Hyponatremia in Stable Patients with Advanced Heart Failure: Association to Hemodynamics and Outcome.

INTRODUCTION: Hyponatremia is associated with worse outcomes in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF). However, it is unclear whether the worse prognosis is driven by hemodynamic derangement and how this potentially could be associated with hyponatremia. METHODS: The study included 502 patients with HFrEF evaluated for advanced HF therapies, who underwent a right heart catheterization (RHC). Hyponatremia was defined as p-Na ≤136 mmol/L. The risk of all-cause mortality and a composite endpoint including mortality, left ventricular assist device (LVAD) implantation, implantation of total artificial heart (TAH), or heart transplantation (HTx) was evaluated using Cox regression analyses and Kaplan-Meier models. RESULTS: Included patients were predominantly men 79% and had a median age of 54 years (IQR: 43-62). A third (165) of the patients had hyponatremia. In both univariate and multivariate regression analyses, p-Na was associated with increased central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (mPAP) but not with cardiac index. Hyponatremia was significantly associated with the combined endpoint (HR: 1.36 [95% CI, 1.07-1.74]; p = 0.01), but not all-cause mortality in adjusted Cox models. CONCLUSION: In stable HFrEF patients evaluated for advanced HF therapies, lower p-Na was associated with more deranged invasive hemodynamic measurements. Hyponatremia remained significantly associated with the combined endpoint but not all-cause mortality in adjusted Cox models. The study suggests that the increased mortality associated with hyponatremia in HFrEF patients could partly be driven by hemodynamic derangement.

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.

Clinical presentation and outcomes in women and men with advanced heart failure.

OBJECTIVE: To examine clinical characteristics and outcomes in women and men referred for advanced heart failure (HF) therapies such as left ventricular assist device (LVAD) or heart transplantation (HTx). Design: A retrospective study of 429 (23% women) consecutive adult HF patients not on inotropic or mechanical circulatory support with left ventricular ejection fraction ≤45% referred for assessment of advanced HF therapies at a single tertiary institution between 2002 and 2016. Clinical characteristics and outcomes were compared in women and men, and all patients underwent right heart catheterization (RHC). Results: At evaluation, women were younger than men (48 ± 13 vs. 51 ± 12 years, p = .02), and less likely to have ischemic cardiomyopathy. There were no significant differences in NYHA class, contemporary HF therapy use, or physical examination findings, except for lower jugular vein distension and body surface area in women. On RHC, women had lower cardiac filling pressures, but similar pulmonary vascular resistance and cardiac index. Peak oxygen uptake from cardiopulmonary exercise testing was similar in both sexes. At total follow-up time, there were 164 deaths (21% vs. 44%, p < .0001), 46 LVADs (3% vs. 13%, p = .005), 110 HTxs (32% vs. 25%, p = .15), and 82 HTxs without requiring LVAD (29% vs. 16%, p = .03) in women and men. The time from RHC to HTx (±LVAD) was significantly shorter in women compared to men. Female sex was significantly associated with higher survival independent of time-trend, age, and comorbidities. Conclusion: At evaluation, hemodynamics were less deranged in women. A higher proportion of women received HTx, their waitlist time was shorter, and survival greater.

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.

Influence of socioeconomic status on rates of advanced heart failure therapies.

BACKGROUND: Socioeconomic deprivation is associated with a lower likelihood of referral for advanced heart failure (HF) evaluation, but it is not known whether it influences rates of advanced HF therapies independently of key hemodynamic measures and comorbidity following advanced HF evaluation in a universal healthcare system. METHODS: We linked data from a single-center Danish clinical registry of consecutive patients evaluated for advanced HF with patient-level information on socioeconomic status. Patients were divided into groups based on the level of education (low, medium, and high), combined degree of socioeconomic deprivation (low, medium, and high), and household income quartiles. Rates of the combined outcome of left ventricular assist device implantation or heart transplantation (advanced HF therapy) with death as a competing risk were estimated with cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, central venous pressure, cardiac index, and comorbidities. RESULTS: We included 629 patients, median age 53 years, of whom 77% were men. During a median follow-up of 5 years, 179 (28%) underwent advanced HF therapy. The highest level of education was associated with higher rates (high vs low, adjusted HR 1.81 95% CI 1.14-2.89, p = 0.01), whereas household income quartile groups (Q4 vs Q1, adjusted HR 1.37 95% CI 0.76-2.47, p = 0.30) or groups of combined socioeconomic deprivation (high vs low degree of deprivation, adjusted HR 0.86 95% CI 0.50-1.46, p = 0.56) were not significantly associated with rates of advanced HF therapy. CONCLUSIONS: Patients with a lower level of education might be disfavored for advanced HF therapies and could require specific attention in the advanced HF care center.

The relation between socioeconomic status and invasive haemodynamics at evaluation for advanced heart failure.

AIMS: Socioeconomic deprivation is a risk marker for worse prognosis in patients with heart failure (HF), and a potential barrier to referral for advanced HF evaluation. The relationship between socioeconomic status (SES) and invasive haemodynamics in patients undergoing evaluation for advanced HF therapies is unknown. METHODS: We combined a consecutive clinical registry of patients evaluated for advanced HF with patient-level data on SES (household income, education, workforce status, cohabitant status and distance from home to tertiary HF centre) derived from nationwide registries. Using this information, the cohort was divided into groups of low-, medium- and high degree of socioeconomic deprivation. The associations between SES and invasive haemodynamics were explored with multiple linear regression adjusted for age and sex. RESULTS: A total of 631 patients were included. The median age was 53 years, and 23% were women. Patients in the highest income quartile versus the lowest (Q4 vs. Q1) were older (median age 57 vs. 50 years) and more often male (83% vs. 67%), both P < 0.001. Increasing household income (per 100 000 Danish kroner,1 EUR = 7.4 DKK) was associated with lower pulmonary capillary wedge pressure (PCWP) [-0.18 mmHg, 95% confidence interval (CI) -0.36 to -0.01, P = 0.036] but not significantly associated with central venous pressure (CVP) (-0.07 mmHg, 95% CI -0.21 to 0.06, P = 0.27), cardiac index (-0.004 L/min/m2, 95% CI -0.02 to 0.01, P = 0.60), or pulmonary vascular resistance (PVR) (-0.003 Wood units, 95% CI -0.37 to 0.16, P = 0.84). Comparing the most deprived with the least deprived group, adjusted mean PVR was higher (0.35 Wood units, 95% CI 0.02 to 0.68, P = 0.04), but PCWP (0.66 mmHg, 95% CI -1.49 to 2.82, P = 0.55), CVP (-0.26 mmHg, 95% CI -1.76 to 1.24, P = 0.73) and cardiac index (-0.03 L/min/m2, 95% CI -0.22 to 0.17, P = 0.78) were similar. CONCLUSIONS: Most haemodynamic measurements were similar across layers of SES. Nevertheless, there were some indications of worse haemodynamics in patients with lower household income or a high accumulated burden of socioeconomic deprivation. Particular attention may be warranted in socioeconomically deprived patients to ensure timely referral for advanced HF evaluation.

Pleural Effusion and Invasive Hemodynamic Measurements in Advanced Heart Failure.

BACKGROUND: Pleural effusion is present in 50% to 80% of patients with acute heart failure, depending on image modality. We aim to describe the association between the presence and size of pleural effusion and central hemodynamics, including pulmonary capillary wedge pressure (PCWP) in an advanced heart failure population. METHODS: An observational, cross-sectional study in a cohort of patients with advanced heart failure (left ventricular ejection fraction ≤45%) who underwent right heart catheterization at The Department of Cardiology at Copenhagen University Hospital, Rigshospitalet, Denmark, between January 1, 2002 and October 31, 2020. The presence and size of pleural effusion were determined by a semiquantitative score of chest x-rays or computed tomography scans performed within 2 days of right heart catheterization. RESULTS: In 346 patients (50±13 years; 78% males) with median left ventricular ejection fraction of 20% (15-25), we identified 162 (47%) with pleural effusion. The pleural effusion size was medium in 38 (24%) and large in 30 (19%). Patients with pleural effusion had a 4.3 mm Hg (2.5-6.1) higher PCWP and 2.4 mm Hg (1.2-3.6) higher central venous pressure (P<0.001 for both). Patients with a medium/large pleural effusion had statistically significantly higher filling pressures than patients with a small effusion. Higher PCWP (odds ratio [OR], 1.06 [1.03-1.10]) and central venous pressure (OR, 1.09 [1.05-1.15]) were associated with pleural effusion in multivariable logistic regression adjusted for age, sex, and heart failure medications (P<0.001 for both). In a subgroup of 204 (63%) patients with serum albumin data, PCWP (OR, 1.06 [1.01-1.11]; P=0.032), central venous pressure (OR, 1.14 [1.06-1.23]; P<0.001) and serum albumin level (OR, 0.89 [0.83-0.95]; P<0.001) were independently associated with the presence of a medium/large-sized pleural effusion. CONCLUSIONS: In patients with left ventricular ejection fraction ≤45% undergoing right heart catheterization as part of advanced heart failure work-up, pleural effusion was associated with higher PCWP and central venous pressure and lower serum albumin.

Diabetes mellitus and hemodynamics in advanced heart failure.

BACKGROUND: The presence of diabetes in patients with heart failure (HF) is associated with a worse prognosis. It is unclear if hemodynamics in HF patients with DM differ from those of non-diabetic patients and how this might influence outcome. This study aims to discover the impact of DM on hemodynamics in HF patients. METHODS: Consecutive patients (n = 598) with HF and reduced ejection fraction (LVEF ≤40%) undergoing invasive hemodynamic evaluation were included (non-DM: n = 473, DM: n = 125). Hemodynamic parameters included pulmonary capillary wedge pressure (PCWP), central venous pressure (CVP), cardiac index (CI) and mean arterial pressure (MAP). Mean follow-up was 9.5 ± 5.1 years. RESULTS: Patients with DM (82.7% male, mean age 57.1 ± 10.1 years, mean HbA1c 60 ± 21 mmol/mol) had higher PCWP, mPAP, CVP and higher MAP. Adjusted analysis demonstrated that DM patients had higher PCWP and CVP. Increasing HbA1c-values were correlated with higher PCWP (p = 0.017) and CVP (p = 0.043). CONCLUSION: Patients with DM, especially those with poor glycemic control, have higher filling pressures. This may be a feature of diabetic cardiomyopathy, however, other unknown mechanisms beyond hemodynamic factors are likely to explain the increased mortality associated with diabetes in HF.

Importance of heart failure duration for development of pulmonary hypertension in advanced heart failure.

BACKGROUND AND OBJECTIVES: Pulmonary vascular resistance (PVR) is critical when evaluating candidacy for advanced heart failure (HF) therapies, but risk factors for elevated PVR are not well studied. We hypothesized that HF duration would be associated with elevated PVR. METHODS: Danish single-center registry of consecutive in- and outpatients undergoing right heart catheterization as part of advanced HF work up. The relation between HF duration and PVR was estimated by regression analysis. Finally, the relation between PVR and long-term mortality was assessed by Cox proportional hazards regression and Kaplan-Meier analyses. RESULTS: A total of 549 patients (77% men, median age 54 (43-61) years, median HF duration 1.6 years (0.1-7.1)) were included. Univariate linear regression displayed an association between longer HF duration and increasing PVR (p = 0.014). PVR > 3 WU was present in 92 patients (17%) who were older (median p < 0.001) and had longer HF duration (p = 0.03). HF duration (per 1 year increase) did not predict PVR > 3 WU after adjustment for covariables (OR 1.00; p = 0.99). During a mean follow-up time of 4.5 years, there were 240 (44%) deaths. Increasing PVR was associated with elevated all-cause mortality risk (adjusted HR 1.24; p < 0.001). PVR > 3 WU was associated with higher mortality (adjusted HR 1.49; p = 0.027). CONCLUSION: Longer duration of HF was associated with higher PVR in patients with advanced HF, but this association disappeared in multivariate analyses. Longer HF duration per se likely does not cause elevated PVR and should not discourage evaluation for heart transplantation.