Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure.

BACKGROUND: Plasma levels of cardiotonic steroids are elevated in volume-expanded states, such as chronic kidney disease, but the role of these natriuretic hormones in subjects with heart failure (HF) is unclear. We sought to determine the prognostic role of the cardiotonic steroids marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes. METHODS AND RESULTS: We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 patients with HF. All-cause mortality, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort, median (interquartile range) MBG was 583 (383-812) pM. Higher MBG was associated with higher myeloperoxidase (r=0.42, P<0.0001), B-type natriuretic peptide (r=0.25, P=0.001), and asymmetrical dimethylarginine (r=0.32, P<0.001). Elevated levels of MBG were associated with measures of worse right ventricular function (RV s', r=-0.39, P<0.0001) and predicted increased risk of adverse clinical outcomes (MBG≥574 pmol/L: hazard ratio 1.58 [1.10-2.31], P=0.014) even after adjustment for age, sex, diabetes mellitus, and ischemic pathogenesis. In mice, a left anterior descending coronary artery ligation model of HF lead to increases in MBG, whereas infusion of MBG into mice for 4 weeks lead to significant increases in myeloperoxidase, asymmetrical dimethylarginine, and cardiac fibrosis. CONCLUSIONS: In the setting of HF, elevated plasma levels of MBG are associated with right ventricular dysfunction and predict worse long-term clinical outcomes in multivariable models adjusting for established clinical and biochemical risk factors. Infusion of MBG seems to directly contribute to increased nitrative stress and cardiac fibrosis.

Response and tolerance to oral vasodilator up-titration after intravenous vasodilator therapy in advanced decompensated heart failure.

AIMS: The aim of this study was to assess the haemodynamic response and tolerance to aggressive oral hydralazine/isosorbide dinitrate (HYD/ISDN) up-titration after intravenous vasodilator therapy in advanced decompensated heart failure (ADHF). METHODS AND RESULTS: Medical records of 147 consecutive ADHF patients who underwent placement of a pulmonary artery catheter and received intravenous vasodilator therapy were reviewed. Intravenous sodium nitroprusside and sodium nitroglycerin as first-line agent for those with preserved blood pressures were utilized in 143 and 32 patients, respectively. Sixty-one percent of patients were converted to oral HYD/ISDN combination therapy through a standardized conversion protocol. These patients had a significantly higher admission mean pulmonary arterial wedge pressure compared with patients not converted (28 ± 7 vs. 25 ± 8 mmHg, respectively; P-value 0.024). Beneficial haemodynamic response to decongestive therapy, defined as low cardiac filling pressures and cardiac index ≥2.20 L/min/m(2) without emergent hypotension, was achieved in 32% and 29% of patients who did or did not receive oral HYD/ISDN, respectively (P-value 0.762). HYD/ISDN dosing was progressively and consistently decreased up to the moment of hospital discharge and during outpatient follow-up, primarily due to incident hypotension. CONCLUSION: The use of a standardized haemodynamically guided up-titration protocol for conversion from intravenous to oral vasodilators may warrant subsequent dose reductions upon stabilization.

Novel urinary biomarkers in detecting acute kidney injury, persistent renal impairment, and all-cause mortality following decongestive therapy in acute decompensated heart failure.

BACKGROUND: New urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18), are proposed to allow a more reliable early diagnosis and prognosis of acute kidney injury (AKI) in acute decompensated heart failure (ADHF). Our aim was to compare the predictive value of urinary NGAL, KIM-1, and IL-18 for the occurrence of AKI, persistent renal impairment, and mortality in ADHF. METHODS AND RESULTS: Eighty-three patients admitted for ADHF were analyzed. Urinary creatinine (Cr), NGAL, KIM-1, and IL-18 were measured at baseline. Serum Cr was measured daily during the next 4 days and again at outpatient follow-up after 6 months. Mortality data were prospectively collected. Urinary NGAL, KIM-1, and IL-18 were modestly correlated with each other (Spearman ρ ≤0.61) and poorly correlated with estimated glomerular filtration rate (eGFR; Spearman ρ ≤0.28). None predicted AKI, defined as a 25% decrease in eGFR, during the index hospitalization, but urinary IL-18/Cr was the strongest predictor of persistently elevated serum Cr ≥0.3 mg/dL after 6 months compared with baseline (area under the receiver operating characteristic curve 0.674; P = .013). Urinary IL-18 was also significantly associated with all-cause mortality (hazard ratio 1.48, 95% confidence interval 1.16-1.87; P = .001). CONCLUSIONS: Like urinary NGAL, urinary KIM-1 and IL-18 are relatively modest predictors of AKI in ADHF. Among these novel renal biomarkers examined, further investigations regarding the prognostic value of urinary IL-18 are warranted.

Lack of concordance in defining worsening renal function by rise in creatinine vs rise in cystatin C.

Worsening renal function (WRF) during treatment of acute decompensated heart failure (ADHF) is generally associated with adverse outcomes. An increase ≥0.3 mg/dL in creatinine level is widely used as the definition of WRF. The authors sought to determine the level of agreement between WRF based on changes in creatinine and changes in cystatin C (CysC) by analyzing data from 121 ADHF patients with available admission and day 3 creatinine and CysC levels. Admission creatinine and CysC levels were 1.39 (0.98-2.11) mg/dL and 1.95 (1.42-2.69) mg/L, respectively, and correlated well (r=0.81). On average, creatinine (-0.04±0.40 mg/dL) and CysC (0.001±0.34 mg/L) changed minimally from admission to day 3. Although the correlation between both markers on day 3 was still good (r=0.79), the correlation between changes therein was only modest (r=0.43). From the 14 and 15 patients who had WRF based on a ≥0.3 mg/dL increase in creatinine and ≥0.3 mg/L increase in CysC, respectively, only four (about 30%) met both definitions. These observations, together with recent insights in the inconsistencies of creatinine-defined concept of worsening renal function and outcomes, raises the need to research more reliable measures of renal function during treatment of ADHF.

Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment.

AIMS: 'Worsening renal function' (WRF) and 'improvement in renal function' (IRF) monitored by changes in serum creatinine are frequently encountered during treatment of acute decompensated heart failure (ADHF). We sought to establish the important haemodynamic determinants of alterations in serum creatinine. METHODS AND RESULTS: We reviewed data from 443 patients treated for ADHF with haemodynamic guidance in a single centre. WRF and IRF were defined as a 25% increase or decrease in estimated glomerular filtration rate (eGFR) from time of admission to pulmonary artery catheter removal, respectively. Of the 443 patients, 46 (10%) experienced WRF and 127 (29%) had IRF. Baseline eGFR was lower in patients with IRF when compared with stable patients or those with WRF (45 ± 25 vs. 63 ± 30 vs. 68 ± 27 mL/min/m(2), respectively, P < 0.0001). In contrast, the relative decrease in mean blood pressure (BP) was more pronounced in patients with WRF when compared with stable patients or those with IRF (15 ± 15 vs. 9 ± 17 vs. 4 ± 15%, respectively, P = 0.003). With larger decreases in mean BP, there was greater likelihood of experiencing WRF (P = 0.04) but less likelihood of experiencing IRF (P = 0.01). In contrast, the degree of changes in right atrial pressure or cardiac index did not affect the propensity for developing WRF or IRF. There was no difference in adverse clinical outcomes (death, heart transplantation, LV assist device implantation, or readmission) between the three groups (P = 0.56). CONCLUSION: Blood pressure decrease, rather than alterations in cardiac output or central venous pressure, were associated with changes in serum creatinine during treatment of ADHF.

Differential response to cardiac resynchronization therapy and clinical outcomes according to QRS morphology and QRS duration.

OBJECTIVES: The goal of this study was to examine the relative impact of QRS morphology and duration in echocardiographic responses to cardiac resynchronization therapy (CRT) and clinical outcomes. BACKGROUND: At least one-third of all patients treated with CRT fail to derive benefit. Patients without left bundle branch block (LBBB) or patients with smaller QRS duration (QRSd) respond less or not at all to CRT. METHODS: We retrospectively assessed baseline characteristics, clinical and echocardiographic response, and outcomes of all patients who received CRT at our institution between December 2003 and July 2007. Patients were stratified into 4 groups according to their baseline QRS morphology and QRSd. RESULTS: A total of 496 patients were included in the study; 216 (43.5%) had LBBB and a QRSd ≥150 ms, 85 (17.1%) had LBBB and QRSd <150 ms, 92 (18.5%) had non-LBBB and a QRSd ≥150 ms, and 103 (20.8%) had non-LBBB and QRSd <150 ms. Echocardiographic response (change in ejection fraction) was better in patients with LBBB and QRSd ≥150 ms (12 ± 12%) than in those with LBBB and QRSd <150 ms (8 ± 10%), non-LBBB and QRSd ≥150 ms (5 ± 9%), and non-LBBB and QRSd <150 ms (3 ± 11%) (p < 0.0001). In a multivariate stepwise model with change in ejection fraction as the dependent variable, the presented classification was the most important independent variable (p = 0.0003). Long-term survival was better in LBBB patients with QRSd ≥150 ms (p = 0.02), but this difference was not significant after adjustment for other baseline characteristics (p = 0.15). CONCLUSIONS: QRS morphology is a more important baseline electrocardiographic determinant of CRT response than QRSd.