and majority in NYHA-class III-IV (79%). Median plasma somatostatin concentration was 18 pmol/L. In univariable regression analysis, log(somatostatin) was associated with increased central venous pressure (CVP; r2 = 0.14, p = 0.003) and a reduced cardiac index (CI; r2 = 0.15, p = 0.004). When adjusted for selected clinical variables (age, gender, LVEF, eGFR and BMI), log(somatostatin) remained a significant predictor of CVP (p = 0.044). Increased somatostatin concentrations predicted mortality in multivariable models (hazard ratio: 5.2 [1.2-22.2], p = 0.026) but not the combined endpoint of death, LVAD implantation or HTX. CONCLUSIONS: Somatostatin concentrations were associated with CVP and CI in patients with HF. The pathophysiological mechanism may be related to congestion and/or hypoperfusion of the intestine. Somatostatin was an independent predictor of mortality in advanced HF.

Right Ventricular and Pulmonary Vascular Function are Influenced by Age and Volume Expansion in Healthy Humans.

BACKGROUND: Patients with heart failure (HF) often show signs of right ventricular (RV) dysfunction. The RV function of coupled with the pulmonary circulation (tricuspid annular plane systolic excursion [TAPSE]/pulmonary arterial systolic pressure [PASP]) has been shown to divide HF patients into distinct prognostic strata, but less is known about which factors influence this prognostic marker, and whether those factors can be modified. We sought to obtain normative values and discern the individual effects of age, sex, and fluid overload on RV function. METHODS AND RESULTS: Sixty healthy subjects aged 20-80 years were enrolled in this prospective study. Right heart catheterization with hemodynamic measurements were performed at rest after a rapid saline solution infusion (10 mL/kg, 150 mL/min). Linear regression and Spearman correlation models were used to estimate associations between TAPSE/PASP and relevant variables. In healthy persons of all ages, the median (5th-95th percentiles) normative TASPE-PASP ratio was 1.25 (0.81-1.78) mm/mm Hg. The correlation between progressive age and declining TAPSE/PASP was significant (r = -0.35; P = .006). Sex did not influence TAPSE/PASP (P = .30). Rapid fluid expansion increased central venous pressure from 5 ± 2 mm Hg to 11 ± 4 mm Hg after fluid infusion (P < .0001). This resulted in a 32% decrease in the TAPSE-PASP ratio after fluid infusion, compared to baseline (P < .0001). CONCLUSIONS: The TAPSE-PASP ratio was affected by age, but not sex. TAPSE/PASP is not only a reflection of intrinsic RV function and pulmonary vascular coupling, but fluid status also dynamically affects this index of RV function. Normative values with invasive measurements were obtained for future assessment of HF patients.

Relationship between invasive hemodynamics and liver function in advanced heart failure.

Objective. To examine how liver function (LF) relates to invasive hemodynamics cross-sectionally and longitudinally, in advanced heart failure (AHF) patients treated with maximally tolerated medical HF therapy. Design. A retrospective study of 309 consecutive AHF patients with a left ventricular ejection fraction < 45% treated with maximally tolerated medical HF therapy who were referred for AHF therapies. All patients underwent right heart catheterization (RHC) using Swan-Ganz catheters. Cardiac output was measured using thermodilution. Measurements of pulmonary capillary wedge pressure (PCWP), central venous pressure (CVP), cardiac index (CI) and mean arterial pressure (MAP) were obtained. RHC and evaluation of LF were repeated (median (IQR) = 186.5 (150-208) days) in 33 patients. Results. Mean (SD) age was 50 (±13) years, and 239 (77%) were men. Only 22 (7%) were treated with inotropes, and none were receiving mechanical circulatory support. Median (IQR) plasma alanine transaminase (ALT) was 32 (22-53) U/l, alkaline phosphatase (ALP) 82 (63-122) U/l, bilirubin 14 (9-22) µmol/l, albumin 39 (35-43) g/l, lactate dehydrogenase 212 (175-275) U/l, and the prothrombin time/International Normalized Ratio (PT/INR) 1.1 (1.0-1.3). In multivariate analyses significant associations between LF tests and hemodynamics were seen for CVP: ALP (ß = 0.031, p = .0002), bilirubin (ß = 0.027, p = .004), and INR (ß = 0.013, p = .002). PCWP (ß = 0.020, p = .002) and CI (ß = -0.17, p = .005) were also associated with bilirubin. Over time, changes in bilirubin correlated positively with changes in CVP (ß = 1.496, p = .005). Conclusion. In optimally treated AHF patients, CVP was associated with both markers of biliary excretion and liver synthesis function, whereas changes in CVP were associated with changes in markers of biliary excretion. Decongestion may improve measures of LF in AHF.

Relation between invasive hemodynamics and measured glomerular filtration rate by 51Cr-EDTA clearance in advanced heart failure.

The interaction between hemodynamics and kidney function in heart failure (HF) is incompletely understood. We investigated the association between invasive hemodynamic parameters and measured glomerular filtration rate (mGFR) by plasma clearance of 51-chromium-labeled ethylenediamine tetra-acetic acid (51Cr-EDTA) in patients with advanced HF and tested the hypothesis that patients with reduced mGFR have lower cardiac index (CI) and mean arterial pressure (MAP) as well as higher central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP). We retrospectively studied 242 patients (mean age 50 ± 13 years) referred for evaluation for heart transplantation or implantation of a left ventricular assist device with a left ventricular ejection fraction < 45% on optimal medical therapy, who underwent right heart catheterization (RHC) and measurement of 51Cr-EDTA clearance. Mean mGFR was 63 ± 21 mL/min/1.73 m2, CI was 2.3 ± 0.7 L/min/m2, PCWP was 21 ± 9 mmHg, and CVP was 10.3 ± 5.2 mmHg. Univariate analysis demonstrated a significant correlation between mGFR and CI (r2 = 0.030, p = .007) and CVP (r2 = 0.017, p = .049) but not between mGFR and MAP or PCWP. In multivariate analyses, none of the hemodynamic variables remained significantly associated with mGFR. While CVP and CI were correlated with mGFR in univariate analysis the results of analyses adjusted for multiple covariates suggest that hemodynamics are only correlated to renal function in advanced HF to a modest degree challenging the hypothesis that renal dysfunction in HF mainly is a consequence of renal congestion.

Efficacy and safety of angiotensin-converting enzyme inhibitors in patients with left ventricular systolic dysfunction and hyponatremia.

BACKGROUND: The presence of hyponatremia has been perceived to increase the risk of adverse events on initiation of treatment with angiotensin-converting enzyme inhibition in heart failure patients. The aim of this study was to investigate if baseline hyponatremia (plasma Na(+) <135 mmol/L) predicts development of hypotension and renal impairment in patients with myocardial infarction (MI) and left ventricular dysfunction (LVD) treated with angiotensin-converting enzyme inhibitors. METHODS AND RESULTS: A retrospective analysis was performed with data from the Trandolapril Cardiac Evaluation (TRACE) a double-blind randomized study. Plasma sodium levels were available in 1,731 patients, who were considered as the study population. Patients 3-7 days after MI with left LVD (LVEF ≤0.35), were randomized to trandolapril (n = 876) or placebo (n = 873). Baseline hyponatremia did not predict development of hypotension or worsening renal function after 1 month in patients treated with trandolapril compared with placebo (122 ± 19.1 mm Hg vs 123.2 ± 20.4 mm Hg [P = .84]; and creatinine clearance 57.4 ± 21.4 mL/min vs 55.2 ± 21.0 mL/min [P = .8]). There was no interaction between hyponatremia and the effect of trandolapril (P = .68). CONCLUSIONS: Mild hyponatremia was not a contraindication for the initiation of treatment with angiotensin-converting enzyme inhibitors in patients with post-MI heart failure.

Plasma copeptin levels and prediction of outcome in heart failure outpatients: relation to hyponatremia and loop diuretic doses.

BACKGROUND: Copeptin, a stable fragment of the vasopressin prohormone, has been shown to be a significant biomarker for morbidity and mortality in heart failure. The aims of this study were to evaluate the influence of plasma sodium on the prognostic significance of copeptin concentrations in heart failure outpatients and to determine whether increased copeptin concentrations predict future development of hyponatremia. METHODS AND RESULTS: A total of 340 heart failure patients with left ventricular systolic dysfunction were followed for 55 months (median) in a Danish heart failure clinic. A baseline measurement of plasma copeptin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and sodium was performed, and the sodium concentrations were recorded during 3 months after the baseline visit in the heart failure clinic. Patients were divided into 3 groups according to copeptin tertiles. In multivariate Cox proportional hazard models adjusted for confounders, including plasma sodium, loop diuretic dose, and NT-proBNP, copeptin was a significant predictor of hospitalization or death (hazard ratio 1.4, 95% confidence interval 1.1-1.9; P < .019) but did not predict mortality independently from NT-proBNP. Additionally, copeptin concentrations did not predict future development of hyponatremia. CONCLUSIONS: Plasma copeptin levels predict mortality in outpatients with chronic heart failure independently from clinical variables, plasma sodium, and loop diuretic doses. Furthermore, copeptin predicts the combined end point of hospitalization or death independently from NT-proBNP.

Lung diffusion capacity in advanced heart failure: relation to central haemodynamics and outcome.

AIMS: Patients with heart failure (HF) are known to have a reduced pulmonary diffusion capacity for carbon monoxide (DLCO ), but little is known about how lung function relates to central haemodynamics. The aim of this study was to investigate the association between haemodynamic variables and pulmonary diffusion capacity adjusted for alveolar volume in congestive HF patients and to analyse how predicted DLCO /VA affects mortality in relation to the haemodynamic status. METHODS AND RESULTS: We retrospectively studied right heart catheterization (RHC) and lung function data on 262 HF patients (mean age 51 ± 13 years) with a left ventricular ejection fraction < 45% referred non-urgently for evaluation for heart transplantation (HTX) or left ventricular assist device (LVAD). Univariate and multivariate linear regression models were constructed to examine the associations between predicted values of DLCO /VA , forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1 ), and haemodynamic parameters [pulmonary capillary wedge pressure (PCWP), central venous pressure, cardiac index, mean pulmonary artery pressure, and mean arterial pressure] as well as other factors known to affect lung function in HF. FEV1 was reduced to <80% of predicted value in 55% of the population, and DLCO/ VA was reduced in 63% of the population. DLCO /VA correlated positively with pulmonary capillary wedge pressure in both univariate and multivariate analyses for all included patients (P < 0.001 and P = 0.045, respectively) and a restricted population of patients with the shortest time between RHC and lung function testing (P = 0.005, P = 0.015). DLCO /VA predicted mortality in multivariate models [hazard ratio 1.5 (1.1-2.1)] but not the combined endpoint of death, LVAD implantation, or HTX. There was no significant correlation between haemodynamics and predicted FVC or FEV1 . CONCLUSIONS: Pulmonary diffusion capacity correlates positively with left ventricular fillings pressures, and reduced values predict increased mortality in patients with HF. This might be driven by increased lung capillary volume in patients with pulmonary congestion.

Copeptin levels and invasive hemodynamics in patients with advanced heart failure.

AIM: Arginine vasopressin is a potent vasoconstrictory hormone and arginine vasopressin release is upregulated in heart failure (HF). The aim of this study was to evaluate if copeptin (the C-terminal part of provasopressin) is related to invasive hemodynamics in HF. METHODS & RESULTS: Right heart catheterization was performed in patients with advanced HF referred for evaluation for heart transplantation. Sixty-five patients (mean age 54 ± 12 years, left ventricular ejection fraction 19 ± 8% and median copeptin levels of 16.7 pmol/l (interquartile range: 11-30 pmol/l) were included. In multivariate analysis, increased levels of log (copeptin) were associated with a reduced CI (r = 0.65 and p = 0.04). CONCLUSION: Increased copeptin levels in plasma are associated with hemodynamic parameters obtained at right heart catheterization in patients with HF, in particular-reduced cardiac index. Copeptin could be a useful biomarker for abnormal resting hemodynamics in HF.

The Influence of Age on Hemodynamic Parameters During Rest and Exercise in Healthy Individuals.

OBJECTIVES: In this study, the authors sought to obtain hemodynamic estimates across a wide age span and in both sexes for future reference and compare these estimates with current guideline diagnostic hemodynamic thresholds for abnormal filling pressure and pulmonary hypertension. BACKGROUND: At present, the influence of age on hemodynamic function is largely unknown. Because many diseases with proposed cardiac impact are more prevalent in the older population, it is pivotal to know how hemodynamic parameters are affected by age itself to discern the influence of disease from that of physiological aging. METHODS: Sixty-two healthy participants, evenly distributed with respect to age (20 to 80 years) and sex (32 women/30 men), were prospectively enrolled in the study. Participants were all deemed healthy by medical history, echocardiography, exercise test, spirometry, blood tests, and electrocardiogram. Participants had hemodynamic parameters measured using right heart catheterization during rest, passive leg raise, and incremental exercise. RESULTS: During rest, all hemodynamic parameters were similar between age groups, apart from blood pressure. During leg raise and incremental exercise, there was augmented filling pressure (p < 0.0001) and diminished cardiac output (p = 0.001) and hence a higher pressure:flow ratio (pulmonary artery pressure/capillary wedge pressure to cardiac output) with progressive age, evident from the earliest ages. All indexed hemodynamic measures were similar between sexes. The diagnostic threshold (pulmonary capillary wedge pressure ≥25 mm Hg) currently used during exercise testing to diagnose abnormal left ventricular filling pressure was measured in 30% of our healthy elderly participants. CONCLUSIONS: Cardiac aging was progressive without sex differences in healthy participants. The hemodynamic reference values obtained suggest that the diagnostic threshold for abnormal filling pressure should be individually determined according to age of the patient.

Copeptin in Heart Failure.

Heart failure (HF) is one of the most common causes of hospitalization and mortality in the modern Western world and an increasing proportion of the population will be affected by HF in the future. Although HF management has improved quality of life and prognosis, mortality remains very high despite therapeutic options. Medical management consists of a neurohormonal blockade of an overly activated neurohormonal axis. No single marker has been able to predict or monitor HF with respect to disease progression, hospitalization, or mortality. New methods for diagnosis, monitoring therapy, and prognosis are warranted. Copeptin, a precursor of pre-provasopressin, is a new biomarker in HF with promising potential. Copeptin has been found to be elevated in both acute and chronic HF and is associated with prognosis. Copeptin, in combination with other biomarkers, could be a useful marker in the monitoring of disease severity and as a predictor of prognosis and survival in HF.

Relation between pressure and volume unloading during ramp testing in patients supported with a continuous-flow left ventricular assist device.

Pulmonary capillary wedge pressure (PCWP) is the key to describing left ventricular (LV) unloading; however, the relation between pressure and the echocardiography-derived surrogate of LV volume (LV end-diastolic diameter [LVEDD]) as a function of pump speed (revolutions per minute [RPM]) in continuous-flow LV assist device (CF-LVAD) patients is unknown. In this study, the pressure-volume relation as a function of RPM during ramp testing was investigated by simultaneously measuring PCWP by Swan-Ganz catheter and LVEDD by echocardiography. The ramp protocol started at usual pump setting (ramp-base) and then went from 8,000 RPM (ramp-low) increasing by 400 RPM/5 minutes until reaching 12,000 RPM or suction/arrhythmic event (ramp-high). The study was finalized by a 25 Watt exercise test at two ramp steps. Ten patients with ramp-base of 9,300 ± 241 RPM (at which 3 of 10 had aortic valve opening) were examined. At ramp-low, ramp-base, and ramp-high, PCWP was 20 ± 4, 14 ± 4, and 7 ± 3 mm Hg (p < 0.001 for all comparisons) and LVEDD 6.6 ± 1.0, 6.7 ± 0.9, and 5.5 ± 1.7 cm (p < 0.05 for all comparisons but ramp-low versus ramp-base). Correlation between PCWP and LVEDD slopes; R = 0.53 (p = 0.02). In conclusion, PCWP as a function of RPM is weakly correlated with changes in LVEDD. Thus, LVEDD is not an accurate measure of unloading in CF-LVAD patients.

Copeptin as a biomarker in heart failure.

Increased neurohormonal activation is a key feature of heart failure (HF). Copeptin is a surrogate marker for proarginine vasopressin and the prognostic value of copeptin has been reported for multiple disease states of both nonvascular and cardiovascular etiology. Elevated plasma copeptin in HF has been associated with adverse outcomes such as increased mortality, risk of hospitalization and correlates with the severity of HF. Copeptin may add prognostic information to already established predictors such as clinical variables and natriuretic peptides in HF. In addition, copeptin has been found to be a superior marker when compared with BNP and NT-proBNP in HF patients discharged after hospitalization caused by HF or myocardial infarction (MI). The optimal use of copeptin in HF remains unresolved and future appropriately sized and randomized trials must determine the role of copeptin in HF as a marker of adverse outcomes, risk stratification or as a target in biomarker-guided therapy with arginine vasopressin-antagonists in individualized patient treatment and everyday clinical practice.

Prevalence and prognostic significance of hyponatraemia in outpatients with chronic heart failure.

AIM: Hyponatraemia has been reported to be a potent predictor of poor outcome in patients hospitalized for heart failure (HF). The aim of the study was to determine the prevalence and prognostic significance of hyponatraemia in a large cohort of HF outpatients followed in clinics participating in the Danish Heart Failure Clinics Network. METHODS AND RESULTS: The study population consisted of consecutive patients referred for HF management in 18 Danish heart failure clinics. Overall, 2863 patients (83%) had a normal plasma sodium (p-sodium) level and 602 patients (17%) had hyponatraemia with a p-sodium level <136 mmol/L. Outcome data were obtained from a validated, national registry. Patients were elderly with a mean age of 68 years. The mean P-[Na+] was 139.6 ± 2.4 mmol/L among patients with normonatraemia and 132.4 ± 3.2 mmol/L among patients with hyponatraemia. In multivariate Cox Proportional Hazard Models adjusted for confounders (age, gender, hospitalization within the last 90 days, loop diuretics, creatinine level, systolic blood pressure, New York Heart Association class III-IV, left ventricular ejection fraction <0.46, ischaemic heart disease and diabetes) hyponatraemic patients had increased risk of hospitalization or death [hazard ratio (HR) 1.2 (95% confidence interval (CI) 1.0-1.4, P = 0.011)]. Hyponatraemia was also an independent predictor of all-cause mortality [HR 1.5 (95% CI 1.2-1.9, P< 0.001)]. There was no interaction between hyponatraemia and the covariables on outcome in the multivariable models. CONCLUSION: The presence of hyponatraemia in outpatients with HF is associated with increased risk of hospitalization or death.