The Association between Placenta Accreta Spectrum Severity and Incidence of Small for Gestational Age Neonates.

OBJECTIVE: The aim of the study is to evaluate whether pathologic severity of placenta accreta spectrum (PAS) is correlated with the incidence of small for gestational age (SGA) and neonatal birthweight. STUDY DESIGN: This was a multicenter cohort study of viable, non-anomalous, singleton gestations delivered with histology-proven PAS. Data including maternal history, neonatal birthweight, and placental pathology were collected and deidentified. Pathology was defined as accreta, increta, or percreta. The primary outcome was rate of SGA defined by birth weight less than the 10th percentile. The secondary outcomes included incidence of large for gestational age (LGA) babies as defined by birth weight greater than the 90th percentile as well as incidence of SGA and LGA in preterm and term gestations. Statistical analysis was performed using Chi-square, Kruskal-Wallis, and log-binomial regression. Increta and percreta patients were each compared with accreta patients. RESULTS: Among the cohort of 1,008 women from seven United States centers, 865 subjects were included in the analysis. The relative risk (RR) of SGA for increta and percreta did not differ from accreta after adjusting for confounders (adjusted RR = 0.63, 95% confidence interval [CI]: 0.36-1.10 for increta and aRR = 0.72, 95% CI: 0.45-1.16 for percreta). The results were stratified by placenta previa status, which did not affect results. There was no difference in incidence of LGA (p = 1.0) by PAS pathologic severity. The incidence of SGA for all PAS patients was 9.2% for those delivered preterm and 18.7% for those delivered at term (p = 0.004). The incidence of LGA for all PAS patients was 12.6% for those delivered preterm and 13.2% for those delivered at term (p = 0.8203). CONCLUSION: There was no difference in incidence of SGA or LGA when comparing accreta to increta or percreta patients regardless of previa status. Although we cannot suggest causation, our results suggest that PAS, regardless of pathologic severity, is not associated with pathologic fetal growth in the preterm period. KEY POINTS: · PAS severity is not associated with SGA in the preterm period.. · PAS severity is not associated with LGA.. · Placenta previa does not affect the incidence of SGA in women with PAS..

Impact of time to surgery from injury on postoperative infection and deep vein thrombosis in periprosthetic knee fractures.

PURPOSE: Periprosthetic fracture (PPF) is a serious complication that occurs in 0.3%-2.5% of all total knee arthroplasties used to treat end-stage arthritis. To our knowledge, there are no studies in the literature that evaluate the association between time to surgery after PPF and early postoperative infections or deep vein thrombosis (DVT). This study tests our hypothesis that delayed time to surgery increases rates of postoperative infection and DVT after PPF surgery. METHODS: Our study cohort included patients undergoing PPF surgery in the American College of Surgeons National Surgical Quality Improvement Program database (2006-2015). The patients were dichotomized based on time to surgery: group 1 with time ≤2 days and group 2 with time >2 days. A 2-by-2 contingency table and Fisher's exact test were used to evaluate the association between complications and time to surgery groups, and multivariate logistic regression was used to adjust for demographics and known risk factors. RESULTS: A total of 263 patients (80% females) with a mean age of 73.9 ± 12.0 years were identified receiving PPF surgery, among which 216 patients were in group 1 and 47 patients in group 2. Complications in group 1 included 3 (1.4%) superficial infections (SI), 1 (0.5%) organ space infection (OSI), 1 (0.5%) wound dehiscence (WD), and 4 (1.9%) deep vein thrombosis (DVT); while complications in group 2 included 1 (2.1%) SI, 1 (2.1%) OSI, 1 (2.1%) DVT, and no WD. No significant difference was detected in postoperative complications between the two groups. However, patients in group 2 were more likely (p = 0.0013) to receive blood transfusions (57.5%) than those in group 1 (32.4%). CONCLUSION: Our study indicates patients with delayed time to surgery have higher chance to receive blood transfusions, but no significant difference in postoperative complications (SI, OSI, WD, or DVT) between the two groups.

Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure.

BACKGROUND: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). METHODS AND RESULTS: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) µmol/L, 10.9 (8.4-14.0) µmol/L, and 43.8 (37.1-53.0) µmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] µmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] µmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). CONCLUSION: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.

Insufficient natriuretic response to continuous intravenous furosemide is associated with poor long-term outcomes in acute decompensated heart failure.

BACKGROUND: Treatment of acute decompensated heart failure (ADHF) with loop diuretics, such as furosemide, is frequently complicated by insufficient urine sodium excretion. We hypothesize that insufficient natriuretic response to diuretic therapy, characterized by lower urine sodium (UNa) and urine furosemide, is associated with subsequent inadequate decongestion, worsening renal function, and adverse long term events. METHODS AND RESULTS: We enrolled 52 consecutive patients with ADHF and measured serum and urine sodium (UNa), urine creatinine (UCr), and urine furosemide (UFurosemide) levels on a spot sample taken after treatment with continuous intravenous furosemide, and followed clinical and renal variables as well as adverse long-term clinical outcomes (death, rehospitalizations, and cardiac transplantation). We observed similar correlations between UNa:UFurosemide ratio and UNa and fractional excretion of sodium (FENa) with 24-hour net urine output (r = 0.52-0.64, all P < .01) and 24-hour weight loss (r = 0.44-0.56; all P < .01). Interestingly, FENa (but not UNa or UNa:UFurosemide) were influenced by estimated glomerular filtration rate (eGFR). We observed an association between lower UNa:UFurosemide with greater likelihood of worsening renal function (hazard ratio [HR] 3.01; P = .02) and poorer adverse clinical outcomes (HR 1.63, P = .008) after adjusting for age and eGFR. Meanwhile, both diminished weight loss and net fluid output over 24 hours of continuous intravenous furosemide were observed when UNa:UFurosemide ratios were <2 mmol/mg or when UNa <50 mmol. CONCLUSION: In patients with ADHF receiving continuous furosemide infusion, impaired natriuretic response to furosemide is associated with greater likelihood of worsening renal function and future adverse long-term outcomes, independently from and incrementally with decreasing intrinsic glomerular filtration.

Diminished global arginine bioavailability as a metabolic defect in chronic systolic heart failure.

BACKGROUND: Systemic alterations in arginine bioavailability occur in heart failure (HF) patients with more advanced myocardial dysfunction and poorer clinical outcomes, and they improve with beta-blocker therapy. METHODS AND RESULTS: We measured fasting plasma levels of L-arginine and related biogenic amine metabolites in 138 stable symptomatic HF patients with left ventricular ejection fraction ≤35% and comprehensive echocardiographic evaluation. Long-term adverse clinical outcomes (death and cardiac transplantation) were followed for 5 years. Lower global arginine bioavailability ratio (GABR; ratio of L-arginine to L-ornithine + L-citrulline) was associated with higher plasma natriuretic peptide levels, more advanced left ventricular diastolic dysfunction, and more severe right ventricular systolic dysfunction (all P < .001). Patients taking beta-blockers had significantly higher GABR than those not taking beta-blockers (0.86 [interquartile range (IQR) 0.68-1.17] vs 0.61 [0.44-0.89]; P < .001). Subjects with higher GABR experienced fewer long-term adverse clinical events (hazard ratio 0.61 [95% confidence interval 0.43-0.84]; P = .002). In an independent beta-blocker naïve patient cohort, GABR increased following long-term (6 month) beta-blocker therapy (0.89 [IQR 0.52-1.07] to 0.97 [0.81-1.20]; P = .019). CONCLUSIONS: In patients with chronic systolic heart failure, diminished global L-arginine bioavailability is associated with more advanced myocardial dysfunction and poorer long-term adverse clinical outcomes. GABR levels improved with beta-blocker therapy.

Protein carbamylation in chronic systolic heart failure: relationship with renal impairment and adverse long-term outcomes.

BACKGROUND: Protein carbamylation, a posttranslational modification promoted during uremia and catalyzed by myeloperoxidase (MPO) at sites of inflammation, is linked to altered protein structure, vascular dysfunction, and poor prognosis. We examine the relationship between plasma protein-bound homocitrulline (PBHCit) levels, a marker of protein lysine residue carbamylation, with cardiorenal function and long-term outcomes in chronic systolic heart failure (HF). METHODS AND RESULTS: In 115 patients with chronic systolic HF (left ventricular ejection fraction ≤35%), we measured plasma PBHCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. In our study cohort, the median PBHCit level was 87 (interquartile range 59-128) µmol/mol lysine. Higher plasma PBHcit levels were associated with poorer renal function (estimated glomerular filtration rate [eGFR]: Spearman r = -0.37; P < .001), cystatin C (r = 0.31; P = .001), and elevated plasma amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (r = 0.26; P = .006), but not with markers of systemic inflammation or oxidant stress (high-sensitivity C-reactive protein and myeloperoxidase [MPO]: P > .10 for each). Furthermore, elevated plasma PBHCit levels were not related to indices of cardiac structure or function (P > .10 for all examined) except modestly with increased right atrial volume index (r = 0.31; P = .002). PBHCit levels predicted adverse long-term events (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.3-2.6; P < .001), including after adjustment for age, eGFR, MPO, and NT-proBNP (HR 1.9, 95% CI 1.2-3.1; P = .006). CONCLUSIONS: In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardiorenal indices of adverse prognosis.

Increasing serum soluble angiotensin-converting enzyme 2 activity after intensive medical therapy is associated with better prognosis in acute decompensated heart failure.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system that has been recently identified in circulating form. We aimed to investigate the relationship among changes in soluble ACE2 (sACE2) activity, myocardial performance, and long-term clinical outcomes in patients with acute decompensated heart failure (ADHF). We hypothesized that increasing sACE2 activity levels during intensive medical treatment are associated with improved myocardial performance and long-term clinical outcomes. METHODS AND RESULTS: In 70 patients admitted to the intensive care unit with ADHF, serum sACE2 activity levels, echocardiographic data, and hemodynamic variables were collected within 12 hours of admission (n = 70) and 48-72 hours after intensive medical treatment (n = 57). The median [interquartile range] baseline and 48-72-hour serum sACE2 activity levels were 32 [23-43] ng/mL and 40 [28-60] ng/mL, respectively. Baseline serum sACE2 activity levels correlated with surrogate measures of right ventricular diastolic dysfunction, including right atrial volume index (RAVi; r = 0.31; P = .010), tricuspid E/A ratio (r = 0.39; P = .007), and B-type natriuretic peptide (r = 0.32; P = .008). However, there were no correlations between serum sACE2 and left ventricular systolic or diastolic dysfunction. After intensive medical therapy, a 50% increase in baseline serum sACE2 levels predicted a significant reduction in risk of death, cardiac transplantation, or ADHF rehospitalization, including after adjustment for baseline age, RAVi, and BNP levels (hazard ratio 0.35, 95% confidence interval 0.12-0.84; P = .018). CONCLUSIONS: In patients admitted with ADHF, increasing serum sACE2 activity levels during intensive medical therapy predict improved outcomes independently from underlying cardiac indices.

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.

Using an Environmentally Friendly Disposal Bag to Discard Leftover Opioids After Gynecologic Surgery.

OBJECTIVE: To evaluate the effects of an environmentally friendly drug deactivation bag on opioid disposal among patients undergoing gynecologic surgery. METHODS: This prospective cohort study included patients undergoing gynecologic procedures requiring an opioid prescription from March 2020 to December 2020. Patients were managed on a restrictive opioid prescribing algorithm and given an opioid disposal bag. The carbon drug deactivation bag neutralizes the opioid medication and can be discarded safely in the trash. Patients were educated about pain management goals and the disposal bag. Patients were surveyed at their postoperative visit to evaluate satisfaction, number of leftover pills, and disposal methods. Statistical analysis was performed using SPSS Statistics 26. RESULTS: Two hundred patients were asked to complete the survey, with a response rate of 78%. The most common procedures were exploratory laparotomy (50%) and minimally invasive hysterectomy (41%). Most patients (91%, 95% CI 91-97) filled their opioid prescription and 64 (41%, 95% CI 34-48) had leftover opioid pills. Most patients with leftover opioid pills (73%, 95% CI 67-79) discarded them; 78%, 95% CI 69-80 used the disposal bag. Patients undergoing an exploratory laparotomy most commonly used the disposal bag. All patients who used the disposal bag stated they would use it again. CONCLUSION: Despite a restrictive opioid prescribing algorithm, 41% of gynecologic surgical patients had leftover opioid pills. This study demonstrated that leftover opioid pills were safely discarded 73% of the time when patients were provided an opioid disposal bag and preoperative education.

Impact of left ventricular remodeling on diagnostic and prognostic value of tissue Doppler indices in chronic systolic heart failure.

BACKGROUND: The ratio of peak transmitral pulsed Doppler early velocity to early diastolic tissue Doppler velocity (TDI) of the lateral or septal mitral annulus (E/Ea) is considered a reliable estimation of LV filling pressure. We aim to examine the impact of left ventricular (LV) dimensions on the relationship between lateral and septal E/Ea in the determination of diastolic dysfunction patterns in the setting of chronic systolic heart failure (HF). METHODS AND RESULTS: In 207 patients with chronic systolic HF (LV ejection fraction ≤40%, New York Heart Association Classes I-IV), comprehensive transthoracic echocardiography was performed and long-term outcomes followed up to a median of 40 months. The median lateral and septal Ea (interquartile range) were 7.0 (4.7 to 9.5) cm/s and 4.5 (3.5 to 5.6) cm/s, respectively. The median E/lateral Ea, E/septal Ea, and E/average Ea (interquartile range) were 10.8 (7.1 to 15.1), 16.1 (11.1 to 23.0), and 12.7 (8.8 to 17.7), respectively. In the first 2 tertiles of indexed left ventricular end-diastolic volume (LVEDVi) (<92 mL/m(2) and 92 to 130 mL/m(2)), all 3 E/Ea indices rise with increasing diastolic stage (all P < .001). However, in the highest tertile of indexed LVEDVi (≥130 mL/m(2)), E/average Ea and E/septal Ea (but not E/lateral Ea) increased with increasing diastolic stage, and only E/septal Ea correlated with natriuretic peptide levels (r = 0.38, P = .018) and adverse cardiac events (Hazard ratio 1.91, 95% confidence interval 1.25 to 2.96, P = .003). CONCLUSIONS: In the setting of chronic systolic heart failure with extensive cardiac remodeling, septal TDI measurements may be more reliable and clinically relevant than lateral TDI measurements in the assessment of diastolic dysfunction.

Renal dysfunction is a stronger determinant of systemic neutrophil gelatinase-associated lipocalin levels than myocardial dysfunction in systolic heart failure.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is released by renal tubular cells in response to inflammation and injury. Recent studies have demonstrated that NGAL is up-regulated in cardiomyocytes within the failing myocardium. However, the overall relationship between systemic NGAL levels and myocardial structure and performance has not been established. METHODS AND RESULTS: We measured systemic NGAL levels in 130 subjects with chronic systolic heart failure (HF) and comprehensive echocardiographic evaluation, as well as 69 subjects with acute decompensated systolic HF and hemodynamic evaluation. In the chronic HF cohort, higher plasma NGAL levels were modestly associated with increasing age (r = 0.18; P = .035), higher New York Heart Association functional class (rank sums: P = .022) and impaired renal function (eGFR: r = -0.53; P < .0001; cystatin C: r = 0.60; P < .0001). Plasma NGAL levels were modestly associated with indices of diastolic dysfunction (mitral E/Ea: r = 0.27; P = .002; LAVi: r = 0.25; P = .011; tricuspid E/Ea: r = 0.20; P = .029), but not after adjustment for renal function (P > .10 for all). In Cox proportional hazards analysis, plasma NGAL predicted cardiac death or transplantation after adjustment for age, gender, left ventricular ejection fraction, and mitral E/Ea (hazard ratio 1.68, 95% confidence interval 1.08-2.57; P = .022), but not after adjustment for renal function (P = .83). In the acute HF cohort, we did not observe any relationship between NGAL and hemodynamic indices, but NGAL strongly correlated with renal function. CONCLUSIONS: Systemic NGAL levels are largely determined by underlying impairment of renal rather than myocardial function. Our findings did not support any prognostic significance or relationship between systemic NGAL levels and indices of cardiac structure and function after adjustment for underlying renal function.

Antiinflammatory autoimmune cellular responses to cardiac troponin I in idiopathic dilated cardiomyopathy.

BACKGROUND: Autoimmune mechanisms, particularly through generation of autoantibodies, may contribute to the pathophysiology of idiopathic dilated cardiomyopathy (iDCM). The precise role of cellular autoimmune responses to cardiac-specific antigens has not been well described in humans. The purpose of this study was to characterize the cellular autoimmune response to cardiac troponin I (cTnI), specifically, the release of cytokines by peripheral blood mononuclear cells (PBMCs), in subjects with iDCM and healthy control subjects. METHODS AND RESULTS: We performed enzyme-linked immunospot assays on PBMCs isolated from subjects with iDCM and healthy control subjects to examine the ex vivo interferon-gamma (IFN-γ) and interleukin-10 (IL-10) production in response to cTnI exposure. Thirty-five consecutive subjects with iDCM (mean age 53 ± 11 years, 60% male, left ventricular ejection fraction 23 ± 7%) and 26 control subjects (mean age 46 ± 13 years, 46% male) were prospectively enrolled. IFN-γ production in response to cTnI did not differ between the groups (number of secreting cells 26 ± 49 vs 38 ± 53, respectively; P = .1). In contrast, subjects with iDCM showed significantly higher IL-10 responses to cTnI compared with control subjects (number of secreting cells 386 ± 428 vs 152 ± 162, respectively; P < .05). Among iDCM subjects, heightened IL-10 response to cTnI was associated with reduced systemic inflammation and lower prevalence of advanced diastolic dysfunction compared with those with normal IL-10 response to cTnI. CONCLUSIONS: Our preliminary findings suggest that a heightened cellular autoimmune IL-10 response to cTnI is detectable in a subset of patients with iDCM, which may be associated with reduced systemic levels of high-sensitivity C-reactive protein and lower prevalence of advanced diastolic dysfunction.

Serum neutrophil gelatinase-associated lipocalin (NGAL) in predicting worsening renal function in acute decompensated heart failure.

BACKGROUND: The development of worsening renal function (WRF, defined as creatinine rise >or=0.3mg/dL) occurs frequently in the setting of acute decompensated heart failure (ADHF) and strongly predicts adverse clinical outcomes. Neutrophil gelatinase-associated lipocalin (NGAL) is produced by the nephron in response to tubular epithelial damage and serves as an early marker for acute renal tubular injury. We sought to determine the relationship between admission serum NGAL levels and WRF in the setting of ADHF. METHODS AND RESULTS: We measured serum NGAL levels in 91 patients admitted to the hospital with ADHF. Patients were adjudicated by independent physician into those that did or did not develop WRF over the ensuing 5 days of in-hospital treatment. In our study cohort (68% male, mean age 61+/-15 years, mean left ventricular ejection fraction 31+/-14%), median admission serum NGAL level was 165 ng/mL (interquartile range [IQR] 108-235 ng/mL). Thirty-five patients (38%) developed WRF within the 5-day follow-up. Patients who developed WRF versus those without WRF had significantly higher median admission serum NGAL levels (194 [IQR 150-292] ng/mL vs. 128 [IQR 97-214] ng/mL, P=.001). High serum NGAL levels at admission were associated with greater likelihood of developing WRF (odds ratio: 1.92, 95% confidence interval 1.23-3.12, P=.004). In particular, admission NGAL >or=140 ng/mL had a 7.4-fold increase in risk of developing WRF, with a sensitivity and specificity of 86% and 54%, respectively. CONCLUSIONS: The presence of elevated admission serum NGAL levels is associated with heightened risk of subsequent development of WRF in patients admitted with ADHF.

Plasma corin levels provide minimal prognostic utility incremental to natriuretic peptides in chronic systolic heart failure.

BACKGROUND: Corin is a serine protease that cleaves pro-atrial and pro-B-type natriuretic peptides into biologically active hormones. The relationship between soluble plasma corin levels, plasma natriuretic peptide levels, myocardial structure and performance, and long-term clinical outcomes in the setting of chronic systolic heart failure has not been described. METHODS AND RESULTS: In 126 patients with chronic systolic heart failure (left ventricular ejection fraction

Clinical significance of endogenous vasoactive neurohormones in chronic systolic heart failure.

BACKGROUND: Neurohormonal activation is a pathophysiological hallmark of acute and chronic heart failure (HF). The clinical significance of more recently discovered endogenous vasoactive hormones has not been well-characterized. METHODS AND RESULTS: In 154 subjects with stable, chronic systolic HF (New York Heart Association Class I-IV, left ventricular [LV] ejection fraction or=12.1 pM (HR: 2.02, 95% CI: 1.08-3.93, P = .029) and ET-1 >or=2.29 pM (HR: 2.52, 95% CI: 1.24-5.03, P = .011) remained significant independent risk factors for adverse clinical events. CONCLUSION: Higher levels of plasma levels of UCN-1 and ET-1 but not UT-II were associated with worse LV diastolic performance and poorer long-term clinical outcomes in patients with chronic systolic HF.

Cardiorenal syndrome: diagnosis, treatment, and clinical outcomes.

The pathophysiologic interactions that link the heart and kidney are multiple and complex, and have been grouped under the umbrella term "cardiorenal syndrome." In the setting of acute decompensated heart failure, worsening renal function has been directly associated with poor clinical prognosis and complicates treatment. However, the pathophysiology underlying acute cardiorenal syndrome remains incompletely understood and treatment options remain limited. Traditionally, the development of worsening renal function in acute decompensated heart failure has been attributed to renal arterial underfilling due to reduced cardiac output or intravascular volume depletion. However, increasing data have expanded our understanding of the roles that venous congestion and intra-abdominal pressure play in driving renal injury, with important implications for therapeutic management and the development of novel renal-sparing therapies.

Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established. METHODS AND RESULTS: We measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF]

Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure.

AIMS: To investigate the association of arginine methylation with myocardial function and prognosis in chronic systolic heart failure patients. METHODS AND RESULTS: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), as well as N-mono-methylarginine (MMA) and methyl-lysine, were simultaneously measured by tandem mass spectrometry in 132 patients with chronic systolic heart failure with echocardiographic evaluation and follow-up. Increasing ADMA and SDMA levels were associated with elevated natriuretic peptide levels (both P < 0.001), and increasing SDMA levels were associated with worsening renal function (P < 0.001). Higher plasma levels of methylated arginine metabolites (but not methyl-lysine) were associated with the presence of left ventricular (LV) diastolic dysfunction (E/septal E', Spearman's r = 0.31-0.36, P < 0.001). Patients taking beta-blockers had lower ADMA levels than those not taking beta-blockers [0.42 (0.33, 0.50) vs. 0.51 (0.40, 0.58), P < 0.001]. Only increasing ADMA levels were associated with advanced right ventricular (RV) systolic dysfunction. Elevated ADMA levels remained a consistent independent predictor of adverse clinical events (hazard ratio = 1.64, 95% CI: 1.20-2.22, P = 0.002). CONCLUSION: In chronic systolic heart failure, accumulation of methylated arginine metabolites is associated with the presence of LV diastolic dysfunction. Among the methylated derivatives of arginine, ADMA provides the strongest independent prediction of disease progression and adverse long-term outcomes.

Usefulness of C-reactive protein and left ventricular diastolic performance for prognosis in patients with left ventricular systolic heart failure.

High-sensitivity C-reactive protein (hs-CRP) is a hepatocyte-derived inflammatory cytokine shown to be increased in the setting of acute heart failure (HF), particularly with increased intracardiac filling pressures. In the chronic HF setting, the relation between hs-CRP and echocardiographic indexes of left ventricular (LV) diastolic performance has not been examined. We measured plasma hs-CRP levels using a particle-enhanced immunonephelometry assay (Dade Behring, Inc., Deerfield, Illinois) in 136 subjects with chronic HF (LV ejection fraction [EF]

Impact of myocardial function on cystatin C measurements in chronic systolic heart failure.

BACKGROUND: The influence of myocardial function on plasma levels of cystatin C (CysC), a sensitive marker of renal function, in chronic systolic heart failure (HF) has not been well established. METHODS: We prospectively identified 139 subjects with stable, chronic HF (left ventricular ejection fraction < or = 35%) and measured plasma levels of CysC. We prospectively tracked patients' long-term adverse clinical outcomes (death, cardiac transplantation, and HF hospitalizations). RESULTS: Plasma levels of CysC were elevated in 41% of patients with preserved renal function and directly correlated with N-terminal prohormone brain natriuretic peptide (r = 0.57, P < .0001). There was a significant association between CysC and mitral E/septal E' ratio (r = 0.34, P < .001), right ventricular systolic dysfunction severity (r = 0.30, P < .001), and mitral regurgitation severity (r = 0.31, P < .001), but not left ventricular ejection fraction. At the cutoff of 1.23 mg/dL, CysC remains a significant independent risk factor for adverse clinical outcomes (hazard ratio 1.88, 95% confidence interval 1.15-3.09, P = .012) after adjusting for estimated glomerular filtration rate, left ventricular ejection fraction, and E/septal E'. CONCLUSION: CysC is associated with more advanced left ventricular diastolic dysfunction and right ventricular systolic dysfunction and remains an independent predictor of long-term prognosis in chronic systolic HF after adjusting for myocardial factors.