Spot urinary sodium guided titration of intravenous diuretic therapy in acute heart failure: A pilot randomised controlled trial.

BACKGROUND: Spot urinary sodium concentration (UNa) is advocated in guidelines to assess diuretic response and titrate dosage in acute heart failure (AHF). However, no randomised controlled trial data exists to support this approach. We performed a prospective pilot trial to investigate the feasibility of this approach. METHODS: 60 patients with AHF (n = 30 in each arm) were randomly assigned to titration of loop diuretics for the first 48 hours of admission according to UNa levels (intervention arm) or based on clinical signs and symptoms of congestion (standard care arm). Diuretic insufficiency was defined as UNa < 50 mmol/L. Endpoints relating to diuretic efficacy, safety and AHF outcomes were evaluated. RESULTS: UNa-guided therapy patients experienced less acute kidney injury (20% vs 50%, p = 0.01) and a tendency towards less hypokalaemia (serum K+<3.5 mmol, 7% vs 27%, p = 0.04), with greater weight loss (3.3 kg vs 2.1 kg, p = 0.01). They reported a greater reduction in the clinical congestion score (-4.7 vs -2.6, p < 0.01) and were more likely to report marked symptom improvement (40% vs 13.3%, p = 0.04) at 48 hours. There was no difference in the length of hospital stay (median LOS: 8 days in both groups, p = 0.98), 30-day mortality or readmission rate. CONCLUSION: UNa-guided titration of diuretic therapy in AHF is feasible and safer than titration based on clinical signs and symptoms of congestion, with more effective decongestion at 48 hours. Further large-scale trials are needed to determine if the superiority of this approach translates into improved patient outcomes.

Contemporary management of acute heart failure in the emergency department and the potential impact of early diuretic therapy on outcomes.

OBJECTIVE: Acute heart failure (AHF) is one of the most common conditions presenting to the ED and patients often require hospitalisation. Emerging evidence suggests early diagnosis and administration of diuretics are associated with improved patient outcomes. Currently, there is limited literature on the management of AHF in the Australian ED context. METHODS: A retrospective review of consecutive AHF presentations to the ED in a metropolitan hospital. Patient demographics, clinical status and management were assessed including timeliness of diuretics administration and association with outcomes including ED length of stay (LOS) and inpatient mortality using linear regression. RESULTS: One hundred and ninety-one presentations (median age 81 years, 50.8% male) were identified. Common cardiovascular comorbidities were prevalent. Fifty-four patients (28.3%) had ≥1 clinical high-risk feature at presentation. The median time from presentation to furosemide administration was 187 min (interquartile range 97-279 min); only 35 patients received diuretics within 60 min of presentation. Early diuretics was associated with shorter ED LOS (246 min vs 275 min, P = 0.03) and a lower but non-significant inpatient mortality (4.9% vs 6.3%, P = 0.21) and a non-significant increased rate of discharge home from ED (8.6% vs 4.7%, P = 0.15). The likelihood of discharge home was significantly more pronounced in patients receiving early diuretics without clinical high-risk features (16.7% vs 4.3%, P = 0.028). CONCLUSION: Despite symptoms and signs being well recognised at presentation, time to diuretics was relatively long. Early diuretics administration was associated with improved patient outcomes, particularly in clinically more stable patients. Due to the limitations of the study design, results should be interpreted with caution and warrant further research to identify factors that delay timely administration of diuretics.

Prognostic utility of serum NT-proBNP (fragments 1-76aa and 13-71aa) and galectin-3 in predicting death and re-hospitalisation due to cardiovascular events in patients with heart failure.

Patients with heart failure (HF) are at a higher risk of rehospitalisation. In this study, we investigated the prognostic utility of galectin-3 (Gal-3) and NT-proBNP fragments (1-76aa and 13-71aa) as biomarkers to predict outcomes for patients with HF. We collected blood samples from patients with HF (n = 101). Gal-3 and NT-proBNP fragments (1-76aa and 13-71aa) concentrations were measured by immunoassay. Survival analysis and Cox proportional regression models were used to determine the prognostic utility of Gal-3 and NT-proBNP fragments. In patients with increased baseline levels of NT-proBNP1-76 the time to primary endpoint (cardiovascular death or re-hospitalisation) was significantly shorter (p = 0.0058), but not in patient with increased baseline levels of Gal-3 or NTproBNP13-71. Patients with increased levels of NT-proBNP13-71aa at 1 month showed reduced time to the primary endpoint (p = 0.0123). Our findings demonstrated that Gal-3 and NT-proBNP can be used as prognostic biomarkers to stratify patients with HF.

Long-term survival and life expectancy following an acute heart failure hospitalization in Australia and New Zealand.

AIMS: Contemporary long-term survival following a heart failure (HF) hospitalization is uncertain. We evaluated survival up to 10 years after a HF hospitalization using national data from Australia and New Zealand, identified predictors of survival, and estimated the attributable loss in life expectancy. METHODS AND RESULTS: Patients hospitalized with a primary diagnosis of HF from 2008-2017 were identified and all-cause mortality assessed by linking with Death Registries. Flexible parametric survival models were used to estimate survival, predictors of survival and loss in life expectancy. A total of 283 048 patients with HF were included (mean age 78.2 ± 12.3 years, 50.8% male). Of these, 48.3% (48.1-48.5) were surviving by 3 years, 34.1% (33.9-34.3) by 5 years and 17.1% (16.8-17.4) by 10 years (median survival 2.8 years). Survival declined with age with 53.4% of patients aged 18-54 years and 6.2% aged ≥85 years alive by 10 years (adjusted hazard ratio [aHR] for mortality 4.84, 95% confidence interval [CI] 4.65-5.04 for ≥85 years vs. 18-54 years) and was worse in male patients (aHR 1.14, 95% CI 1.13-1.15). Prior HF (aHR 1.20, 95% CI 1.18-1.22), valvular and rheumatic heart disease (aHR 1.11, 95% CI 1.10-1.13) and vascular disease (aHR 1.07, 95% CI 1.04-1.09) were cardiovascular comorbidities most strongly associated with long-term death. Non-cardiovascular comorbidities and geriatric syndromes were common and associated with higher mortality. Compared with the general population, HF was associated with a loss of 7.3 years in life expectancy (or 56.6% of the expected life expectancy) and reached 20.5 years for those aged 18-54 years. CONCLUSION: Less than one in five patients hospitalized for HF were surviving by 10 years with patients experiencing almost 60% loss in life expectancy compared with the general population, highlighting the considerable persisting societal burden of HF. Concerted multidisciplinary efforts are needed to improve post-hospitalization outcomes of HF.

The association between urinary sodium concentration (UNa) and outcomes of acute heart failure: a systematic review and meta-analysis.

AIMS: Urinary sodium concentration (UNa) is a simple test advocated to assess diuretics efficacy and predict outcomes in acute heart failure (AHF). We performed a systematic review and meta-analysis to examine the association of UNa with outcomes of AHF. METHODS AND RESULTS: We searched Embase and Medline for eligible studies that reported the association between UNa and outcomes of urinary output, weight loss, worsening renal function, length of hospital stay, re-hospitalization, worsening heart failure, and all-cause mortality in AHF. Nineteen observational studies out of 1592 screened records were included. For meta-analyses of outcomes, we grouped patients into high vs. low UNa, with most studies defining high UNa as >48-65 mmol/L. In the high UNa group, pooled data showed a higher urinary output (mean difference 502 mL, 95% CI 323-681, P < 0.01), greater weight loss (mean difference 1.6 kg, 95% CI 0.3-2.9, P = 0.01), and a shorter length of stay (mean difference -1.4 days, 95% CI -2.8 to -0.1, P = 0.03). There was no significant difference in worsening kidney function (OR 0.54, 95% CI 0.25-1.16, P = 0.1). Due to the small number of studies, we did not report pooled estimates for re-hospitalization and worsening heart failure. High UNa was associated with lower odds of 30-day (OR 0.27; 95% CI 0.14-0.49, P < 0.01), 90-day (OR 0.39,95% CI 0.25-0.59, P < 0.01) and 12-month (OR 0.35; 95% CI 0.20-0.61, P < 0.01) mortality. CONCLUSION: High UNa after diuretic administration is associated with higher urinary output, greater weight loss, shorter length of stay, and lower odds of death. UNa is a promising marker of diuretic efficacy in AHF which should be confirmed in randomized trials.

Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (-)-noradrenaline.

Omecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. To assist translation to clinical practice we investigated OMs effect on explanted human failing hearts, specifically; contractile dynamics, interaction with the ß1 -adrenoceptor (AR) agonist (-)-noradrenaline and spontaneous contractions. Left and right ventricular trabeculae from 13 explanted failing hearts, and trabeculae from 58 right atrial appendages of non-failing hearts, were incubated with or without a single concentration of OM for 120 min. Time to peak force (TPF) and 50% relaxation (t50% ) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration-effect curves were established to (-)-noradrenaline at ß1 -ARs in the absence or presence of OM. OM prolonged TPF and t50% in ventricular trabeculae (600 nM, 2 µM, p < .001). OM had no significant inotropic effect but reduced time dependent deterioration in contractile strength compared to control (p < .001). OM did not affect the generation of spontaneous contractions. The potency of (-)-noradrenaline (pEC50 6.05 ± 0.10), for inotropic effect, was unchanged in the presence of OM 600 nM or 2 µM. Co-incubation with (-)-noradrenaline reduced TPF and t50% , reversing the negative diastolic effects of OM. OM, at both 600 nM and 2 µM, preserved contractile force in left ventricular trabeculae, but imparted negative diastolic effects in trabeculae from human failing heart. (-)-Noradrenaline reversed the negative diastolic effects, co-administration may limit the titration of inotropes by reducing the threshold for ischemic side effects.

Heart Transplantation From Brain Dead Donors: A Systematic Review of Animal Models.

Despite advances in mechanical circulatory devices and pharmacologic therapies, heart transplantation (HTx) is the definitive and most effective therapy for an important proportion of qualifying patients with end-stage heart failure. However, the demand for donor hearts significantly outweighs the supply. Hearts are sourced from donors following brain death, which exposes donor hearts to substantial pathophysiological perturbations that can influence heart transplant success and recipient survival. Although significant advances in recipient selection, donor and HTx recipient management, immunosuppression, and pretransplant mechanical circulatory support have been achieved, primary graft dysfunction after cardiac transplantation continues to be an important cause of morbidity and mortality. Animal models, when appropriate, can guide/inform medical practice, and fill gaps in knowledge that are unattainable in clinical settings. Consequently, we performed a systematic review of existing animal models that incorporate donor brain death and subsequent HTx and assessed studies for scientific rigor and clinical relevance. Following literature screening via the U.S National Library of Medicine bibliographic database (MEDLINE) and Embase, 29 studies were assessed. Analysis of included studies identified marked heterogeneity in animal models of donor brain death coupled to HTx, with few research groups worldwide identified as utilizing these models. General reporting of important determinants of heart transplant success was mixed, and assessment of posttransplant cardiac function was limited to an invasive technique (pressure-volume analysis), which is limitedly applied in clinical settings. This review highlights translational challenges between available animal models and clinical heart transplant settings that are potentially hindering advancement of this field of investigation.

The potential prognostic utility of salivary galectin-3 concentrations in heart failure.

BACKGROUND: Patients with HF are at a higher risk of rehospitalisation and, as such, significant costs to our healthcare system. A non-invasive method to collect body fluids and measure Gal-3 could improve the current management of HF. In this study, we investigated the potential prognostic utility of salivary Galectin-3 (Gal-3) in patients with heart failure (HF). METHODS: We collected saliva samples from patients with HF (n = 105) either at hospital discharge or during routine clinical visits. Gal-3 concentrations in saliva samples were measured by ELISA. The Kaplan-Meier survival curve analysis and Cox proportional regression model were used to determine the potential prognostic utility of salivary Gal-3 concentrations. RESULTS: The primary end point was either cardiovascular death or hospitalisation. Salivary Gal-3 concentrations were significantly higher (p < 0.05) in patients with HF who subsequently experienced the primary endpoint compared to those who did not. HF patients with salivary Gal-3 concentrations > 172.58 ng/mL had a significantly (p < 0.05) higher cumulative risk of the primary endpoint compared to those with lower salivary Gal-3 concentrations. In patients with HF, salivary Gal-3 concentration was a predictor of the primary endpoint even after adjusting for other covariates. CONCLUSIONS: In our pilot study, HF patients with salivary Gal-3 concentrations of > 172.58 ng/mL demonstrated a higher cumulative risk of the primary outcome compared to those with lower Gal-3 levels, even after adjusting for other variables. Confirming our findings in a larger multi-centre clinical trial in the future would enable salivary Gal-3 measurements to form part of routine management for patients with HF.

Correction to: The potential prognostic utility of salivary galectin-3 concentrations in heart failure.

The original version of this article unfortunately contained a mistake.

Reliability of thermodilution derived cardiac output with different operator characteristics.

Cardiac output (CO) is commonly measured using the thermodilution technique at the time of right heart catheterisation (RHC). However inter-operator variability, and the operator characteristics which may influence that, has not been quantified. Therefore, this study aimed to assess inter-operator variability with the thermodilution technique using a mock circulation loop (MCL) with calibrated flow sensors. Participants were blinded and asked to determine 4 levels of CO using the thermodilution technique, which was compared with the MCL calibrated flow sensors. The MCL was used to randomly generate CO between 3.0 and 7.0 L/min through changes in heart rate, contractility and vascular resistance with a RHC inserted through the MCL pulmonary artery. Participant characteristics including gender, specialty, age, height, weight, body-mass index, grip strength and RHC experience were recorded and compared to determine their relationship with CO measurement accuracy. In total, there were 15 participants, made up of consultant cardiologists (6), advanced trainees in cardiology (5) and intensive care consultants (4). The majority (9) had performed 26-100 previous RHCs, while 4 had performed more than 100 RHCs. Compared to the MCL-measured CO, participants overestimated CO using the thermodilution technique with a mean difference of +0.75 ± 0.71 L/min. The overall r2 value for actual vs measured CO was 0.85. The difference between MCL and thermodilution derived CO declined significantly with increasing RHC experience (P < 0.001), increasing body mass index (P < 0.001) and decreasing grip strength (P = 0.033). This study demonstrated that the thermodilution technique is a reasonable method to determine CO, and that operator experience was the only participant characteristic related to CO measurement accuracy. Our results suggest that adequate exposure to, and training in, the thermodilution technique is required for clinicians who perform RHC.

Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.

We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.

Christchurch experience of pulmonary embolism with and without thrombolysis.

AIMS: Thrombolysis for normotensive patients with large clot burden pulmonary embolism remains debatable. We aim to document our current management of pulmonary embolism, examining determinants of therapy and outcomes. METHOD: A retrospective chart-based review of all patients admitted with pulmonary embolism under Cardiology service in Christchurch Hospital between 2002-2007. All related CT pulmonary angiograms were also reviewed for quantification of clot burden and evidence of right ventricular strain. RESULTS: 120 patients were admitted during the audit period. Hypotensive patients had a significantly higher troponin level and Qanadli scores. RV/LV ratio >1 in CTPA was 80% sensitive and 57% specific in predicting RV strain on echocardiogram. Forty-six patients were thrombolysed, most with large clot burden and right ventricular strain. No treatment related death or intracranial haemorrhages occurred; however six patients required blood transfusion and six patients had persistent pulmonary hypertension at 6 months. There was a higher in-patient event rate in thrombolysed group, due to increased bleeding, compared to non-thrombolysed patients. CONCLUSION: Thrombolysis was successfully performed with relatively low in-patient and 6-month event rate. Long term advantage over routine anticoagulation was not demonstrated. The role of thrombolysis in normotensive patients with large clot burden remains uncertain. CTPA markers of RV strain correlated well with echocardiography.