Borlaug, Barry A.

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.

Respiratory muscle dysfunction is thought to contribute to exercise intolerance in heart failure with preserved ejection fraction (HFpEF); however, the underlying mechanisms are unknown. In the present study, patients with HFpEF had greater increases in leg muscle vascular resistance index and greater decreases in leg muscle blood flow index compared with controls during inspiratory resistive breathing (to activate the metaboreflex). Furthermore, respiratory muscle blood flow index responses normalized to pressure generation during inspiratory resistive breathing were exaggerated in HFpEF compared with controls.

Abstract Aims Despite their universal predisposition, diagnosing diastolic dysfunction in patients post-Fontan palliation is challenging. Our aim was to compare exercise haemodynamics between adults post-Fontan and patients with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnoea (NCD). Methods and results Twenty-four adults (age ≥18 years) post-Fontan palliation with resting and exercise pulmonary artery wedge pressure (PAWP) measured during supine biking were identified. Forty-eight patients with HFpEF and 48 with NCD diagnosed at catheterization were selected for comparison. Mean age for Fontan patients was 30.3 ± 7.5 years; median ventricular ejection fraction was 52.5% (45–55.8), being &lt;50% in 37.5%. Resting PAWP among Fontan patients was 10.2 ± 3.5 mmHg (&gt;12 mmHg in 25%); PAWP was lower in Fontan patients than in HFpEF but higher than NCD. During exercise, PAWP was lower in the Fontan group than HFpEF (22.5 mmHg [19.3–28] vs. 28.2 ± 6.3; p = 0.0006) but higher than NCD (11.2 ± 4.2, p ≤ 0.0001). However, there were no differences in ΔPAWP/ΔQs between Fontan and HFpEF patients (4.0 [2.1–7.3] vs. 2.7 [1.6–4.4]; p = 0.10) with the ratio being higher post-Fontan than in NCD (0.6 [0.2–1.2]; p &lt; 0.0001). ΔPAWP/ΔQs remained similar between HFpEF and Fontan patients even when those with ejection fraction &lt;50% were excluded (2.7 [1.6–4.4] vs. 2.7 [1.0–5.8]; p = 0.97). Conclusion There were no differences in ΔPAWP/ΔQs ratios between post-Fontan and HFpEF patients, supporting markedly abnormal single ventricle compliance despite lower resting and exercise PAWP. Therefore, exercise invasive haemodynamics may represent a novel tool for the diagnosis of diastolic dysfunction in Fontan patients.

ImportanceTransthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP.ObjectiveTo derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF.Design, Setting, and ParticipantsRetrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation.Main Outcomes and MeasuresPerformance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials.ResultsParticipant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48% ), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6% ), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range −1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P &amp;lt; .001) and calibration (Hosmer-Lemeshow; χ2 = 4.6; P = .46) were strong. Discrimination (AUC ≥ 0.84; P &amp;lt; .001 for all) and calibration (Hosmer-Lemeshow χ2 = 2.8; P = .84; Hosmer-Lemeshow χ2 = 4.4; P = .35; Hosmer-Lemeshow χ2 = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score.Conclusions and RelevanceA simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community. Further validation in larger and more diverse populations is needed.