Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult. METHODS: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts. RESULTS: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD+/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice. CONCLUSIONS: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

Coronary artery bypass grafting vs. percutaneous coronary intervention in severe ischaemic cardiomyopathy: long-term survival.

BACKGROUND AND AIMS: The optimal revascularization strategy in patients with ischaemic cardiomyopathy remains unclear with no contemporary randomized trial data to guide clinical practice. This study aims to assess long-term survival in patients with severe ischaemic cardiomyopathy revascularized by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). METHODS: Using the Australian and New Zealand Society of Cardiac and Thoracic Surgeons and Melbourne Interventional Group registries (from January 2005 to 2018), patients with severe ischaemic cardiomyopathy [left ventricular ejection fraction (LVEF) <35%] undergoing PCI or isolated CABG were included in the analysis. Those with ST-elevation myocardial infarction and cardiogenic shock were excluded. The primary outcome was long-term National Death Index-linked mortality up to 10 years following revascularization. Risk adjustment was performed to estimate the average treatment effect using propensity score analysis with inverse probability of treatment weighting (IPTW). RESULTS: A total of 2042 patients were included, of whom 1451 patients were treated by CABG and 591 by PCI. Inverse probability of treatment weighting-adjusted demographics, procedural indication, coronary artery disease extent, and LVEF were well balanced between the two patient groups. After risk adjustment, patients treated by CABG compared with those treated by PCI experienced reduced long-term mortality [adjusted hazard ratio 0.59, 95% confidence interval (CI) 0.45-0.79, P = .001] over a median follow-up period of 4.0 (inter-quartile range 2.2-6.8) years. There was no difference between the groups in terms of in-hospital mortality [adjusted odds ratio (aOR) 1.42, 95% CI 0.41-4.96, P = .58], but there was an increased risk of peri-procedural stroke (aOR 19.6, 95% CI 4.21-91.6, P < .001) and increased length of hospital stay (exponentiated coefficient 3.58, 95% CI 3.00-4.28, P < .001) in patients treated with CABG. CONCLUSIONS: In this multi-centre IPTW analysis, patients with severe ischaemic cardiomyopathy undergoing revascularization by CABG rather than PCI showed improved long-term survival. However, future randomized controlled trials are needed to confirm the effect of any such benefits.

Long term safety and outcomes after atrial shunting for heart failure with preserved or mildly reduced ejection fraction: 5-year and 3-year follow-up in the REDUCE LAP-HF I and II trials.

BACKGROUND: There is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF). METHODS: The REDUCE LAP-HF I (n = 44) and II (n = 621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n = 313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up. RESULTS: At 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P = .006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P = .005; and greater improvement in KCCQ overall summary score [+17.9 ± 20.0 vs. +7.6 ± 20.4], P < .001), while nonresponders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2%-6.1%, P = .032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, P = .041). CONCLUSIONS: With up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up. GOV REGISTRATION: NCT02600234, NCT03088033.

Association between temperature and air pollutants with atrial fibrillation presentations to emergency departments.

INTRODUCTION: Understanding the impact of environmental exposures on disease incidence is important for environmental guidelines, health services management, and advising patients. We aimed to assess the relationship between daily mean temperature and common pollutants with atrial fibrillation (AF) presentations to emergency departments (EDs). METHODS: The study included consecutive adult patients presenting with AF to EDs from 1/1/2014 to 31/12/2020 with linkage to hospital and emergency discharge diagnosis data. A time series quasi-Poisson regression with a distributed lag nonlinear model was fitted to assess the association between AF with mean air temperature and five common pollutants, overall and according to sex and region, with adjustment for season, day of the week, long-term trend, and co-pollutants. RESULTS: In 82 575 AF presentations to EDs during the study period, mean (standard deviations [SD]) (SD) age was 69.6 (SD 14.7) years and 50.7% were female. AF presentations were associated with elevated levels of Particulate Matter (PM) 2.5 (≥57.7 µg/m3) and nitrous dioxide (NO2) (≥16.5 parts per billion), but not mean air temperature or other pollutants (carbon monoxide, sulphur dioxide, or ozone). The attributable fraction of AF presentations relating to above optimal NO2 and PM 2.5 levels was 7.24% and 3.81% resulting in 854 and 450 annual excess AF presentations, respectively. CONCLUSIONS: High levels of NO2 and PM 2.5 are associated with increased risk of AF presentations to EDs. These findings have important implications for environmental policies and advice to patients susceptible to AF presentations to EDs, especially in regions with higher baseline levels of PM 2.5 or NO2.

Reversible cerebral vasoconstriction syndrome post-cardiac transplantation: a therapeutic dilemma: case report.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by diffuse, multifocal segmental narrowing of cerebral arteries and can result in ischaemic stroke. Causal factors, identified in 60% of cases, include immunosuppressant pharmacotherapy. The few reports following heart transplantation are almost all in Asian recipients. We report on a Caucasian Australian patient with immunotherapy induced RCVS post heart transplantation to highlight the state of knowledge of the condition and the treatment dilemma it poses. CASE PRESENTATION: A 51-year-old female underwent orthotopic heart transplantation at our institution. Induction immunotherapy comprised basiliximab, mycophenolate mofetil and methylprednisolone. On day 6 post-transplantation the patient was transitioned to oral prednisolone and tacrolimus. On day 7 the patient began to experience bilateral, severe, transient occipital and temporal headaches. On day 9 tacrolimus dose was up-titrated. A non-contrast computed tomography brain (CTB) was normal. Endomyocardial biopsy on day 12 demonstrated moderate Acute Cellular Rejection (ACR), which was treated with intravenous methylprednisolone. That evening the patient experienced a 15-minute episode of expressive dysphasia. The following morning she became confused, aphasic, and demonstrated right sided neglect and right hemianopia. A CT cerebral perfusion scan demonstrated hypoperfusion in the left middle cerebral artery (MCA) territory and cerebral angiography revealed widespread, focal multi-segmental narrowing of the anterior and posterior circulations. A diagnosis of RCVS was made, and nimodipine was commenced. As both steroids and tacrolimus are potential triggers of RCVS, cyclosporin replaced tacrolimus and methylprednisolone dose was reduced. A further CTB demonstrated a large left MCA territory infarct with left M2 MCA occlusion. The patient made steady neurological improvement. She was discharged 34 days post-transplantation with mild residual right lower limb weakness and persistent visual field defect on verapamil, cyclosporine, everolimus, mycophenolate mofetil and prednisolone. CONCLUSION: Reversible cerebral vasoconstriction syndrome is rare after orthotopic heart transplantation. Until now, RCVS has been almost exclusively described in Asian recipients, and is typically caused by immunotherapy. The condition may lead to permanent neurological deficits, and in the absence of definitive treatments, early recognition and imaging based diagnosis is essential to provide the opportunity to remove the causal agent(s). Co-existent ACR, can pose unique treatment difficulties.

HeartMate 3 implantation with an emphasis on the biventricular configuration.

OBJECTIVES: Right ventricular failure following implantation of a durable left ventricular assist device (LVAD) is a major driver of mortality. Reported survival following biventricular (BiVAD) or total artificial heart (TAH) implantation remains substantially inferior to LVAD alone. We report our outcomes with LVAD and BiVAD HeartMate 3 (HM3). METHODS: Consecutive patients undergoing implantation of an HM3 LVAD between November 2014 and December 2021, at The Alfred, Australia were included in the study. Comparison was made between the BiVAD and LVAD alone groups. RESULTS: A total of 86 patients, 65 patients with LVAD alone and 21 in a BiVAD configuration underwent implantation. The median age of the LVAD and BiVAD groups was 56 years (Interquartile range 46-62) and 49 years (Interquartile range 37-55), respectively. By 4 years after implantation, 54% of LVAD patients and 43% of BiVAD patients had undergone cardiac transplantation. The incidence of stroke in the entire experience was 3.5% and pump thrombosis 5% (all in the RVAD). There were 14 deaths in the LVAD group and 1 in the BiVAD group. The actuarial survival for LVAD patients at 1 year was 85% and BiVAD patients at 1 year was 95%. CONCLUSIONS: The application of HM 3 BiVAD support in selected patients appears to offer a satisfactory solution to patients requiring biventricular support.

Current surgical management of chronic thromboembolic pulmonary disease.

Chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) is an important potential consequence of venous thromboembolic disease. Untreated CTEPD with pulmonary hypertension (CTEPH) is associated with high rates of morbidity and mortality. Several treatment options are now available for patients with CTEPD and CTEPH, including pulmonary endarterectomy (PEA), balloon pulmonary angioplasty, medical therapy or a combination of therapies. Choice of treatment depends on the location of the thromboembolic disease burden, presence and severity of PH and patient factors, including frailty, parenchymal lung disease and other comorbidities. PEA is a complex surgery that can result in excellent outcomes and resolution of disease, but also comes with the risk of serious perioperative complications. This manuscript examines the history of PEA and its place in Australasia, and reports on outcomes from the main Australasian CTEPH expert centre. It provides a summary of up-to-date guidance on how PEA should be utilised in the overall management of these patients and describes opportunities and challenges for the future diagnosis and management of this disease, particularly in the Australasian setting.

New-onset atrial fibrillation prediction: the HARMS2-AF risk score.

AIMS: Lifestyle risk factors are a modifiable target in atrial fibrillation (AF) management. The relative contribution of individual lifestyle risk factors to AF development has not been described. Development and validation of an AF lifestyle risk score to identify individuals at risk of AF in the general population are the aims of the study. METHODS AND RESULTS: The UK Biobank (UKB) and Framingham Heart Study (FHS) are large prospective cohorts with outcomes measured >10 years. Incident AF was based on International Classification of Diseases version 10 coding. Prior AF was excluded. Cox proportional hazards regression identified independent AF predictors, which were evaluated in a multivariable model. A weighted score was developed in the UKB and externally validated in the FHS. Kaplan-Meier estimates ascertained the risk of AF development. Among 314 280 UKB participants, AF incidence was 5.7%, with median time to AF 7.6 years (interquartile range 4.5-10.2). Hypertension, age, body mass index, male sex, sleep apnoea, smoking, and alcohol were predictive variables (all P < 0.001); physical inactivity [hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.96-1.05, P = 0.80] and diabetes (HR 1.03, 95% CI 0.97-1.09, P = 0·38) were not significant. The HARMS2-AF score had similar predictive performance [area under the curve (AUC) 0.782] to the unweighted model (AUC 0.802) in the UKB. External validation in the FHS (AF incidence 6.0% of 7171 participants) demonstrated an AUC of 0.757 (95% CI 0.735-0.779). A higher HARMS2-AF score (≥5 points) was associated with a heightened AF risk (score 5-9: HR 12.79; score 10-14: HR 38.70). The HARMS2-AF risk model outperformed the Framingham-AF (AUC 0.568) and ARIC (AUC 0.713) risk models (both P < 0.001) and was comparable to the CHARGE-AF risk score (AUC 0.754, P = 0.73). CONCLUSION: The HARMS2-AF score is a novel lifestyle risk score which may help identify individuals at risk of AF in the general community and assist population screening.

The Impact of Diabetes on Haemodynamic and Cardiometabolic Responses in Heart Failure With Preserved Ejection Fraction.

AIMS: Heart failure with preserved ejection (HFpEF) and diabetes mellitus (DM) commonly co-exist. However, it is unclear if DM modifies the haemodynamic and cardiometabolic phenotype in patients with HFpEF. We aimed to interrogate the haemodynamic and cardiometabolic effects of DM in HFpEF. METHODS: We compared the haemodynamic and metabolic profiles of non-DM patients and patients with DM-HFpEF at rest and during exercise using right heart catheterisation and mixed venous blood gas analysis. RESULTS: Of 181 patients with HFpEF, 37 (20%) had DM. Patients with DM displayed a more adverse exercise haemodynamic response vs HFpEF alone (mean pulmonary arterial pressure: 47 mmHg [interquartile range {IQR} 42-55] vs 42 [38-47], p<0.001; workload indexed pulmonary capillary wedge pressure indexed: 0.80 mmHg/W [0.44-1.23] vs 0.57 [0.43-1.01], p=0.047). HFpEF-DM patients had a lower mixed venous oxygen saturation at rest (70% [IQR 66-73] vs 72 [69-75], p=0.003) and were unable to enhance O2 extraction to the same extent (Δ-28% [-33 to -15] vs -29 [-36 to -21], p=0.029), this occurred at a 22% lower median workload. Resting mixed venous lactate levels were higher in those with DM (1.5 mmol/L [IQR 1.1-1.9] vs 1 [0.9-1.3], p<0.001), and during exercise indexed to workload (0.09 mmol/L/W [0.06-0.13] vs 0.08 [0.05-0.11], p=0.018). CONCLUSION: Concurrent diabetes and HFpEF was associated with greater metabolic responses at rest, with enhanced wedge driven pulmonary hypertension and relative lactataemia during exercise without appropriate augmentation of oxygen consumption.

Comparison of Characteristics and Outcomes in Patients With Acute Decompensated Heart Failure Admitted Under General Medicine and Cardiology Units.

BACKGROUND: Acute decompensated heart failure (ADHF) is a leading cause of cardiovascular disease hospitalisations associated with significant morbidity and mortality. In hospitals, HF patients are typically managed by cardiology or physician teams, with differences in patient demographics and clinical outcomes. This study utilises contemporary HF registry data to compare patient characteristics and outcomes in those with ADHF admitted into General Medicine and Cardiology units. METHODS: The Victorian Cardiac Outcomes Registry was utilised to identify patients hospitalised with ADHF 30-day period in each of four consecutive years. We compared patient characteristics, pharmacological management and outpatient follow-up of patients admitted to General Medicine and Cardiology units. Primary outcome measures included in-hospital mortality, 30-day readmission, and 30-day mortality. RESULTS: Between 2014 and 2017, a total of 1,253 patients with ADHF admissions were registered, with 53% admitted in General Medicine units and 47% in Cardiology units. General Medicine patients were more likely to be older (82 vs 71 years; p<0.001), female (51% vs 34%; p<0.001), and have higher prevalence of comorbidities and preserved left ventricular function (p<0.001). There were no differences in primary outcome measures between General Medicine and Cardiology in terms of: in-hospital mortality (5.0% vs 3.9%; p=0.35), 30-day readmission (23.4% vs 23.6%; p=0.93), and 30-day mortality (10.0% vs 8.0%; p=0.21). CONCLUSIONS: Hospitalised patients with HF continue to have high mortality and rehospitalisation rates. The choice of treatment by General Medicine or Cardiology units, based on the particular medical profile and individual needs of the patients, provides equivalent outcomes.

The Role of Comorbidities in Predicting Functional Improvement After Transcatheter Aortic Valve Implantation.

BACKGROUND: Patients undergoing transcatheter aortic valve implantation (TAVI) have a high comorbidity burden. We sought to stratify patients into functional outcomes using the Kansas City Cardiomyopathy Questionnaire (KCCQ-12), a patient-reported outcome with benefits over both the New York Heart Association (NYHA) classification and the original 23-item KCCQ, and to evaluate the importance of comorbidities in predicting failure of functional improvement post-TAVI in a contemporary cohort. METHODS: In total, 366 patients with severe aortic stenosis undergoing TAVI with baseline KCCQ-12 were retrospectively analysed and divided into two groups. Failure to improve was defined as a score <60 and a change in score <10 at 1 year in either overall score (KCCQ-OS) or clinical summary score (KCCQ-CSS). RESULTS: Failure to improve was noted in 13% of patients, who were more likely to have lower KCCQ-OS at baseline (47 [35-59] vs 56 [42-74]), chronic obstructive pulmonary disease (COPD) (19% vs 8%), severe chronic kidney disease (CKD) (13% vs 2%), a clinical frailty score (CFS) ≥5 (41% vs 14%), and lower serum albumin (36 g/L [34-38] vs 38 g/L [35-40]). On multivariate analysis, with an area under the curve of 0.71 (0.63-0.78), baseline KCCQ-OS (adjusted odds ratio [aOR] 0.3 [0.1-0.6], p=0.04), COPD (aOR 2.8 [1.2-6.5], p=0.02), and severe CKD (aOR 5.7 [1.7-18.5], p=0.004) remained independent predictors. CFS alone had a similar predictive value as the multivariable model (OR 2.0 [1.3-3.4], area under the curve 0.69 [0.59-0.80], p<0.001). CONCLUSIONS: KCCQ scores were effective in delineating functional outcomes, with most patients in our relatively lower surgical risk cohort showing significant functional improvements post-TAVI. Low baseline KCCQ, moderate or worse COPD, and severe CKD were associated with failure of improvement post-TAVI. Baseline CFS appears to be a good screening tool to predict poor improvement. These factors should be evaluated and weighted accordingly in pre-TAVI assessments and decision-making.

Effect of COVID-19 Pandemic Lockdown on Emergency Medical Service Utilisation, and Percutaneous Coronary Intervention Volume-An Australian Perspective.

BACKGROUND: Acute coronary syndrome (ACS) admissions and percutaneous coronary intervention (PCI) volume declined during periods of COVID-19 lockdown internationally in 2020. The effect of lockdown on emergency medical service (EMS) utilisation, and PCI volume during the initial phase of the pandemic in Australia has not been well described. METHOD: We analysed data from the Victorian Cardiac Outcomes Registry (VCOR), a state-wide PCI registry, linked with the Ambulance Victoria EMS registry. PCI volume, 30-day major adverse cardiovascular and cerebrovascular events (MACCE; composite of mortality, myocardial infarction, stent thrombosis, unplanned revascularisation, and stroke), and EMS utilisation were compared over four time periods: lockdown (26 Mar 2020-12 May 2020); pre-lockdown (26 Feb 2020-25 Mar 2020); post-lockdown (13 May 2020-10 Jul 2020); and the year prior (26 Mar 2019-12 May 2019). Interrupted time series analysis was performed to assess PCI trends within and between consecutive periods. RESULTS: The EMS utilisation for ACS during lockdown was higher compared with other periods: lockdown 39.4% vs pre-lockdown 29.7%; vs post-lockdown 33.6%; vs year prior 27.1%; all p<0.01. Median daily PCI cases were similar: 31 (IQR 10, 38) during lockdown; 39 (15, 49) pre-lockdown; 39.5 (11, 44) post-lockdown; and, 42 (10, 49) the year prior; all p>0.05. Median door-to-procedure time for ACS indication during lockdown was shorter at 3 hours (1.2, 20.6) vs pre-lockdown 3.9 (1.7, 21); vs post-lockdown 3.5 (1.5, 21.26); and, the year prior 3.5 (1.5, 23.7); all p<0.05. Lockdown period was associated with lower odds for 30-day MACCE compared to pre-lockdown (odds ratio [OR] 0.55 [0.33-0.93]; p=0.026); post-lockdown (OR 0.66; [0.40-1.06]; p=0.087); and the year prior (OR 0.55 [0.33-0.93]; p=0.026). CONCLUSIONS: Contrary to international trends, EMS utilisation for ACS increased during lockdown but PCI volumes remained similar throughout the initial stages of the pandemic in Victoria, with no observed adverse effect on 30-day MACCE during lockdown. These data suggest that the public health response in Victoria was not associated with poorer quality cardiovascular care in patients receiving PCI.

Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.

BACKGROUND: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. METHODS: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. RESULTS: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004). CONCLUSIONS: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial.

BACKGROUND: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. METHODS: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033. FINDINGS: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (pinteraction=0·012 [≥29·7 mL/m2, worse outcomes]), and sex (pinteraction=0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11). INTERPRETATION: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. FUNDING: Corvia Medical.

Alcohol Abstinence in Drinkers with Atrial Fibrillation.

BACKGROUND: Excessive alcohol consumption is associated with incident atrial fibrillation and adverse atrial remodeling; however, the effect of abstinence from alcohol on secondary prevention of atrial fibrillation is unclear. METHODS: We conducted a multicenter, prospective, open-label, randomized, controlled trial at six hospitals in Australia. Adults who consumed 10 or more standard drinks (with 1 standard drink containing approximately 12 g of pure alcohol) per week and who had paroxysmal or persistent atrial fibrillation in sinus rhythm at baseline were randomly assigned in a 1:1 ratio to either abstain from alcohol or continue their usual alcohol consumption. The two primary end points were freedom from recurrence of atrial fibrillation (after a 2-week "blanking period") and total atrial fibrillation burden (proportion of time in atrial fibrillation) during 6 months of follow-up. RESULTS: Of 140 patients who underwent randomization (85% men; mean [±SD] age, 62±9 years), 70 were assigned to the abstinence group and 70 to the control group. Patients in the abstinence group reduced their alcohol intake from 16.8±7.7 to 2.1±3.7 standard drinks per week (a reduction of 87.5%), and patients in the control group reduced their alcohol intake from 16.4±6.9 to 13.2±6.5 drinks per week (a reduction of 19.5%). After a 2-week blanking period, atrial fibrillation recurred in 37 of 70 patients (53%) in the abstinence group and in 51 of 70 patients (73%) in the control group. The abstinence group had a longer period before recurrence of atrial fibrillation than the control group (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; P = 0.005). The atrial fibrillation burden over 6 months of follow-up was significantly lower in the abstinence group than in the control group (median percentage of time in atrial fibrillation, 0.5% [interquartile range, 0.0 to 3.0] vs. 1.2% [interquartile range, 0.0 to 10.3]; P = 0.01). CONCLUSIONS: Abstinence from alcohol reduced arrhythmia recurrences in regular drinkers with atrial fibrillation. (Funded by the Government of Victoria Operational Infrastructure Support Program and others; Australian New Zealand Clinical Trials Registry number, ACTRN12616000256471.).

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy.

BACKGROUND: Circulating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect. METHODS AND RESULTS: High-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14-1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed. CONCLUSIONS: hs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

Device therapy with interatrial shunt devices for heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction is responsible for half of all heart failure and confers substantial morbidity and mortality, and yet to date, there have been no effective pharmacologic interventions. Although the pathophysiology is complex, the primary aetiology of exercise intolerance is due to an elevated left atrial pressure, particularly with exercise. In this context, device-based therapy has become a focus. Several companies have developed techniques to percutaneously create an iatrogenic left to right shunt at the atrial level, thereby reducing left atrial pressure and reducing transmitted pressures to the pulmonary circulation and reducing pulmonary congestion. In this review, we explore the pathophysiology, evidence base, benefits, and considerations of these devices and their place in the therapeutic landscape of heart failure with preserved ejection fraction.

Incidence and severity of cytomegalovirus infection in seropositive heart transplant recipients.

BACKGROUND: The frequency and significance of cytomegalovirus (CMV) infection in seropositive (R+) heart transplant recipients (HTR) is unclear, with preventative recommendations mostly extrapolated from other groups. We evaluated the incidence and severity of CMV infection in R+ HTR, to identify risk factors and describe outcomes. METHODS: R+ HTR from 2010 to 2019 were included. Antiviral prophylaxis was not routinely used, with clinically guided monitoring the local standard of care. The primary outcome was CMV infection within one-year post-transplant; secondary outcomes included other herpesvirus infections and mortality. RESULTS: CMV infection occurred in 27/155 (17%) R+ HTR. Patients with CMV had a longer hospitalization (27 vs. 20 days, unadjusted HR 1.02, 95% CI 1.00-1.02, p = .01), higher rate of intensive care readmission (26% vs. 9%, unadjusted HR 3.46, 1.46-8.20, p = .005), and increased mortality (33% vs. 8%, unadjusted HR 10.60, 4.52-24.88, p < .001). The association between CMV and death persisted after adjusting for multiple confounders (HR 24.19, 95% CI 7.47-78.30, p < .001). Valganciclovir prophylaxis was used in 35/155 (23%) and was protective against CMV (infection rate 4% vs. 27%, adjusted HR .07, .01-.72, p = .025), even though those receiving it were more likely to have received thymoglobulin (adjusted OR 10.5, 95% CI 2.01-55.0, p = .005). CONCLUSIONS: CMV infection is common in R+ HTR and is associated with a high burden of disease and increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection, despite being at higher risk. These findings support the routine use of antiviral prophylaxis following heart transplantation in all CMV R+ patients.

Towards practice change: a qualitative study examining the impact of a Child Psychiatric Access Program (Project TEACH) on Primary Care Provider practices in New York State during pandemic times.

BACKGROUND: This study aims to explore the perceived impact of Project TEACH (Training and Education for the Advancement of Children's Health), a New York State Office of Mental Health funded Child Psychiatric Access Program (CPAP), on pediatric Primary Care Providers (PCPs) and their practice. Practice change over time was assessed in the context of rising mental health needs and in the context of COVID19 pandemic. METHODS: Focus groups utilizing a semi-structured format were conducted with pediatric PCPs who have been high utilizers of Project TEACH over the past 5-10 years and PCPs in similar regions who have been low or non-utilizers of the program. The semi-structured interview focused on practice change, asking about pediatric mental health, practice setting and flow, professional development, and changes over time in the context of COVID-19 pandemic and Project TEACH. RESULTS: Themes identified include increasing confidence of PCPs, particularly those who are high utilizers of the phone consultation line, increased routine use of screening and comfort bridging pediatric patients with mental health needs. Challenges include rising mental health needs, inadequate mental health services, difficulties with family follow through and high emotional burden on PCPs caring for these patients. In this context, participants noted that collaboration with Project TEACH provided needed emotional support. CONCLUSIONS: Integrated care and CPAPs such as Project TEACH are vital to helping PCPs handle rising mental health needs particularly in current crisis times. Ongoing systemic challenges accessing care remain and contribute to emotional burden placed on pediatric PCPs.

Healthcare cost burden of acute chest pain presentations.

BACKGROUND: This study aimed to estimate the direct healthcare cost burden of acute chest pain attendances presenting to ambulance in Victoria, Australia, and to identify key cost drivers especially among low-risk patients. METHODS: State-wide population-based cohort study of consecutive adult patients attended by ambulance for acute chest pain with individual linkage to emergency and hospital admission data in Victoria, Australia (1 January 2015-30 June 2019). Direct healthcare costs, adjusted for inflation to 2020-2021 ($A), were estimated for each component of care using a casemix funding method. RESULTS: From 241 627 ambulance attendances for chest pain during the study period, mean chest pain episode cost was $6284, and total annual costs were estimated at $337.4 million ($68 per capita per annum). Total annual costs increased across the period ($310.5 million in 2015 vs $384.5 million in 2019), while mean episode costs remained stable. Cardiovascular conditions (25% of presentations) were the most expensive (mean $11 523, total annual $148.7 million), while a non-specific pain diagnosis (49% of presentations) was the least expensive (mean $3836, total annual $93.4 million). Patients classified as being at low risk of myocardial infarction, mortality or hospital admission (Early Chest pain Admission, Myocardial infarction, and Mortality (ECAMM) score) represented 31%-57% of the cohort, with total annual costs estimated at $60.6 million-$135.4 million, depending on the score cut-off used. CONCLUSIONS: Total annual costs for acute chest pain presentations are increasing, and a significant proportion of the cost burden relates to low-risk patients and non-specific pain. These data highlight the need to improve the cost-efficiency of chest pain care pathways.