Borlaug, Barry A.

Abstract Aims There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease. Methods and results Echocardiography represents the primary non-invasive method to phenotype cardiac anatomy, function, and haemodynamics in these complex patients. However, comprehensive right heart evaluation requires the use of multiple echocardiographic parameters and optimized techniques to ensure optimal image acquisition. The PVDOMICS echo protocol outlines the best practice approach to echo phenotypic assessment of the right heart/pulmonary artery unit. Conclusion Novel workflow processes, methods for quality control, data for feasibility of measurements, and reproducibility of right heart parameters derived from this study provide a benchmark frame of reference. Lessons learned from this protocol will serve as a best practice guide for echocardiographic image acquisition and analysis across the spectrum of right heart/pulmonary vascular disease.

Abstract Aims A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO – heart rate and stroke volume – and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses. Methods and results Data from two prospective trials of HFpEF ( n = 108) and a study of healthy participants ( n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39–56% of patients with HFpEF and 3–56% of healthy participants depending on the definition used, but some ( n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m 2 , healthy participants: +24 ± 12 mL/m 2 , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF. Conclusion The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response.

Aims To investigate the prognostic value of diagnostic scores for heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results Consecutive patients with HFpEF admitted for unequivocal decompensated HF treated with intravenous loop diuretics were evaluated ( n = 443; mean age 78 ± 12 years; 60% women). The HFA‐PEFF and H 2 FPEF scores were calculated for all patients with echocardiography data available within 1 year and the population was stratified according to HFA‐PEFF scores 2–4 ( n = 79), 5 ( n = 93), or 6 ( n = 271) and H 2 FPEF score probabilities <90% ( n = 80), 90–95% ( n = 61), and 96–100% ( n = 293). HF readmission rates (95% confidence intervals) increased from 28.9 (22.7–35.0) per 100 patient‐years in HFA‐PEFF 2–4 to 46.0 (38.5–53.5) in HFA‐PEFF 5 and 45.0 (40.1–49.8) in HFA‐PEFF 6. Similarly, HF readmission rates increased with increasing H 2 FPEF probability: <0.90 [31.8 (25.3–38.2) per 100 patient‐years], 0.90–0.95 [41.5 (32.9–50.1)], and 0.96–1.00 [45.9 (41.2–50.6]. Median survival was 65 months (36–89 months) in HFA‐PEFF score 2–4, 45 months (26–59 months) in HFA‐PEFF score 5, and 28 months (22–42 months) in HFA‐PEFF score 6 ( P < 0.001), while the hazard ratio (95% confidence interval) for all‐cause mortality was 1.16 (1.02–1.32) per 0.10 increase in H 2 FPEF probability. Conclusions Among patients hospitalized with HFpEF, higher HFpEF probability according to diagnostic scores is associated with increased risk of subsequent HF readmissions and all‐cause mortality.

Background In heart failure, the exercise gas exchange Weber (A to D) and ventilatory classifications (VC‐1 to VC‐4) historically define disease severity and prognosis. However, their applications in the modern heart failure population of any left ventricular ejection fraction combined with hemodynamics are undefined. We aimed at revisiting and implementing these classifications by cardiopulmonary exercise testing imaging. Methods and Results 269 patients with heart failure with reduced (n=105), mid‐range (n=88) and preserved (n=76) ejection fraction underwent cardiopulmonary exercise testing imaging, primarily assessing the cardiac output (CO), mitral regurgitation, and mean pulmonary arterial pressure (mPAP)/CO slope. Within both classes, a progressively lower exercise CO, higher mPAP/CO slopes, and mitral regurgitation ( P <0.01 all) were observed. After adjustment for age and sex, Cox proportional hazard regression analyses showed that Weber (hazard ratio [HR], 2.9; 95% CI, 1.8–4.7; P <0.001) and ventilatory classes (HR, 1.4; 95% CI, 1.1–2.0; P =0.017) were independently associated with outcome. The best stratification was observed when combining Weber (A/B or C/D) with severe ventilation inefficiency (VC‐4) (HR, 2.7; 95% CI, 1.6–4.8; P <0.001). At multivariable analysis the best hemodynamic determinants of peak oxygen consumption and ventilation to carbon dioxide production slope were CO (β‐coefficient, 0.72±0.16; P <0.001) and mPAP/CO slope (β‐coefficient, 0.72±0.16; P <0.001), respectively. Conclusions In the contemporary heart failure population, the Weber and ventilatory classifications maintain their prognostic ability, especially when combined. Exercise CO and mPAP/CO slope are the best predictors of peak oxygen consumption and ventilation to carbon dioxide production slope classifications representing the main targets of interventions to impact functional class and, likely, event rate.

Abstract Aims Elevated cardiac filling pressures producing clinical congestion in heart failure (HF) patients may be secondary to intravascular volume expansion or abnormalities in cardiac diastolic properties. The objective of this study was to assess the extent to which measures of myocardial function and intravascular volume correlate with haemodynamic abnormalities in chronic HF. Methods and results Subjects underwent invasive haemodynamic assessment, measurement of total blood volume (TBV) using radiolabel indicator‐dilution methodology, and echocardiography to evaluate cardiac structure and function. Patients were divided into those with hypervolaemia (defined as TBV > +8% above referenced normal volume) and normal volume (‘euvolaemia’) (TBV ≤ + 8%). Of 66 patients, 39 (59%) were hypervolaemic and 27 (41%) normal TBV. Central venous pressure (CVP, P = 0.01) and pulmonary capillary wedge pressure (PCWP, P < 0.001) were higher in hypervolaemic compared with euvolaemic patients; however, 15% of hypervolaemic patients displayed normal pressures. Of euvolaemic patients, 70% displayed elevated CVP and 63% elevated PCWP. PCWP was moderately correlated with TBV (r = 0.42), left ventricular diastolic function (e′ velocity, r = −0.44), and left atrial strain (r = −0.47). In multivariable regression TBV, left ventricular e′, and left atrial strain were independently associated with PCWP (all P < 0.05). Conclusions While hypervolaemic patients displayed elevations in filling pressures, a substantial proportion (15%) had normal pressures, and of all subjects with elevated filling pressures nearly one third had normal TBVs. Importantly, of patients with normal volumes, a majority (>60%) display elevated filling pressures. Combined analysis of volume, pressure, and cardiac function may be helpful to guide comprehensive assessments of HF status.

Background: Heart failure with preserved ejection fraction is increasing in prevalence, but few effective treatments are available. Elevated left ventricular (LV) diastolic filling pressures represent a key therapeutic target. Pericardial restraint contributes to elevated LV end-diastolic pressure, and acute studies have shown that pericardiotomy attenuates the rise in LV end-diastolic pressure with volume loading. However, whether these acute effects are sustained chronically remains unknown. Methods: Minimally invasive pericardiotomy was performed percutaneously using a novel device in a porcine model of heart failure with preserved ejection fraction. Hemodynamics were assessed at baseline and following volume loading with pericardium intact, acutely following pericardiotomy, and then again chronically after 4 weeks. Cardiac structure was assessed by magnetic resonance imaging. Results: The increase in LV end-diastolic pressure with volume loading was mitigated by 41% (95% CI, 27%–45%, P <0.0001; ΔLV end-diastolic pressure reduced from +9±3 mm Hg to +5±3 mm Hg, P =0.0003, 95% CI, −2.2 to −5.5). The effect was sustained at 4 weeks (+5±2 mm Hg, P =0.28 versus acute). There was no statistically significant effect of pericardiotomy on ventricular remodeling compared with age-matched controls. None of the animals developed hemodynamic or pathological indicators of pericardial constriction or frank systolic dysfunction. Conclusions: The acute hemodynamic benefits of pericardiotomy are sustained for at least 4 weeks in a swine model of heart failure with preserved ejection fraction, without excessive chamber remodeling, pericarditis, or clinically significant systolic dysfunction. These data support trials evaluating minimally invasive pericardiotomy as a novel treatment for heart failure with preserved ejection fraction in humans.

Abstract Aims To determine whether inorganic nitrite improves peripheral and pulmonary oxygen (O 2 ) transport during exercise in heart failure with preserved ejection fraction (HFpEF). Methods and results Data from two invasive, randomized, double‐blind, placebo‐controlled trials with matched workload exercise of inhaled and intravenous sodium nitrite were pooled for this analysis ( n = 51). Directly measured O 2 consumption (VO 2 ) and blood gas data were used to evaluate the effect of nitrite on skeletal muscle O 2 conductance (Dm), VO 2 kinetics, alveolar capillary membrane O 2 conductance (D L ), and O 2 utilization during submaximal exercise. As compared to placebo, treatment with nitrite resulted in an improvement in Dm (+4.9 ± 6.5 vs. −0.9 ± 4.3 mL/mmHg*min, P = 0.0008) as well as VO 2 kinetics measured by mean response time (−5.0 ± 6.9 vs. −0.6 ± 6.0 s, P = 0.03), with preserved O 2 utilization despite increased convective O 2 delivery through cardiac output (+0.4 ± 0.7 vs. −0.3 ± 0.9 L/min, P = 0.02). Nitrite improved D L (+2.5 ± 6.3 vs. −2.0 ± 9.0 mL/mmHg*min, P = 0.05) with exercise, which was associated with lower pulmonary capillary pressures (r = −0.34, P = 0.02), and reduced pulmonary dead space ventilation fraction (−0.01 ± 0.05 vs. +0.02 ± 0.05, P = 0.02). Conclusion Sodium nitrite enhances skeletal muscle Dm during exercise as well as pulmonary O 2 diffusion, optimizing O 2 kinetics in tandem with increased convective O 2 delivery through cardiac output augmentation. The favourable combined pulmonary, cardiac and peripheral effects of nitrite may improve exercise tolerance in people with HFpEF and requires further investigation. Clinical Trial Registration: ClinicalTrials.gov ID NCT01932606 and NCT02262078.

Abstract Aims Risk stratification of heart failure (HF) patients with preserved ejection fraction (HFpEF) can promote a more personalized treatment. We tested the prognostic value of a multi-parametric evaluation, including biomarkers, cardiopulmonary exercise testing-exercise stress echocardiography (CPET-ESE), and lung ultrasound, in HFpEF patients and subjects at risk of developing HF (HF Stages A and B). Background Risk stratification of heart failure (HF) patients with preserved ejection fraction (HFpEF) can promote a more personalized treatment. Design We tested the prognostic value of a multi-parametric evaluation, including biomarkers, cardiopulmonary exercise testing-exercise stress echocardiography (CPET-ESE), and lung ultrasound, in HFpEF patients and subjects at risk of developing HF (HF Stages A and B). Methods and results We performed a resting clinical/bio-humoural evaluation and a symptom-limited CPET-ESE in 274 patients (45 Stage A, 68 Stage B, and 161 Stage C-HFpEF) and 30 age- and sex-matched healthy controls. During a median follow-up of 18.5 months, we reported 71 HF hospitalizations and 10 cardiovascular deaths. Cox proportional-hazards regression identified five independent predictors and each was assigned a number of points proportional to its regression coefficient: stress-rest ΔB-lines &gt;10 (3 points), peak oxygen consumption &lt;16 mL/kg/min (2 points), minute ventilation/carbon dioxide production slope ≥36 (2 points), peak systolic pulmonary artery pressure ≥50 mmHg (1 point) and resting N-terminal pro-brain natriuretic peptide (NT-proBNP) &gt;900 pg/mL (1 point). The event-free survival probability for low risk (&lt;3 points), intermediate risk (3–6 points), and high risk (&gt;6 points) were 93%, 52%, and 20%, respectively. The area under the curve (AUC) for the scoring system to predict events was 0.92 (95% CI 0.88–0.96), with an accuracy significantly higher than the individual components of the score (all P &lt; 0.01 vs. individual AUCs). Conclusion A weighted risk score including NT-proBNP, markers of cardiopulmonary dysfunction and indices of exercise-induced pulmonary congestion identifies HFpEF patients at increased risk for adverse events and Stage A and B subjects more likely to progress towards more advanced HF stages.

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. Methods and results This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS-HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter-quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P &lt; 0.001), greater burden of co-morbidities, higher intravascular pressures estimated on physical examination (elevated jugular venous pressure: 50% vs. 24.7%, P &lt; 0.001), poorer renal function (creatinine: 1.2 mg/dL [IQR 0.9, 1.5] vs. 1 mg/dL [IQR 0.8, 1.3], P = 0.003), and lower peak VO2 (adjusted mean difference −1.04 mL/kg/min, 95% confidence interval [−1.71, −0.37], P &lt; 0.003). Among hospitalized patients, despite greater in-hospital fluid/weight loss in the ≥moderate oedema group, there was no difference in the improvement in dyspnoea by the visual analogue scale or well-being visual analogue scale from baseline to 3–4 days and no statistically significant difference in the rate of 60 day rehospitalization/death (adjusted hazard ratio 1.44, 95% confidence interval [0.87, 2.39], P = 0.156). Conclusions Patients with HFpEF and oedema display higher body mass, greater burden of co-morbidities, and more severe exercise intolerance, but clinical responses to treatment appear similar. Further research is required to better understand the nature of volume distribution in different HFpEF phenotypes.

Abstract Background Analysis of a 12-lead electrocardiogram (ECG) in sinus rhythm by artificial intelligence (AI) has demonstrated to identify the risk of underlying paroxysmal atrial fibrillation (AF) with reasonable accuracy in the overall population. Purpose This study investigates whether AI based ECG analysis can predict new AF development in patients with heart failure and preserved ejection fraction (HFpEF) without previous AF history, as well as predict AF burden in patients with AF history. Methods This retrospective cohort study includes 424 patients with HFpEF, consecutively admitted to receive treatment with intravenous diuretics for congestion. A previously validated AI algorithm that provides an AF risk score based on ECG analysis was applied in all subjects. Patients were stratified according to AF history: (1) no history; (2) paroxysmal AF; (3) persistent AF; or (4) permanent AF. In patients without AF history, the impact of AI-predicted AF risk on new AF development was assessed. In patients with previous AF episodes, the relationship between AI-predicted AF risk and AF burden as well as underlying echocardiography substrate was evaluated. Results Eighty-three patients had paroxysmal AF (19.5%), 48 persistent AF (11%), and 121 permanent AF (28.5%). AF patients were older, with lower body mass index and higher heart rate. Lower systolic blood pressure, larger left atrial volume index (LAVI), worse diastolic function, more tricuspid valve regurgitation, and more need for pacing were observed with increasing AF severity. In 172 patients without AF history followed for 979±875 days, 61 developed AF (35%) after a median time of 2,118 days. AI-predicted AF risk was associated with new-onset AF after adjustments for age, gender, systolic blood pressure, body mass index and LAVI [HR (95% CI) = 1.15 (1.04–1.28); P-value=0.007; figure]. Only 5/61 patients who developed AF during follow-up (8.2%) were anticoagulated at baseline. In patients with previous AF, the AI-predicted risk score increased significantly with AF burden (46±25% in paroxysmal AF, 59±22% in persistent AF, and 69±17% in permanent AF; P-value&lt;0.001). The score was weakly but significantly correlated with LAVI (Pearson's r=0.27; P-value&lt;0.001) and right ventricular systolic pressure (Pearson's r=0.30; P-value&lt;0.001). When stratifying patients according to AI-predicted AF risk (0–25% versus 26–50% versus 51–75% versus 76–100%), there was a progressively longer time since onset of the first AF episode [29 months (4–77 months) versus 9 months (0–62 months) versus 38 months (2–88 months) versus 54 months (3–112 months), respectively; P-value=0.046]. Conclusions An AI-predicted AF risk score based on ECG analysis was associated with AF burden in HFpEF patients and did independently predict new-onset AF in those without previous history. Time to new onset of atrial fibrillation Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Belgian American Educational Foundation (B.A.E.F.); Special Research Fund (BOF) of Hasselt University (Hasselt, Belgium)