Michael R. Zile

BACKGROUND: Among 508 patients randomized to interatrial shunt implantation versus a placebo procedure in the RELIEVE-HF trial (Reducing Lung Congestion Symptoms Using the V-Wave Shunt in Advanced Heart Failure), 2-year clinical outcomes were improved in heart failure with reduced ejection fraction (HFrEF, n=206) and worsened in heart failure with preserved ejection fraction (HFpEF, n=302). However, randomized trials typically include therapeutic responders and nonresponders. We sought to determine the independent predictors of outcomes and model individual patient risk after atrial shunt implantation in HFrEF and HFpEF. METHODS: The primary outcome included all-cause death, cardiac transplantation or left ventricular assist device implantation, heart failure hospitalizations, and outpatient worsening heart failure events. From 37 baseline clinical, laboratory, echocardiographic, and hemodynamic covariates, the cumulative mean function of recurrent events during follow-up was modeled by the Lin-Wei-Yang-Ying method. RESULTS: Among control patients with HFrEF, independent baseline predictors of outcomes were atrial fibrillation, elevated troponin, lower left ventricular ejection fraction, and greater right atrial pressure. In contrast, independent predictors of outcomes in shunt-treated patients with HFrEF were lower systolic blood pressure and elevated right ventricular end-diastolic area index, pulmonary artery pressure, and pulmonary vascular resistance. Among control patients with HFpEF, independent predictors of outcomes were diabetes, higher heart rate and left ventricular end-systolic volume, and lower right ventricular fractional area change. Conversely, independent predictors in shunt-treated patients with HFpEF were hypertension, smoking, lower 6-minute walk distance, reduced estimated glomerular filtration rate, elevated troponin, and moderate or greater tricuspid regurgitation. Risk modeling estimated that 67.2% of patients with HFrEF might benefit from shunt placement compared with 21.4% of patients with HFpEF. CONCLUSIONS: In RELIEVE-HF, distinct baseline risk factors influenced cardiovascular outcomes before and after atrial shunt treatment in HFrEF and HFpEF. Despite markedly different group responses to atrial shunt treatment in the randomized HFrEF and HFpEF strata, given individual differences in patient risk factor profiles, most but not all patients with HFrEF may benefit, and some patients with HFpEF may also improve after shunt treatment. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03499236.

Aims: Target-dose angiotensin-converting enzyme inhibitors (ACEIs), compared with below-target doses, have been associated with lower risks of death and kidney failure (KF) in patients with heart failure with reduced ejection fraction (HFrEF). We examined these associations in heart failure with preserved ejection fraction (HFpEF). Methods: Among 96 473 Veterans with HFpEF (EF ≥50%) newly initiated on ACEIs (2000–2018), 32 728 received target doses recommended for HFrEF. Propensity scores for receiving target-dose ACEIs were used to assemble a matched cohort of 61 160 patients (target-dose, n = 30 580) while the investigators remained blinded to outcomes. The matched cohort was balanced on 76 baseline characteristics. Outcomes were 5-year all-cause mortality, incident KF, and HF hospitalization. Results: Compared with below-target-dose ACEIs, target-dose ACEIs were associated with a lower KF risk (HR, 0.89; 95% CI, 0.83–0.97), no mortality difference (HR, 0.99; 95% CI, 0.97–1.02), and a higher risk of HF hospitalization (HR, 1.08; 95% CI, 1.04–1.12). Among 16 735 patients with chronic kidney disease (CKD; eGFR 15–59 ml/min/1.73 m2), target-dose ACEIs were associated with a lower risk of KF (HR, 0.82; 95% CI, 0.75–0.90) and mortality (HR, 0.93; 95% CI, 0.89–0.96) without a higher HF hospitalization risk (HR, 0.95; 95% CI, 0.90–1.01). Each association differed significantly from those in patients with eGFR ≥60 ml/min/1.73 m2 (interaction P < .001). Conclusion: In HFpEF, target-dose ACEIs were associated with a lower risk of KF, a higher risk of HF hospitalization, and no association with mortality. These associations were consistently more favourable in the subgroup with CKD. These findings underscore the importance of evaluating treatment strategies within biologically coherent HFpEF phenotypes.

BACKGROUND: While clinical benefits of guideline-directed medical therapy in patients with heart failure (HF) are well established, acute hemodynamic changes after initiation of these agents are not well described. Wireless pulmonary artery pressure (PAP) monitoring using implantable sensors is ideally suited to determine changes in pressure following medication titration. METHODS: We compared PAP from 7 days pre-initiation to the 7-day period following 30 days of newly initiated treatment with core HF therapies: angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, sodium-glucose co-transporter-2 inhibitors, and β-blockers in patients implanted with a PAP sensor (CardioMEMS, Abbott) as part of the GUIDE-HF study (Hemodynamic-Guided Management of HF). Patients with changes in loop diuretics or other core HF therapies during the 30-day interval were excluded from the analysis. RESULTS: Of 2358 patients in the study, 50 patients had new angiotensin receptor-neprilysin inhibitor initiation, 97 patients had new sodium-glucose co-transporter-2 inhibitor initiation, 112 patients had new mineralocorticoid receptor antagonist initiation, and 33 had new β-blocker initiation at least 30 days post-implant, continued to take the medication for at least 30 days, and were included in this analysis. Following angiotensin receptor-neprilysin inhibitor or mineralocorticoid receptor antagonist initiation, diastolic PAP decreased by −1.56 (95% CI, −3.54 to −0.40) and −1.15 (95% CI, −1.82 to −0.47) mm Hg, respectively, in the absence of changes in loop diuretics or other core HF therapies. By contrast, there was no detectable change in PAP following the new initiation of the sodium-glucose co-transporter-2 inhibitor. A trend to higher PAP was observed after β-blocker initiation though differences were not significant. CONCLUSIONS: These results may inform the selection of pharmacological therapy to manage elevated filling pressures during hemodynamic-guided therapy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03387813.

Aims: Myocardial inflammation has been proposed as a central mechanism in heart failure with preserved ejection fraction (HFpEF), supported by experimental work suggesting immune cell-mediated activation of pro-fibrotic signalling. However, bulk transcriptomic analyses of human HFpEF myocardium did not demonstrate an activation of pro-inflammatory mediators or pathways. Here we investigated whether immune cell enrichment is present in human HFpEF myocardium. Methods: We analysed left ventricular (LV) epicardial biopsies from 28 adults undergoing elective coronary artery bypass grafting with preserved LV ejection fraction (≥50%). Participants were classified as referent controls (n = 10), preclinical HFpEF Stage B (n = 10), or overt HFpEF Stage C (n = 8). High-resolution spatial transcriptomics and quantitative immunofluorescence for CD45, CD68, and CD3G were used to determine the abundance and phenotypic composition of immune lineage cells. Results: Heart failure with preserved ejection fraction patients were older and more obese when compared to control subjects. Spatial transcriptomic profiling revealed normal immune cell abundances across all groups (mean 0.68 ± 0.52% in controls, 0.90 ± 0.49% in HFpEF Stage B, and 0.78 ± 0.29% in HFpEF Stage C; P = NS), without differences in immune cell subsets or adaptive immune cell signatures. Immunofluorescence confirmed the absence of differences. Conclusions: Spatially resolved human myocardial profiling did not demonstrate an increase in immune lineage cells in preclinical or overt HFpEF, challenging the concept that myocardial immune cell infiltration is a major driver of HFpEF. These findings support a model in which haemodynamic load and systemic factors, rather than local immune cell expansion, drive myocardial hypertrophy and fibrosis in HFpEF.

Aims: While elevated heart rate is an established marker of risk in HF, the prognostic relevance of heart rate is less certain in patients with comorbid atrial fibrillation/flutter (AFF). We investigated the associations between heart rate and outcomes according to AFF status in 5 HFmrEF/HFpEF clinical trials. Methods: In a participant-level pooled analysis of the CHARM-Preserved, I-PRESERVE, TOPCAT-Americas, PARAGON-HF, and DELIVER trials, associations between baseline heart rate and outcomes according to AFF status on ECG at enrolment were assessed with multivariable Cox and Poisson regression models. The primary outcome was CV death or HF hospitalization. Results: Among 19 975 participants, 5816 (29%) had AFF on baseline ECG. Patients with AFF were older, more frequently male, had a higher baseline heart rate (75 vs 68 bpm, P < .001), and had an increased risk for the primary outcome (adj HR 1.19 [1.10–1.27]). A significant interaction between heart rate, AFF status, and clinical outcomes was observed, such that patients in sinus rhythm had higher event rates with increasing heart rates, while the incident rates for participants in AFF were similar across the range of baseline heart rate (Pinteraction < .001 for the primary outcome). This relationship was not further modified by concomitant β-blocker use. Conclusions: In this analysis of five HFmrEF/HFpEF trials, baseline heart rate was associated with significantly higher rates of events only in patients in sinus rhythm but not in those with AFF. The optimal management of AFF in the context of HFmrEF/HFpEF requires a dedicated study.

BACKGROUND: Patient-reported outcomes are increasingly used as end points in clinical trials. However, the magnitude of observed changes in control arms attributable to placebo effects, as compared with other benefits of trial participation, has not been described. This study seeks to estimate the magnitude of the placebo effect by calculating changes in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores, which quantify the impact of heart failure on patients’ symptoms, function, and quality of life, after participants were unblinded to treatment. METHODS: REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II) randomized participants to atrial shunt or sham procedure, with unblinding after 2 years. The KCCQ was collected at baseline, 2, and 3 years after randomization. KCCQ-OS change from baseline to 2 years (placebo effect plus other benefits from trial participation) and the change from 2 to 3 years (placebo effect loss after unblinding) were calculated in sham-treated patients using mean±SD, as were changes from 2 to 3 years in shunt-treated patients (placebo effect benefit). RESULTS: The analytic cohort included 421 participants (median age, 72 years; 65.6% female). Among sham-treated participants (N=182), the mean±SD KCCQ-OS 2-year improvement from baseline was +9.3±22.4 points, with a decrement after unblinding of −1.7±18.2 points from 2 to 3 years. Among shunt-treated patients (N=239), mean±SD KCCQ-OS 2-year improvement was +12.7±22.8 points, with an improvement after unblinding of +1.9±18.2 points. In a hypothetical unblinded trial where placebo effect benefit would be expected in the active intervention arm, and none in the untreated arm, the combined effects would be 3.6 points. CONCLUSIONS: In a sham-controlled device trial that collected patient-reported outcome data during blinded allocation to treatment or sham and after unblinding, the estimated mean placebo effect benefit and loss on the KCCQ-OS were small (≤2 points). Finding a modest placebo effect on patient-reported outcomes may increase confidence in their use as clinical trial outcomes.

The RELIEVE-HF trial randomized 508 patients with heart failure (HF) to interatrial shunt-treatment vs placebo-procedure. Randomization was stratified into 2 patient groups with HF with reduced ejection fraction (HFrEF;LVEF≤40%) and HF with preserved EF (HFpEF;LVEF>40%). HF event rates (all-cause death, transplantation/LVAD, HF hospitalization/outpatient worsening) after shunt treatment during 2-year follow-up were directionally opposite: decreased by 51% in HFrEF, increased by 69% in HFpEF. To examine differences in cardiac structure and function before and after interatrial shunt placement in patients with HFrEF vs HFpEF that might underlie these discordant clinical outcomes. Serial changes from baseline to 12 months in 17 transthoracic echocardiographic parameters in shunt-treated vs control patients in HFrEF vs HFpEF were assessed and compared by ANCOVA. In shunt-treated vs control patients with HFrEF, there were reductions in median LV end-diastolic (-11.9[-21.3, -2.5]ml/m²,p=0.01) and LV end-systolic (-8.9[-17.2, -20.7]ml/m²,p=0.01) volumes indicative of reverse LV remodeling. There were no significant changes in right ventricular(RV), right atrial(RA), or inferior vena cava(IVC) sizes, or pulmonary artery systolic pressure (PASP). In contrast, shunt-treated vs control patients with HFpEF did not have LV remodeling, but had increased RV, RA, and IVC dimensions, and PASP increased (4.7[0.9, 8.5]mmHg,p=0.02). LV and RV diastolic compliance were decreased in HFpEF vs HFrEF at baseline and decreased further after shunt-treatment in HFpEF. Differential changes in left and right heart remodeling and PASP following interatrial shunt placement in patients with HFrEF vs HFpEF provide a mechanistic basis for the variable effects on clinical outcomes observed in RELIEVE-HF. Clinical Trial.gov Identifier: NCT03499236.