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Importance Reduced heart rate during exercise is common and associated with impaired aerobic capacity in heart failure with preserved ejection fraction (HFpEF), but it remains unknown if restoring exertional heart rate through atrial pacing would be beneficial. Objective To determine if implanting and programming a pacemaker for rate-adaptive atrial pacing would improve exercise performance in patients with HFpEF and chronotropic incompetence. Design, Setting, and Participants Single-center, double-blind, randomized, crossover trial testing the effects of rate-adaptive atrial pacing in patients with symptomatic HFpEF and chronotropic incompetence at a tertiary referral center (Mayo Clinic) in Rochester, Minnesota. Patients were recruited between 2014 and 2022 with 16-week follow-up (last date of follow-up, May 9, 2022). Cardiac output during exercise was measured by the acetylene rebreathe technique. Interventions A total of 32 patients were recruited; of these, 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no pacing first for 4 weeks, followed by a 4-week washout period and then crossover for an additional 4 weeks. Main Outcomes and Measures The primary end point was oxygen consumption (V̇ o 2 ) at anaerobic threshold (V̇ o 2,AT ); secondary end points were peak V̇ o 2 , ventilatory efficiency (V̇ e /V̇ co 2 slope), patient-reported health status by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Results Of the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇ o 2 and V̇ o 2 at anaerobic threshold (V̇ o 2,AT ) were both correlated with peak exercise heart rate ( r = 0.46-0.51, P < .02 for both). Pacing increased heart rate during low-level and peak exercise (16/min [95% CI, 10 to 23], P < .001; 14/min [95% CI, 7 to 21], P < .001), but there was no significant change in V̇ o 2,AT (pacing off, 10.4 [SD, 2.9] mL/kg/min; pacing on, 10.7 [SD, 2.6] mL/kg/min; absolute difference, 0.3 [95% CI, −0.5 to 1.0] mL/kg/min; P = .46), peak V̇ o 2 , minute ventilation (V̇ e) /carbon dioxide production (V̇ co 2 ) slope, KCCQ-OSS, or NT-proBNP level. Despite the increase in heart rate, atrial pacing had no significant effect on cardiac output with exercise, owing to a decrease in stroke volume (−24 mL [95% CI, −43 to −5 mL]; P = .02). Adverse events judged to be related to the pacemaker device were observed in 6 of 29 participants (21%). Conclusions and Relevance In patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events. Trial Registration ClinicalTrials.gov Identifier: NCT02145351

ABSTRACT Aims Elevated left atrial (LA) pressure is a pathophysiologic hallmark of heart failure with preserved ejection fraction (HFpEF). Chronically elevated LA pressure leads to LA enlargement, which may impair LA function and increase pulmonary pressures. We sought to evaluate the relationship between LA volume and pulmonary arterial haemodynamics in patients with HFpEF. Methods and results Data from 85 patients (aged 69 ± 8 years) who underwent exercise right heart catheterization and echocardiography were retrospectively analysed. All had symptoms of heart failure, left ventricular ejection fraction ≥50% and haemodynamic features of HFpEF. Patients were divided into LA volume index-based tertiles (≤34 ml/m2, >34 to ≤45 ml/m2, >45 ml/m2). A subgroup analysis was performed in patients with recorded LA global reservoir strain (n = 60), with reduced strain defined as ≤24%. Age, sex, body surface area and left ventricular ejection fraction were similar between volume groups. LA volume was associated with blunted increases in cardiac output with exercise (padjusted <0.001), higher resting mean pulmonary artery pressure (padjusted = 0.003), with similar wedge pressure (padjusted = 1). Pulmonary vascular resistance (PVR) increased with increasing LA volume (padjusted <0.001). Larger LA volumes featured reduced LA strain (padjusted <0.001), with reduced strain associated with reduced PVR–compliance time (0.34 [0.28–0.40] vs. 0.38 [0.33–0.43], p = 0.03). Conclusion Increasing LA volume may be associated with more advanced pulmonary vascular disease in HFpEF, featuring higher PVR and pulmonary pressures. Reduced LA function, worse at increasing LA volumes, is associated with a disrupted PVR–compliance relationship, further augmenting impaired pulmonary haemodynamics.

Background: Improvement in renal function (IRF) in acute decompensated heart failure is associated with adverse outcomes. The mechanisms driving this paradox remain undefined. Methods: Using the ROSE-AHF study (Renal Optimization Strategies Evaluation–Acute Heart Failure), 277 patients were grouped according to renal function, with IRF defined by a ≥20% increase (N=75), worsening renal function by a ≥20% decline (N=53), and stable renal function (SRF) by a <20% change (N=149) in estimated glomerular filtration rate between baseline and 72 hours. Three well-validated renal tubular injury markers, NGAL (neutrophil gelatinase-associated lipocalin), NAG (N-acetyl-β-d-glucosaminidase), and KIM-1 (kidney injury molecule 1), were evaluated at baseline and 72 hours. Patients were also classified by the pattern of change in these markers. Results: Patients with IRF had the lowest admission estimated glomerular filtration rate (IRF, 37 [28 to 51] mL/min per 1.73 m 2 ; worsening renal function, 43 [35 to 55] mL/min per 1.73 m 2 ; and SRF, 43 [32 to 55] mL/min per 1.73 m 2 ; P trend =0.032) but greater cumulative urine output (IRF, 8780 [7025 to 11 208] mL; worsening renal function, 7860 [5555 to 9765] mL; and SRF, 8150 [6325 to 10 456] mL; P trend =0.024) and weight loss (IRF, –9.0 [–12.4 to –5.3] lb; worsening renal function, –5.1 [–8.1 to –1.3] lb; and SRF, –7.1 [–11.9 to –3.2] lb; P trend <0.001) despite similar diuretic doses ( P trend =0.16). There were no differences in the relative change in NGAL, NAG, or KIM-1 between renal function groups ( P trend >0.19 for all). Patients with IRF had worse survival than patients with SRF (27% versus 54%; hazard ratio, 1.98 [1.10–3.58]; P =0.024). Conclusions: IRF during decongestive therapy for acute decompensated heart failure was not associated with improved markers of renal tubular injury and was associated with worsened survival, likely driven by the presence of greater underlying cardiorenal dysfunction and more severe congestion.

Abstract Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarizes methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilizing phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimize the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF.

Abstract Aims Little data are available regarding prognostic implications of invasive exercise testing in heart failure with preserved ejection fraction (HFpEF). The present study aimed to investigate whether rest and exercise central haemodynamic abnormalities are associated with adverse clinical outcomes in patients with dyspnea. Methods and results Patients with exertional dyspnoea and ejection fraction ≥50% (n = 764) underwent invasive exercise testing and follow-up for heart failure hospitalization or death. There were 117 patients with events over a median follow-up of 2.7 (interquartile range 0.5–4.6) years. Among patients with normal resting pulmonary artery wedge pressure (PAWP) (&lt;15 mmHg, n = 380 [50%]), increased exercise PAWP (≥25 mmHg) was present in 187 (24% of cohort) and was associated with 2.4-fold higher risk of events compared to those with normal exercise PAWP (&lt;25 mmHg, n = 193 [25%]) (hazard ratio [HR] 2.44; 95% confidence interval [CI] 1.11–5.36; p = 0.03), while patients with elevated resting PAWP (≥15 mmHg, n = 384 [50%]) displayed even higher risk compared to HFpEF with normal resting PAWP (HR 2.24; 95% CI 1.38–3.65; p = 0.001). Similar findings were observed for rest/exercise right atrial pressure, and rest/exercise pulmonary artery pressures. Higher peak oxygen consumption was associated with decreased risk of events, and this relationship was solely explained by exercise cardiac output. In a multivariable-adjusted Cox model, each 1 standard deviation (SD) increase in exercise PAWP was associated with a 41% greater hazard of events (HR 1.41; 95% CI 1.13–1.76; p = 0.002), while each 1 SD decrease in exercise cardiac output was associated with a 37% increased risk (HR 0.63; 95% CI 0.47–0.83; p = 0.001). Conclusions Haemodynamic abnormalities currently used for diagnosis of HFpEF are associated with increased risk for adverse events. Treatments that reduce central pressures while improving cardiac output reserve may offer greatest benefit to improve outcomes in HFpEF.

Abstract Introduction Cardiac geometry is affected by body composition, with total body adipose volume being related to left ventricular (LV) dilatation (due to increased intravascular volume and cardiac output), and visceral adipose tissue (VAT) to smaller LV cavity size and concentric remodelling (because of insulin resistance) [1]. As such we hypothesised that changes in VAT and total body weight during weight loss would have a differential impact on cardiac geometry. Alongside this, we hypothesised that, as the pericardium is a fixed volume, changes in epicardial adipose tissue (EAT), may have an additional mechanical effect by reducing pericardial restraint. Purpose We sought to investigate long term changes in VAT, total weight and EAT following bariatric surgery and relate them to changes in cardiac geometry. Methods Forty patients underwent cardiac magnetic resonance (CMR) imaging before and after bariatric surgery, including 21 who underwent short-term (median 209 days), 28 medium-term (median 428 days) and 12 long-term (median 1030 days) imaging follow up. Cardiac volumes (left atrial (LA), LV end-diastolic volume (LVEDV) and stroke volume (LVSV)) were assessed using cardiac MRI. VAT was assessed at L5 using a T1 weighted, water suppressed sequence. EAT volumes were calculated by manual contouring in end-ventricular systole on short axis slices from the mitral valve to the apex. Percentage changes in volumes were calculated between scans for each individual. Results Patients on average lost 32kg within the first 428 days following bariatric surgery (54% excess weight loss, p&lt;0.0001), with no significant change in weight at the longer-term time point (Figure 1A). Most VAT loss occurred in the first 209 days (−42%, p&lt;0.0001) with no subsequent change observed at the final two timepoints (Figure 1B). Similarly, EAT loss occurred in the first 209 days (−13%, mean 10ml, p&lt;0.0001) with non-significant changes thereafter (Figure 1C). There was a significant decrease in both LA (13%, mean 12ml, p&lt;0.0001) and LVEDV (4%, mean 8ml, p=0.0249) at 209 days post-surgery. Both LA volume and LVEDV had returned to baseline by the longest term time point of 1030 days (Figure 2). LVSV followed a similar pattern being reduced at 209 days (by 10%, mean 9ml, p=0.0019), then returning to levels similar to those pre-weight loss at 1030 days (p=0.44) (Figure 2C). Conclusions Cardiac volumes show a biphasic response to weight loss, initially becoming smaller and then returning to baseline by 1030 days. We hypothesise that the early drop in LA and LV cavity size is a response to reduced volume from body mass reduction. In contrast, we propose that the increase in LA and LVEDV that follows results from the longer-term effects of reducing VAT, and increased space within the pericardium resulting from EAT loss allowing expansion to occur. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): We acknowledge support from the British Heart Foundation Oxford Center of Research Excellence

Background: The purpose of this study was to assess the relationship between exercise-induced hypertension (EIH) and cardiovascular events, and to determine whether exercise blood pressure (BP) improved risk stratification in adults with repaired coarctation of aorta. Methods: Retrospective study of patients with repaired coarctation of aorta on antihypertensive therapy that underwent exercise testing and exercise test (2003–2019). BP was measured at rest in 3 different clinical settings and averaged to determine the resting BP. Indices of left ventricular function and afterload were obtained from the echocardiogram. EIH was defined as systolic BP >210 (males) or >190 (females) at peak exercise. Cardiovascular event was defined as atrial fibrillation, ventricular tachycardia, heart failure hospitalization, heart transplant, and cardiovascular death. Results: Of 327 patients (age 35±13 years), 116 (35%) had EIH. Although the resting BP was similar between patients with versus without EIH, the EIH group had higher pulsatile arterial load, more advanced left ventricular remodeling, and were less likely to be on angiotensin converting enzyme inhibitor/angiotensin receptor blocker. EIH was associated with cardiovascular events (hazard ratio, 1.06 [95% CI, 1.02–1.08]) independent of resting systolic BP, and improved prognostic accuracy above resting systolic BP ( C statistic, 0.671 [95% CI, 0.645–0.694] to 0.727 [95% CI, 0.709–0.750]; P =0.01). Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker was associated with a lower risk of cardiovascular events. Conclusions: EIH was associated with cardiovascular events independent of resting BP, and patients receiving angiotensin-converting enzyme inhibitor/angiotensin receptor blocker had lower risk of cardiovascular events. These data suggest that exercise BP could be used to assess adequacy of antihypertensive therapy, and to guide titration of antihypertensive therapy.