Early Discharge to Clinic-Based Therapy of Patients Presenting With Decompensated Heart Failure (EDICT-HF): Study Protocol for a Multi-Centre Randomised Controlled Trial.

BACKGROUND: Acute decompensated heart failure involves a high rate of mortality and complications. Management typically involves a multi-day hospital admission. However, patients often lose part of their function with each successive admission, and are at a high risk for hospital-associated complications such as nosocomial infection. This study aims to determine the safety and efficacy of the management of patients presenting with acute decompensated heart failure to clinic-based therapy vs usual inpatient care using a reproducible management pathway. METHOD: An investigator-initiated, prospective, non-inferiority, 1:1 randomised-controlled trial, stratified by left ventricular ejection fraction including 460 patients with a minimum follow-up of 7 days. This is a multi-centre study to be performed in centres across Victoria, Australia. Participants will be patients with either heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), admitted for acute decompensation of heart failure. INTERVENTION: Early discharge to an outpatient-based Heart Failure Rapid Access Clinical Review (RACER) in addition to frequent medical/nursing at-home review for patients admitted with decompensated heart failure. RESULTS: The primary endpoint will be a non-inferiority assessment of re-hospitalisation at 30 days. Secondary outcomes include superiority assessment of hospitalisation at 30 days, a composite clinical endpoint of major adverse cardiac and cerebrovascular event (MACCE), hospital re-admission or mortality at 3 months, achievement of guideline-directed medical therapy, patient assessment of symptoms (visual-analogue scale quantified as area under curve and Kansas City Cardiomyopathy Questionnaire-12 [KCCQ-12]), attendance at 3-month outpatient follow-up, number of bed stays/clinics attended, proportion of patients free from congestion, change in serum creatinine level, treatment for electrolyte disturbances, time to transition from intravenous to oral diuretics, and health economics analysis (cost-benefit analysis, cost-utility analysis, incremental cost-effectiveness ratio). CONCLUSIONS: The Early Discharge to Clinic-Based Therapy of Patients Presenting with Decompensated Heart Failure (EDICT-HF) trial will help determine whether earlier discharge to out-of-hospital care is non-inferior to the usual practice of inpatient care, in patients with heart failure admitted to hospital for acute decompensation, as an alternative model of care.

Effect of Age on Clinical Outcomes in Elderly Patients (>80 Years) Undergoing Percutaneous Coronary Intervention: Insights From a Multi-Centre Australian PCI Registry.

OBJECTIVES: To evaluate the effect of age in an all-comers population undergoing percutaneous coronary intervention (PCI). BACKGROUND: Age is an important consideration in determining appropriateness for invasive cardiac assessment and perceived clinical outcomes. METHODS: We analysed data from 29,012 consecutive patients undergoing PCI in the Melbourne Interventional Group (MIG) registry between 2005 and 2017. 25,730 patients <80 year old (78% male, mean age 62±10 years; non-elderly cohort) were compared to 3,282 patients ≥80 year old (61% male, mean age 84±3 years; elderly cohort). RESULTS: The elderly cohort had greater prevalence of hypertension, diabetes and previous myocardial infarction (all p<0.001). Elderly patients were more likely to present with acute coronary syndromes, left ventricular ejection fraction <45% and chronic kidney disease (p<0.0001). In-hospital, 30-day and long-term all-cause mortality (over a median of 3.6 and 5.1 years for elderly and non-elderly cohorts, respectively) were higher in the elderly cohort (5.2% vs. 1.9%; 6.4% vs. 2.2%; and 43% vs. 14% respectively, all p<0.0001). In multivariate Cox regression analysis, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (HR 3.8, 95% CI: 3.4-4.3), cardiogenic shock (HR 3.0, 95% CI: 2.6-3.4), ejection fraction <30% (HR 2.5, 95% CI: 2.1-2.9); and age ≥80 years (HR 2.8, 95% CI: 2.6-3.1) were independent predictors of long-term all-cause mortality (all p<0.0001). CONCLUSION: The elderly cohort is a high-risk group of patients with increasing age being associated with poorer long-term mortality. Age, thus, should be an important consideration when individualising treatment in elderly patients.

Reduction in mortality from implantable cardioverter-defibrillators in non-ischaemic cardiomyopathy patients is dependent on the presence of left ventricular scar.

Aims: In patients with non-ischaemic cardiomyopathy (NICM), the mortality benefit of a primary prevention implantable cardioverter-defibrillator (ICD) has been challenged. Left ventricular (LV) scar identified by cardiac magnetic resonance (CMR) imaging is associated with a high risk of malignant arrhythmia in NICM. We aimed to determine the impact of LV scar on the mortality benefit from a primary prevention ICD in NICM. Methods and results: We recruited 452 consecutive heart failure patients [New York Heart Association (NYHA) Class II/III] with NICM and LV ejection fraction ≤35% from a state-wide CMR service. All patients fulfilled European Society of Cardiology guidelines for primary prevention ICD implantation; however, the decision to implant was at the treating physician's discretion. Baseline clinical and CMR data were recorded prospectively and heart failure mortality risk (MAGGIC score) was calculated. The primary study outcome measurement was all-cause mortality based on presence or absence of ICD, stratified by LV scar. Median follow-up was 37.9 months and there was no difference in MAGGIC score between those who did and did not receive a primary prevention ICD (19.30 ± 5.46 vs. 18.90 ± 5.67, P = 0.50). In patients without LV scar, ICD implantation was not associated with improved mortality [hazard ratio (HR) = 1.22, 95% confidence interval (CI): 0.53-2.78, P = 0.64]. In patients with LV scar, ICD implantation was independently associated with reduced mortality (HR = 0.45, 95% CI: 0.26-0.77, P = 0.003). Conclusions: In patients with NICM, primary prevention ICD implantation is only associated with reduced mortality in patients with LV scar. This may enable more effective selection of NICM patients for ICD implantation compared with current guidelines.

Assessing atrial myopathy with cardiac magnetic resonance imaging in embolic stroke of undetermined source.

BACKGROUND: Left atrial myopathy has been implicated in atrial fibrillation (AF)-related stroke and embolic stroke of undetermined source (ESUS). OBJECTIVE: To use advanced cardiac magnetic resonance (CMR) imaging techniques, including left atrial (LA) strain and 4D flow CMR, to identify atrial myopathy in patients with ESUS. METHODS: 20 patients with ESUS and no AF or other cause for stroke, and 20 age and sex-matched controls underwent CMR with 4D flow analysis. Markers of LA myopathy were assessed including LA size, volume, ejection fraction, and strain. 4D flow CMR was performed to measure novel markers of LA stasis such as LA velocities and the LA residence time distribution time constant (RTDtc). These markers of LA myopathy were compared between the two groups. RESULTS: There was no significant difference in: CMR-calculated LA velocities or LA total, passive or active ejection fractions between the groups. There was no significant difference in CMR-derived reservoir, conduit or contractile average longitudinal strain between the ESUS and control groups (22.9 vs 22.6%, p=0.379, 11.2 ± 3.5 vs 12.4 ± 2.6% p=0.224, 10.8 ± 3.2 vs 10.4 ± 2.3%, p=0.625 respectively). Similarly, RTDtc was not significantly longer in ESUS patients compared to controls (1.3 ± 0.2 vs 1.2 ± 0.2, p=0.1). CONCLUSIONS: There were no significant differences in any CMR marker of atrial myopathy in ESUS patients compared to healthy controls, likely reflecting the multiple possible aetiologies of ESUS suggesting that the role LA myopathy plays in ESUS is smaller than previously thought.

Differentiating Nonischemic Dilated Cardiomyopathy With Incidental Infarction From Ischemic Cardiomyopathy by Geometric Indices Derived From Cardiovascular Magnetic Resonance.

PURPOSE: The purpose of this study was to differentiate nonischemic dilated cardiomyopathy with incidental myocardial infarction (NICM with incidental MI) from ischemic cardiomyopathy (ICM) by integrating left ventricular (LV) geometric indices and ischemic late gadolinium enhancement (LGE), obtained from cardiac magnetic resonance (CMR) imaging. MATERIALS AND METHODS: All subjects were studied on a 1.5 Tesla magnetic resonance imaging scanner. All patients had an LV ejection fraction (LVEF) <50% with LV dilation. LV end-diastolic volume (LVEDV), LVEDV index (LVEDVi), LVEF, the number and distribution of ischemic LGE segments, and ratios of volumetric and functional indices to ischemic LGE segments were determined. Logistic regression was used to detect the independent predictor of ICM. Receiver operating characteristic analysis differentiated NICM with incidental MI from ICM. RESULTS: Of a total of 63 patients enrolled, 45 patients had ICM, and 18 patients had NICM with incidental MI. Both groups had similar LVEF. Compared with ICM, NICM with incidental MI had more LV dilation, whereas ICM had more ischemic LGE segments. A higher number of ischamic LGE segments remained an independent predictor of ICM (odds ratio: 18.2, 95% confidence interval: 1.64-201.34, P=0.018). The optimal cut-off value for detecting NICM with incidental MI is the ratio of LVEDVi to the number of ischemic LGE segments over 25 mL/m2/segment (sensitivity 100%, specificity 91%, P<0.0001). CONCLUSION: Patients with NICM with incidental MI can be reliably distinguished from ICM using the ratio of LVEDVi divided by the number of ischemic LGE segments. This technique may improve diagnosis and help aid management of patients with cardiomyopathy and coexistent coronary artery disease.

Measuring atrial stasis during sinus rhythm in patients with paroxysmal atrial fibrillation using 4 Dimensional flow imaging: 4D flow imaging of atrial stasis.

BACKGROUND: Paroxysmal atrial fibrillation (PAF) is associated with cardioembolic risk, however events may occur during sinus rhythm (SR). 4D-flow cardiac magnetic resonance (CMR) imaging allows visualisation of left atrial blood flow, to determine the residence time distribution (RTD), an assessment of atrial transit time. OBJECTIVE: To determine if atrial transit time is prolonged in PAF patients during SR, consistent with underlying atrial stasis. METHOD: 91 participants with PAF and 18 healthy volunteers underwent 4D flow analysis in SR. Velocity fields were produced RTDs, calculated by seeding virtual 'particles' at the right upper pulmonary vein and counting them exiting the mitral valve. An exponential decay curve quantified residence time of particles in the left atrium, and atrial stasis was expressed as the derived constant (RTDTC) based on heartbeats. The RTDTC was evaluated within the PAF group, and compared to healthy volunteers. RESULTS: Patients with PAF (n = 91) had higher RTDTC compared with gender-matched controls (n = 18) consistent with greater atrial stasis (1.68 ±â€¯0.46 beats vs 1.51 ±â€¯0.20 beats; p = .005). PAF patients with greater thromboembolic risk had greater atrial stasis (median RTDTC of 1.72 beats in CHA2DS2-VASc≥2 vs 1.52 beats in CHA2DS2-VASc<2; p = .03), only female gender and left ventricular ejection fraction contributed significantly to the atrial RTDTC (p = .006 and p = .023 respectively). CONCLUSIONS: Atrial stasis quantified by 4D flow is greater in PAF, correlating with higher CHA2DS2-VASc scores. Female gender and systolic dysfunction are associated with atrial stasis. RTD offers an insight into atrial flow that may be developed to provide a personalised assessment of thromboembolic risk.

Impact of sex, socio-economic status, and remoteness on therapy and survival in heart failure.

AIMS: This study aims to determine if traditional markers of disadvantage [female sex, low socio-economic status (SES), and remoteness] are associated with lower prescription of evidence-based therapy and higher mortality among patients with moderate-severe heart failure with reduced ejection fraction. METHODS AND RESULTS: We recruited 452 consecutive class II-III heart failure with reduced ejection fraction patients. Baseline clinical data were recorded prospectively. The primary outcome was the association of female sex on overall survival. Secondary outcomes included association between evidence-based therapy delivery and sex and association of SES and remoteness on heart failure therapy and survival. The Australian Bureau of Statistics generated all indices. Median follow-up was 37.9 months. One hundred and nine patients (24.3%) were women. There was no difference in overall survival based on sex (hazard ratio = 1.19, 95% confidence interval: 0.74-1.92, 0.48). There was no difference in prescription of beta-blockers [χ2 (1) = 0.91, 0.66], angiotensin-converting enzyme inhibitors [χ2 (1) = 0.001, 0.97], nor aldosterone antagonists [χ2 (1) = 2.71, 0.10]. There was no difference in rates of primary prevention implantable cardioverter-defibrillator implantation in men compared with women [χ2 (1) = 0.35, 0.56]. Neither higher SES nor inner city residence conferred an overall survival benefit. CONCLUSIONS: In this Australian cohort of heart failure patients, delivery of care and likelihood of death are comparable between the sexes, SES groups, and rural vs. city residents.

The ventricular residence time distribution derived from 4D flow particle tracing: a novel marker of myocardial dysfunction.

4D flow cardiac magnetic resonance (CMR) imaging allows visualisation of blood flow in the cardiac chambers and great vessels. Post processing of the flow data allows determination of the residence time distribution (RTD), a novel means of assessing ventricular function, potentially providing additional information beyond ejection fraction. We evaluated the RTD measurement of efficiency of left and right ventricular (LV and RV) blood flow. 16 volunteers and 16 patients with systolic dysfunction (LVEF < 50%) underwent CMR studies including 4D flow. The RTDs were created computationally by seeding virtual 'particles' at the inlet plane in customised post-processing software, moving these particles with the measured blood velocity, recording and counting how many exited per unit of time. The efficiency of ventricular flow was determined from the RTDs based on the time constant (RTDc = - 1/B) of the exponential decay. The RTDc was compared to ejection fraction, T1 mapping and global longitudinal strain (GLS). There was a significant difference between groups in LV RTDc (healthy volunteers 1.2 ± 0.13 vs systolic dysfunction 2.2 ± 0.80, p < 0.001, C-statistic = 1.0) and RV RTDc (1.5 ± 0.15 vs 2.0 ± 0.57, p = 0.013, C-statistic = 0.799). The LV RTDc correlated significantly with LVEF (R = - 0.84, P < 0.001) and the RV RTDc had significant correlation with RVEF (R = - 0.402, p = 0.008). The correlation between LV RTDc and LVEF was similar to GLS and LVEF (0.926, p < 0.001). The ventricular residence time correlates with ejection fraction and can distinguish normal from abnormal systolic function. Further assessment of this method of assessment of chamber function is warranted.

Does the subtype of acute coronary syndrome treated by percutaneous coronary intervention predict long-term clinical outcomes?

Aims: The prognosis of patients undergoing percutaneous coronary intervention (PCI) for different subtypes of acute coronary syndromes (ACS) remains unclear. We compared short- and long-term mortality in patients undergoing PCI for unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). Methods and results: This was a retrospective cohort study of 13 184 patients (5966 STEMI, 5307 NSTEMI, and 1911 UA) undergoing PCI between 1 January 2005 and 30 November 2013 in a multi-centre registry. Clinical and procedural characteristics, as well as outcomes, were compared by ACS subtype. Long-term all-cause mortality data were obtained via linkage to the National Death Index (NDI). Patients with STEMI compared with NSTEMI and UA were younger (62.9 ± 12.8 vs. 64.7 ± 12.5 vs. 65.5 ± 11.8 years; P < 0.01), had fewer comorbidities including diabetes, heart failure, and previous myocardial infarction (all P < 0.01). Procedural success was similar across all groups (P = 0.54). In-hospital, 30-day and 1-year all-cause mortality increased significantly from UA to NSTEMI to STEMI patients (1-year mortality 2.5% vs. 4.5% vs. 8.7%; P < 0.01). Kaplan-Meier survival estimates showed increased early mortality in the STEMI group (log-rank P < 0.01). However, after approximately 8.2 years, survival was similar across all groups. In a proportional-odds model using flexible parametric survival modelling, ACS subtype was not an independent predictor of NDI-linked mortality [UA: odds ratio (OR) 0.85, 95% CI 0.71-1.02; STEMI: OR 1.01, 95% confidence interval (CI) 0.88-1.16; NSTEMI as reference category]. Conclusion: Despite disparate baseline characteristics and differences in short-term mortality, long-term mortality was similar across the spectrum of ACS treated by PCI and contemporary medical therapy.

Long-term clinical outcomes of transient and persistent no-reflow following percutaneous coronary intervention (PCI): a multicentre Australian registry.

AIMS: The aim of the study was to evaluate long-term outcomes of transient versus persistent no-reflow. METHODS AND RESULTS: A total of 17,547 patients with normal flow post percutaneous coronary intervention (PCI) were compared to 590 patients (3.2%) with transient no-reflow and 144 patients (0.8%) with persistent no-reflow. Long-term all-cause mortality was obtained by linkage with the National Death Index (NDI). No-reflow patients were more likely to have presented with ST-elevation myocardial infarction (STEMI), out-of-hospital cardiac arrest (OHCA) or cardiogenic shock (all p<0.01). Long-term NDI-linked all-cause mortality was highest in patients with persistent no-reflow (31%) followed by transient no-reflow (22%) and normal flow (14%) over a median follow-up of 5.2, 5.5 and 4.5 years, respectively (all p<0.0001). Kaplan-Meier survival estimates demonstrated a graded increase in all-cause mortality from normal flow, to transient to persistent no-reflow (p<0.01), with the highest mortality occurring early (<30 days) in the persistent no-reflow group (p<0.0001). Multivariate Cox proportional hazards modelling identified glomerular filtration rate <30 mL/min, ejection fraction <30%, persistent no-reflow and transient no-reflow as independent predictors of increased hazard for all-cause mortality (all p<0.05). CONCLUSIONS: Transient and persistent no-reflow were associated with a stepwise reduction in long-term survival. The presence of even transient no-reflow appears to be an important predictor of adverse long-term outcome.

Expression of human fructose-1,6-bisphosphatase in the liver of transgenic mice results in increased glycerol gluconeogenesis.

In type 2 diabetes, increased endogenous glucose production (EGP) as a result of elevated gluconeogenesis contributes to hyperglycemia. An increase in glycerol gluconeogenesis has led to the suggestion that, in obese human subjects with type 2 diabetes, there may be an increase in the activity of the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBPase). The aim of this study was to generate transgenic mice that overexpress human liver FBPase in the liver and assess the consequences to whole-body and hepatic glucose metabolism. FBPase transgenic mice had significantly higher levels of transgene expression in the liver and, as a result, had increased FBPase protein and enzyme activity levels in the liver. This resulted in an increase in the rate of glycerol conversion to glucose but not in EGP. The increased expression of FBPase in the liver did not result in any significant differences compared with littermate control mice in insulin or glucose tolerance. Therefore, it appears that, on its own, an increase in FBPase does not lead to impaired regulation of EGP and hence does not affect whole-body glucose metabolism. This suggests that, for EGP to be increased, other factors associated with obesity are also required.