Sorimachi, Hidemi

ABSTRACT Aim Left atrial (LA) myopathy is increasingly recognized as an important phenotypic trait in heart failure (HF) with preserved ejection fraction (HFpEF). Right atrial (RA) remodelling and dysfunction also develop in HFpEF, but little data are available regarding the clinical characteristics and pathophysiology among patients with isolated LA, RA, or biatrial myopathy. Methods and results Patients with HFpEF underwent invasive haemodynamic exercise testing, comprehensive imaging including speckle tracking strain echocardiography, and clinical follow-up at Mayo Clinic between 2006 and 2018. LA myopathy was defined as LA volume index >34 ml/m2 and/or LA reservoir strain ≤24% and RA myopathy by RA volume index >39 ml/m2 in men and >33 ml/m2 in women and/or RA reservoir strain ≤19.8%. Of 476 consecutively evaluated patients with HFpEF defined by invasive exercise testing with evaluable atrial structure/function, 125 (26%) had no atrial myopathy, 147 (31%) had isolated LA myopathy, 184 (39%) had biatrial myopathy, and 20 (4%) had isolated RA myopathy. Patients with HFpEF and biatrial myopathy had more atrial fibrillation, poorer left ventricular systolic and diastolic function, more severe pulmonary vascular disease, tricuspid regurgitation, ventricular interdependence and right ventricular dysfunction, and poorer cardiac output reserve with exercise. There were 94 patients with events over a median follow-up of 2.9 (interquartile range 1.4–4.6) years. Individuals with biatrial myopathy had an 84% higher risk of HF hospitalization or death as compared to those with isolated LA myopathy (hazard ratio 1.84; 95% confidence interval 1.16–2.92, p = 0.01). Conclusions Biatrial myopathy identifies patients with more advanced HFpEF characterized by more severe pulmonary vascular disease, right HF, poorer cardiac reserve, and a greater risk for adverse outcomes. Further study is required to define optimal strategies to treat and prevent biatrial myopathy in HFpEF.

Abstract Background Pulmonary abnormalities are common in patients with prevalent heart failure (HF). Arterial hypoxemia is considered rare in HF, but this has not been rigorously evaluated in patients with HF and preserved EF (HFpEF). Methods Results Patients with HFpEF (n=539) and no clinically-relevant lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxemia was defined by oxyhaeemoglobin saturation <94%. As compared to those without hypoxemia (n=403), patients with hypoxemia (n=136, 25%) were slightly older, heavier, and had higher NT-proBNP levels. They had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar-arterial O2 difference compared to those without hypoxemia. These differences were replicated in a sensitivity analysis where patients with any spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and capillary pressures were related to lower PaO2. The presence of exertional hypoxemia was associated with two-fold increased risk for death over 2.8 (IQR 0.7-5.5) years of follow up, (Adjusted:HR 2.00 (95%CI: 1.01−3.96), p=0.046). Conclusion One quarter of HFpEF patients displayed arterial desaturation during exercise. Patients with hypoxemia display more severely abnormal hemodynamics and increased mortality. Further study is required to better understand the mechanisms in patients with HFpEF.Hemodynamic changes at rest/exerciseRisk of death in HFpEF with hypoxemia

Abstract Background Right ventricular (RV) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), portends worse prognosis, and is believed to be caused by contractile impairment and remodeling due to afterload mismatch from pulmonary hypertension (PH). The goal of this study was to examine the right heart in patients with HFpEF and resting mean pulmonary arterial (PA) pressure (MPAP)≤20 mmHg. Methods and results Among 621 patients with HFpEF undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing, 159 (26%) had resting MPAP≤20 mmHg (HFpEFMPAP≤20mmHg). In comparison to 73 controls, they were more obese, had more coronary disease and atrial fibrillation. After adjusting for BMI, there were no differences in plasma volume but NTproBNP was higher and peak oxygen consumption lower in HFpEFMPAP≤20mmHg than in controls (p = 0.002, <0.001, respectively). While RV dimension was similar, tricuspid annular plane systolic excursion and RVs’ were lower in HFpEFMPAP≤20mmHg (18±5 vs. 22±4 mm, p = 0.005; 10±2 vs. 12±2 cm/s, p = 0.047, respectively). HFpEFMPAP≤20mmHg and controls displayed similar pulmonary vascular resistance, MPAP and right atrial pressure at rest, but during exercise, MPAP and right atrial pressure were higher in patients with HFpEFMPAP≤20mmHg (41±10 vs. 33±10 mmHg; 18±7 vs. 12±4 mmHg, p<0.001, respectively). PA compliance was lower at both rest and exercise (rest 4.1±2.1 vs. 5.0±1.8; exercise 2.9±1.4 vs. 3.2±1.4 ml/mmHg, p<0.001, for both). Conclusion Right heart dysfunction is present in patients with HFpEF even in the absence of frank PH. These patients display greater pulsatile RV loading by PA compliance even as resistance is not markedly elevated. These data support further study into novel therapies targeting pulsatile RV afterload in HFpEF.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors reduce risk of hospitalization for heart failure in patients who have heart failure with preserved ejection fraction (HFpEF), but the hemodynamic mechanisms underlying these benefits remain unclear. This study sought to determine whether treatment with dapagliflozin affects pulmonary capillary wedge pressure (PCWP) at rest and during exercise in patients with HFpEF. METHODS: This was a single-center, double-blinded, randomized, placebo-controlled trial testing the effects of 10 mg of dapagliflozin once daily in patients with HFpEF. Patients with New York Heart Association class II or III heart failure, ejection fraction ≥50%, and elevated PCWP during exercise were recruited. Cardiac hemodynamics were measured at rest and during exercise using high-fidelity micromanometers at baseline and after 24 weeks of treatment. The primary end point was a change from baseline in rest and peak exercise PCWPs that incorporated both measurements, and was compared using a mixed-model likelihood ratio test. Key secondary end points included body weight and directly measured blood and plasma volumes. Expired gas analysis was performed evaluate oxygen transport in tandem with arterial lactate sampling. RESULTS: Among 38 patients completing baseline assessments (median age 68 years; 66% women; 71% obese), 37 completed the trial. Treatment with dapagliflozin resulted in reduction in the primary end point of change in PCWP at rest and during exercise at 24 weeks relative to treatment with placebo (likelihood ratio test for overall changes in PCWP; P <0.001), with lower PCWP at rest (estimated treatment difference [ETD], −3.5 mm Hg [95% CI, −6.6 to −0.4]; P =0.029) and maximal exercise (ETD, −5.7 mm Hg [95% CI, −10.8 to −0.7]; P =0.027). Body weight was reduced with dapagliflozin (ETD, −3.5 kg [95% CI, −5.9 to −1.1]; P =0.006), as was plasma volume (ETD, −285 mL [95% CI, −510 to −60]; P =0.014), but there was no significant effect on red blood cell volume. There were no differences in oxygen consumption at 20-W or peak exercise, but dapagliflozin decreased arterial lactate at 20 W (−0.70 ± 0.77 versus 0.37 ± 1.29 mM; P =0.006). CONCLUSIONS: In patients with HFpEF, treatment with dapagliflozin reduces resting and exercise PCWP, along with the favorable effects on plasma volume and body weight. These findings provide new insight into the hemodynamic mechanisms of benefit with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04730947.

Abstract Aims It is widely held that heart failure (HF) does not cause exertional hypoxaemia, based upon studies in HF with reduced ejection fraction, but this may not apply to patients with HF and preserved ejection fraction (HFpEF). Here, we characterize the prevalence, pathophysiology, and clinical implications of exertional arterial hypoxaemia in HFpEF. Methods and results Patients with HFpEF (n = 539) and no coexisting lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxaemia (oxyhaemoglobin saturation &lt;94%) was observed in 136 patients (25%). As compared to those without hypoxaemia (n = 403), patients with hypoxaemia were older and more obese. Patients with HFpEF and hypoxaemia had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar–arterial oxygen difference, increased dead space fraction, and greater physiologic shunt compared to those without hypoxaemia. These differences were replicated in a sensitivity analysis where patients with spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and pulmonary capillary pressures were related to lower arterial oxygen tension (PaO2), especially during exercise. Body mass index (BMI) was not correlated with the arterial PaO2, and hypoxaemia was associated with increased risk for death over 2.8 (interquartile range 0.7–5.5) years of follow-up, even after adjusting for age, sex, and BMI (hazard ratio 2.00, 95% confidence interval 1.01–3.96; p = 0.046). Conclusion Between 10% and 25% of patients with HFpEF display arterial desaturation during exercise that is not ascribable to lung disease. Exertional hypoxaemia is associated with more severe haemodynamic abnormalities and increased mortality. Further study is required to better understand the mechanisms and treatment of gas exchange abnormalities in HFpEF.

ABSTRACT Aims Cardiac and extracardiac abnormalities play important roles in heart failure with preserved ejection fraction (HFpEF). Biventricular cardiac power output (BCPO) quantifies the total rate of hydraulic work performed by both ventricles, suggesting that it may help to identify patients with HFpEF and more severe cardiac impairments to better individualize treatment. Methods and results Patients with HFpEF (n = 398) underwent comprehensive echocardiography and invasive cardiopulmonary exercise testing. Patients were categorized as low BCPO reserve (n = 199, &lt; median of 1.57 W) or preserved BCPO reserve (n = 199). As compared to those with preserved BCPO reserve, those with low reserve were older and leaner, with more atrial fibrillation, higher N-terminal pro-B-type natriuretic peptide levels, worse renal function, more impaired left ventricular (LV) global longitudinal strain, worse LV diastolic function and right ventricular longitudinal function. Cardiac filling pressures and pulmonary artery pressures at rest were higher in low BCPO reserve, but central pressures were similar during exercise to those with preserved BCPO reserve. Exertional systemic and pulmonary vascular resistances were higher and exercise capacity was more impaired in those with low BCPO reserve. Reduced BCPO reserve was associated with increased risk for the composite endpoint of heart failure hospitalization or death over 2.9 (interquartile range 0.9–4.5) years of follow-up (hazard ratio 2.77, 95% confidence interval 1.73–4.42, p &lt; 0.0001). Conclusions Inability to enhance BCPO during exercise is associated with more advanced HFpEF, increased systemic and pulmonary vascular resistance, reduced exercise capacity and increased adverse events in patients with HFpEF. Novel therapies that enhance biventricular reserve merit further investigation for patients with this phenotype.

Abstract Aims Ancillary analyses from clinical trials have suggested reduced efficacy for neurohormonal antagonists among patients with heart failure and preserved ejection fraction (HFpEF) and higher ranges of ejection fraction (EF). Methods and results A total of 621 patients with HFpEF were grouped into those with low-normal left ventricular EF (LVEF) (HFpEF&lt;65%, n = 319, 50% ≤ LVEF &lt;65%) or HFpEF≥65% (n = 302, LVEF ≥65%), and compared with 149 age-matched controls undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing. A sensitivity analysis was performed in a second non-invasive community-based cohort of patients with HFpEF (n = 244) and healthy controls without cardiovascular disease (n = 617). Patients with HFpEF≥65% had smaller left ventricular (LV) end-diastolic volume than HFpEF&lt;65%, but LV systolic function assessed by preload recruitable stroke work and stroke work/end-diastolic volume was similarly impaired. Patients with HFpEF≥65% displayed an end-diastolic pressure–volume relationship (EDPVR) that was shifted leftward, with increased LV diastolic stiffness constant β, in both invasive and community-based cohorts. Cardiac filling pressures and pulmonary artery pressures at rest and during exercise were similarly abnormal in all EF subgroups. While patients HFpEF≥57% displayed leftward shifted EDPVR, those with HFpEF&lt;57% had a rightward shifted EDPVR more typical of heart failure with reduced EF. Conclusion Most pathophysiologic differences in patients with HFpEF and higher EF are related to smaller heart size, increased LV diastolic stiffness, and leftward shift in the EDPVR. These findings may help to explain the absence of efficacy for neurohormonal antagonists in this group and raise a new hypothesis, that interventions to stimulate eccentric LV remodelling and enhance diastolic capacitance may be beneficial for patients with HFpEF and EF in the higher range.

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