Verbrugge, Frederik H.

Abstract Background Atrial fibrillation (AF) is common in patients with heart failure and preserved ejection fraction (HFpEF) and associated with left atrial (LA) myopathy, reduced exercise capacity and poor outcomes. However, the mechanisms underlying exercise intolerance in HFpEF with AF are not well-characterized. Purpose To test hypotheses that patients with HFpEF and AF (HFpEF-AF) would display greater acute impairments in right heart-pulmonary vascular coupling during exercise, leading to greater elevations in left and right heart filling pressures and increased lung congestion as compared to patients with HFpEF and no AF (HFpEF-no-AF) and control subjects free of heart failure and AF. As corollary hypotheses, we also posited that these changes would lead to greater ventricular interdependence during exercise in HFpEF-AF, and that pulmonary hypertension in HFpEF-AF was not simply ascribable to the LA dysfunction that accompanies AF, which would provide greater impetus to pursue restoration of sinus rhythm. Methods Subjects with HFpEF-AF (n=35), HFpEF-no-AF (n=85), and controls free of heart failure or AF (n=28) underwent cardiopulmonary exercise testing with invasive hemodynamic assessment and simultaneous echocardiography and lung ultrasound in a prospective study. Results As compared with controls and HFpEF-no-AF, subjects with HFpEF-AF displayed poorer left ventricular (LV) longitudinal strain, lower LA reservoir strain with greater LA volume at rest. With exercise, subjects with HFpEF-AF displayed more severe exercise-induced pulmonary hypertension, higher right atrial pressure (RAP) and more pronounced right ventricular-pulmonary vascular uncoupling. Peak oxygen consumption was lowest in patients with HFpEF-AF, coupled with greater limitations in cardiac output reserve and more severe increases in lung congestion and pulmonary vascular resistance (Figure 1). Dynamic ventricular interaction was greatest in HFpEF-AF, evidenced by greater increases in LV eccentricity index and RAP/PCWP (Figure 2) and less increase in LV transmural pressure compared with HFpEF-no-AF. In a sensitivity analysis, patients with HFpEF-AF displayed more severe pulmonary hypertension and pulmonary vascular disease compared to HFpEF-no-AF even after matching for the severity of LA remodeling and dysfunction. Conclusions Patients with AF and HFpEF display more severe abnormalities in pulmonary vascular reserve with exercise leading to greater lung congestion and enhanced exertional ventricular interdependence compared to patients with HFpEF-no-AF. While many of these differences appear attributable to LA dysfunction, the presence of AF is associated with more severe pulmonary vascular disease independent of LA myopathy, suggesting potential benefit from restoration of sinus rhythm even in the setting of LA myopathy. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): R01 HL128526

Objective Mild aortic valve stenosis (AS) and aortic valve (AV) sclerosis are associated with diastolic dysfunction and increased mortality in the general population. This study specifically investigated the impact of mild AV disease in heart failure with preserved ejection fraction (HFpEF). Methods Consecutive patients hospitalised with HFpEF (n=370) underwent assessment of cardiac structure and function and long-term clinical follow-up. Results In the study cohort, 111 had mild AS (30%), 104 AV sclerosis (28%) and 155 a non-calcified AV (42%). Mild-to-moderate AV regurgitation (AR) was present in 64 (17%). Compared with patients with a normal AV, those with AV disease were older, with worse renal function and more atrial fibrillation. E/e′ increased from non-calcified AV to AV sclerosis to mild AS (13.8 (10.8–16.8) vs 15.0 (10.9–20.0) vs 18.0 (12.7–23.3), respectively; p<0.001)). Left ventricular diastolic pressure–volume relationships were shifted leftwards in patients with AS and AV sclerosis, but not influenced by AR. The left ventricular end-diastolic volume normalised at 20 mm Hg was 117±34 mL, 106±30 mL and 112±30 mL in non-calcified AV, AV sclerosis and mild AS, respectively (p=0.023), while 112±32 mL in mild-to-moderate AR. Over 30 months (IQR, 8–61 months), 247 patients died (67%). The presence of mild AV disease was associated with increased mortality, but this was no longer significant after adjusting for age and sex. Conclusions Low-grade AV disease is common among patients hospitalised for HFpEF and is associated with older age, atrial arrhythmia, renal dysfunction, higher left heart filling pressures and increased left ventricular chamber stiffness.

Approximately half of all patients with heart failure (HF) have a preserved ejection fraction, and the prevalence is growing rapidly given the aging population in many countries and the rising prevalence of obesity, diabetes, and hypertension. Functional capacity and quality of life are severely impaired in heart failure with preserved ejection fraction (HFpEF), and morbidity and mortality are high. In striking contrast to HF with reduced ejection fraction, there are few effective treatments currently identified for HFpEF, and these are limited to decongestion by diuretics, promotion of a healthy active lifestyle, and management of comorbidities. Improved phenotyping of subgroups within the overall HFpEF population might enhance individualization of treatment. This review focuses on the current understanding of the pathophysiologic mechanisms underlying HFpEF and treatment strategies for this complex syndrome.

Abstract Aims Circulating blood volume is functionally divided between the unstressed volume, which fills the vascular space, and stressed blood volume (SBV), which generates vascular wall tension and intravascular pressure. With decreases in venous capacitance, blood functionally shifts to the SBV, increasing central venous pressure and pulmonary venous pressures. Obesity is associated with both elevated venous pressure and heart failure with preserved ejection fraction (HFpEF). To explore the mechanisms underlying this association, we evaluated relationships between blood volume distribution, venous compliance, and body mass in patients with and without HFpEF. Methods and results Subjects with HFpEF ( n = 62) and non‐cardiac dyspnoea (NCD) ( n = 79) underwent invasive haemodynamic exercise testing with echocardiography. SBV was estimated (eSBV) from measured haemodynamic variables fit to a comprehensive cardiovascular model. Compared to NCD, patients with HFpEF displayed a leftward‐shifted central venous pressure–dimension relationship, indicating reduced venous compliance. eSBV was 81% higher at rest and 69% higher during exercise in HFpEF than NCD (both P < 0.0001), indicating reduced venous capacitance. Despite greater augmented eSBV with exercise, the increase in cardiac output was reduced in HFpEF, suggesting operation on the plateau of the Starling curve. Exercise eSBV was directly correlated with higher body mass index (r = 0.77, P < 0.0001) and inversely correlated with right ventricular–pulmonary arterial coupling (r = −0.57, all P < 0.0001). Conclusions Patients with HFpEF display reductions in systemic venous compliance and increased eSBV related to reduced venous capacitance, abnormalities in right ventricular–pulmonary artery interaction, and increased body fat. These data provide new evidence supporting an important role of venous dysfunction in obesity‐related HFpEF and suggest that therapies that improve venous function may hold promise to improve clinical status in this cohort.

Introduction: Coronary microvascular dysfunction (CMD) is prevalent in symptomatic patients with no obstructive coronary artery disease. We postulated that exercise capacity and cardiac output augmentation in response to exercise are linked to coronary microvascular function in this patient population. Methods: Fifty-one consecutive patients with unexplained cardiac exertion symptoms, non-obstructive coronary artery disease on angiography (<50% stenosis), and normal left ventricular ejection fraction (>50%) who underwent concurrent clinically indicated coronary reactivity testing and invasive cardiopulmonary exercise testing (CPEX) were included. Microvascular function was assessed by coronary flow reserve (CFR; hyperemic/resting flow) in response to intracoronary adenosine injection. Cardiac output (CO) was calculated at rest and peak exercise using Fick’s formula. CO limitation was defined as a measured (peak CO - resting CO) <80% than the expected [6*absolute ΔVO 2 (Peak VO 2 -Rest VO 2 ) increase in CO in L/min]. The relationship between CFR, maximal exercise capacity, and CO augmentation at peak exercise was explored. Results: Patients were 56.6±10.5 years old and 73% were females. CFR had a modest positive correlation with measured increase in CO (r=0.42; P=0.003) ( Fig 1A ), and with maximal ergometric exercise capacity [in Watts/Kg] (Pearson’s r=0.33, P=0.02) ( Fig 1B ). Patients with, vs. without impaired cardiac limitations during exercise, had significantly lower CFR levels (2.6±0.5 vs 3.1±0.7; P=0.01) ( Fig 2 ). Conclusion: Impaired coronary microvascular function is associated with lower peak exercise capacity and reduced cardiac output augmentation in response to exercise, underscoring the functional ramification of CMD in symptomatic patients.

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.

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)

Abstract Background Diastolic reserve decreases with aging. A recently developed artificial intelligence (AI) algorithm can predict age based on 12-lead electrocardiogram (ECG) analysis. Purpose This study aims to use a validated AI algorithm to assess cardiac senescence and investigate the impact of obesity on cardiac aging in heart failure with preserved ejection fraction (HFpEF). Methods This retrospective cohort study includes 403 patients with HFpEF, admitted for treatment with intravenous diuretics. ECG age was assessed by a convolutional neural network as previously validated. Patients were stratified according to the presence of obesity (body mass index &gt;30 kg/m2) and ECG age was compared between groups. The relationship between ECG versus calendar age and structural/functional alterations on echocardiography, as well as the risk of atrial fibrillation (AF) development, was evaluated. Results In 253 (63%) obese patients with HFpEF, calendar age was 8 years younger compared with their non-obese counterparts, but ECG age was only 3 years younger. ECG minus calendar age was higher in obese patients (P-value &lt;0.001; figure) and correlated moderately strong with weight, fat free, and fat mass (r=0.35–0.41; P-value &lt;0.001). Older ECG age was correlated with worse diastolic function, but not with left ventricular afterload (table). Calendar age correlated less strongly with diastolic dysfunction (table). ECG age did predict AF development, independently of calendar age, gender, and presence of obesity [HR (95% CI) = 1.31 (1.06–1.63) per 5-year; P-value=0.015]. Conclusions Obesity accelerates cardiac senescence in HFpEF as reflected by more pronounced diastolic dysfunction and a higher AF risk, which was identified from ECG analysis by a validated AI algorithm. Figure 1 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).

Abstract Background The HFA-PEFF algorithm has been recently developed and is recommended by the European Society of Cardiology to make a diagnosis of heart failure with preserved ejection fraction (HFpEF). Based on functional echocardiography criteria, morphological criteria, and natriuretic peptide levels, a score from 1 to 6 is obtained with higher scores indicating a higher probability of HFpEF. Purpose This study investigates the prognostic value of the HFA-PEFF score in HFpEF patients hospitalised for decompensation. Methods This retrospective cohort study includes consecutive patients with HFpEF, admitted to Mayo Clinic Rochester between 2010–2015 and requiring treatment with intravenous loop diuretics for congestion. The HFA-PEFF score was calculated for all patients with echocardiography data available within 1 year and natriuretic peptide levels obtained upon admission. The study population was subsequently stratified according to HFA-PEFF score ≤4 (n=79), =5 (n=93), or =6 (n=271). Incidence rates of recurrent heart failure admissions per 100 patient-years of follow-up, time to all-cause mortality, and mortality causes were compared among strata. Results In 443 patients with HFpEF (78±12 years; 60% women), higher HFA-PEFF score was associated with older age, female gender, higher systolic blood pressure, and worse renal function. Heart failure readmission rates were higher in patients with HFA-PEFF score =5 [46.0 (38.5–53.5)] or HFA-PEFF score =6 [45.0 (40.1–49.8)] versus HFA-PEFF score ≤4 [28.9 (22.7–35.0); P-value&lt;0.001 for differences; see upper panel figure]. Increasing HFA-PEFF score was associated with a shorter median survival (P-value&lt;0.001), which was 65 months (36–89 months) in HFA-PEFF score ≤4, 45 months (26–59 months) in HFA-PEFF score =5, and 28 months (22–42 months) in HFA-PEFF score =6 (see lower panel figure). The proportions of deaths directly related to heart failure were comparable among HFA-PEFF strata (49% versus 49% versus 52%, respectively; P-value=0.903), as was the contribution of cardiovascular death (60% versus 57% versus 63%, respectively; P-value=0.662). Overall, few differences in patterns of mortality causes were observed among strata. There was a lower contribution of primary respiratory disease (mainly chronic obstructive pulmonary disease) to mortality in patients with a higher HFA-PEFF score (26% versus 19% versus 6%, respectively; P-value&lt;0.001). Conclusions Higher HFA-PEFF score in hospitalized patients with HFpEF is associated with increased risk of subsequent heart failure readmissions and all-cause mortality, which includes both heart failure specific and non-heart failure mortality. Heart failure readmissions & mortality 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)

Abstract Aims Central obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF), particularly in women, but the mechanisms remain unclear. We hypothesized that sex-specific differences in visceral adipose tissue (VAT) content would differentially relate to haemodynamic severity of HFpEF in women and men. Methods and results Abdominal computed tomography (CT) and invasive haemodynamic exercise testing were performed in 105 subjects with HFpEF (63 women) and 105 age-, sex-, and body mass index-matched controls. Visceral adipose tissue area was quantified by CT. As compared with control women, VAT area was 34% higher in women with HFpEF (186 ± 112 vs. 139 ± 72 cm2, P = 0.006), while VAT area was not significantly different in men with or without HFpEF (294 ± 158 vs. 252 ± 92 cm2, P = 0.1). During exercise, pulmonary capillary wedge pressure (PCWP) increased markedly and to similar extent in both men and women with HFpEF. Women with increased VAT area displayed 33% higher PCWP during exercise compared with women with normal VAT area (28 ± 10 vs. 21 ± 10 mmHg, P = 0.001), whereas exercise PCWP was similar in men with or without excess VAT (24 ± 9 vs. 25 ± 6, P = 0.89). In women, each 100 cm2 increase in VAT area was associated with a 4.0 mmHg higher PCWP (95% CI 2.1, 6.0 mmHg; P &lt; 0.0001), but there was no such relationship in men (interaction P = 0.009). Conclusions These data suggest that accumulation of excess VAT plays a distinct and important role in the pathophysiology of HFpEF preferentially in women. Further research is needed to better understand the mechanisms and treatment implications for visceral fat in HFpEF.