Vascular limitations in blood pressure regulation with age in women: Insights from exercise and acute cardioselective ß-blockade.

Younger women rely on altering cardiac output ( Q ̇ $\dot{Q}$ ) to regulate blood pressure (BP). In contrast, older women rely more on altering vascular tone. However, evidence suggests that the ability to alter systemic vascular conductance (SVC) is diminished in older women. In the present study, cardioselective ß-blockade was utilized to diminish the relative contribution of Q ̇ $\dot{Q}$ to BP regulation and thereby evaluate age-related vascular limitations in women at rest and during large muscle dynamic exercise. Younger (n = 13, mean age 26.0 years) and older (n = 14, mean age 61.8 years) healthy women performed submaximal bouts of semi-recumbent cycling exercise at varying intensities while receiving an intravenous infusion of esmolol, a ß1-antagonist, or saline control in a repeated-measures crossover design. Q ̇ $\dot{Q}$ was attenuated during esmolol infusion, with greater reductions during exercise (moderate, -1.0 (95% CI, -1.6 to -0.5) L/min, P < 0.001; heavy, -2.0 (95% CI, -2.6 to -1.5) L/min, P < 0.001) than seated rest (-0.5 (95% CI, -1.1 to 0.0) L/min, P = 0.048), and this reduction was not significantly different between age groups (P = 0.122). Older women exhibited a greater attenuation in mean arterial pressure (MAP) during esmolol (-7 (95% CI, -9 to -4) mmHg, P < 0.001) relative to younger women (-2 (95% CI, -5 to 0) mmHg, P = 0.071). These changes coincided with a greater reduction of SVC in the younger women during esmolol (-15 (95% CI, -20 to -10) mL/min/mmHg, P < 0.001) compared to older women (-3 (95% CI, -9 to 2) mL/min/mmHg, P = 0.242). Together, these findings provide evidence that older, postmenopausal women have a diminished ability to adjust SVC in order to regulate MAP.

Pulmonary vascular disease in pulmonary hypertension due to left heart disease: pathophysiologic implications.

AIMS: Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in left heart disease (LHD). This study sought to characterize the pathophysiology of PVD across the spectrum of PH in LHD. METHODS AND RESULTS: Patients with PH-LHD [mean pulmonary artery (PA) pressure >20 mmHg and PA wedge pressure (PAWP) ≥15 mmHg] and controls free of PH or LHD underwent invasive haemodynamic exercise testing with simultaneous echocardiography, expired air and blood gas analysis, and lung ultrasound in a prospective study. Patients with PH-LHD were divided into isolated post-capillary PH (IpcPH) and PVD [combined post- and pre-capillary PH (CpcPH)] based upon pulmonary vascular resistance (PVR <3.0 or ≥3.0 WU). As compared with controls (n = 69) and IpcPH-LHD (n = 55), participants with CpcPH-LHD (n = 40) displayed poorer left atrial function and more severe right ventricular (RV) dysfunction at rest. With exercise, patients with CpcPH-LHD displayed similar PAWP to IpcPH-LHD, but more severe RV-PA uncoupling, greater ventricular interaction, and more severe impairments in cardiac output, O2 delivery, and peak O2 consumption. Despite higher PVR, participants with CpcPH developed more severe lung congestion compared with both IpcPH-LHD and controls, which was associated lower arterial O2 tension, reduced alveolar ventilation, decreased pulmonary O2 diffusion, and greater ventilation-perfusion mismatch. CONCLUSIONS: Pulmonary vascular disease in LHD is associated with a distinct pathophysiologic signature marked by greater exercise-induced lung congestion, arterial hypoxaemia, RV-PA uncoupling, ventricular interdependence, and impairment in O2 delivery, impairing aerobic capacity. Further study is required to identify novel treatments targeting the pulmonary vasculature in PH-LHD.

Haemodynamic determinants of quality of life in chronic heart failure.

BACKGROUND: Heart failure patients demonstrate reduced functional capacity, hemodynamic function, and quality of life (QOL) which are associated with high mortality and morbidity rate. The aim of the present study was to assess the relationship between functional capacity, hemodynamic response to exercise and QOL in chronic heart failure. METHODS: A single-centre prospective study recruited 42 chronic heart failure patients (11 females, mean age 60 ± 10 years) with reduced left ventricular ejection fraction (LVEF = 23 ± 7%). All participants completed a maximal graded cardiopulmonary exercise test with non-invasive hemodynamic (bioreactance) monitoring. QOL was assessed using Minnesota Living with Heart Failure Questionnaire. RESULTS: The average value of QOL score was 40 ± 23. There was a significant negative relationship between the QOL and peak O2 consumption (r = - 0.50, p ≤ 0.01). No significant relationship between the QOL and selected exercise hemodynamic measures was found, including peak exercise cardiac power output (r = 0.15, p = 0.34), cardiac output (r = 0.22, p = 0.15), and mean arterial blood pressure (r = - 0.08, p = 0.60). CONCLUSION: Peak O2 consumption, but not hemodynamic response to exercise, is a significant determinant of QOL in chronic heart failure patients.

Global REACH 2018: the adaptive phenotype to life with chronic mountain sickness and polycythaemia.

KEY POINTS: Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e. polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity. ABSTRACT: Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea-level inhabitants residing at high altitude. By studying this unique population, which has adapted through natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity and characterizing the transport of oxygen through blood rheology, including haemoglobin mass, blood and plasma volume and blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances through pharmacological dissection of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity.

The haemodynamic basis of lung congestion during exercise in heart failure with preserved ejection fraction.

AIMS: Increases in extravascular lung water (EVLW) during exercise contribute to symptoms, morbidity, and mortality in patients with heart failure and preserved ejection fraction (HFpEF), but the mechanisms leading to pulmonary congestion during exercise are not well-understood. METHODS AND RESULTS: Compensated, ambulatory patients with HFpEF (n = 61) underwent invasive haemodynamic exercise testing using high-fidelity micromanometers with simultaneous lung ultrasound, echocardiography, and expired gas analysis at rest and during submaximal exercise. The presence or absence of EVLW was determined by lung ultrasound to evaluate for sonographic B-line artefacts. An increase in EVLW during exercise was observed in 33 patients (HFpEFLW+, 54%), while 28 (46%) did not develop EVLW (HFpEFLW-). Resting left ventricular function was similar in the groups, but right ventricular (RV) dysfunction was two-fold more common in HFpEFLW+ (64 vs. 31%), with lower RV systolic velocity and RV fractional area change. As compared to HFpEFLW-, the HFpEFLW+ group displayed higher pulmonary capillary wedge pressure (PCWP), higher pulmonary artery (PA) pressures, worse RV-PA coupling, and higher right atrial (RA) pressures during exercise, with increased haemoconcentration indicating greater loss of water from the vascular space. The development of lung congestion during exercise was significantly associated with elevations in PCWP and RA pressure as well as impairments in RV-PA coupling (area under the curve values 0.76-0.84). CONCLUSION: Over half of stable outpatients with HFpEF develop increases in interstitial lung water, even during submaximal exercise. The acute development of lung congestion is correlated with increases in pulmonary capillary hydrostatic pressure that favours fluid filtration, and systemic venous hypertension due to altered RV-PA coupling, which may interfere with fluid clearance. CLINICAL TRIAL REGISTRATION: NCT02885636.

Association between heart rate variability and haemodynamic response to exercise in chronic heart failure.

OBJECTIVES: Heart rate variability (HRV) and haemodynamic response to exercise (i.e. peak cardiac power output) are strong predictors of mortality in heart failure. The present study assessed the relationship between measures of HRV and peak cardiac power output. DESIGN: In a prospective observational study of 33 patients (age 54 ± 16 years) with chronic heart failure with reduced left ventricular ejection fraction (29 ± 11%), measures of the HRV (i.e. R-R interval and standard deviation of normal R-R intervals, SDNN) were recorded in a supine position. All patients underwent maximal graded cardiopulmonary exercise testing with non-invasive (inert gas rebreathing) cardiac output assessment. Cardiac power output, expressed in watts, was calculated as the product of cardiac output and mean arterial blood pressure. RESULTS: The mean RR and SDNN were 837 ± 166 and 96 ± 29 ms, peak exercise cardiac power output 2.28 ± 0.85 watts, cardiac output 10.34 ± 3.14 L/min, mean arterial blood pressure 98 ± 14 mmHg, stroke volume 91.43 ± 40.77 mL/beat, and oxygen consumption 19.0 ± 5.6 mL/kg/min. There was a significant but only moderate relationship between the RR interval and peak exercise cardiac power output (r = 0.43, p = .013), cardiac output (r = 0.35, p = .047), and mean arterial blood pressure (r = 0.45, p = .009). The SDNN correlated with peak cardiac power output (r = 0.42, p = .016), mean arterial blood arterial (r = 0.41, p = .019), and stroke volume (r = 0.35, p = .043). CONCLUSIONS: Moderate strength of the relationship between measures of HRV and cardiac response to exercise suggests that cardiac autonomic function is not good indicator of overall function and pumping capability of the heart in chronic heart failure.

Echocardiographic assessment of right heart function in heart transplant recipients and the relation to exercise hemodynamics.

This study aimed to characterize right heart function in heart transplantation (HTx) patients using advanced echocardiographic assessment and simultaneous right heart catheterization (RHC). Comprehensive two-dimensional (2D) and three-dimensional (3D) echocardiographic assessment of right heart function was performed in 105 subjects (64 stable HTx patients and 41 healthy controls). RHC was performed at rest and during semi-supine maximal exercise test. Compared with controls, in conclusion, HTx patients had impaired right ventricle (RV) systolic function in terms of decreased RV-free wall (FW) global longitudinal strain (GLS) (-20 ± 5% vs. -28 ± 5%, P < 0.0001) and 3D-ejection fraction (EF) (50 ± 8% vs. 60 ± 6%, P < 0.0001). In HTx patients, echocardiographic RV systolic function was significantly correlated with NYHA-class (3D-RVEF: r = -0.62, P < 0.0001; RV-FW-GLS: r = -0.41, P = 0.0009) and cardiac allograft vasculopathy (3D-RVEF: r = -0.42, P = 0.0005; RV-FW-GLS: r = -0.25, P = 0.0444). RHC demonstrated a good correlation between invasively assessed resting RV-stroke volume index and exercise capacity (r = 0.58, P < 0.0001) and NYHA-class (r = -0.41, P = 0.0009). RV systolic function is reduced in HTx patients compared with controls. 3D RVEF and 2D longitudinal deformation analyses are associated with clinical performance in stable HTx patients and seem suitable in noninvasive routine right heart function evaluation after HTx. Invasively assessed RV systolic reserve was strongly associated with exercise capacity.

Pulmonary capillary wedge pressure during exercise and long-term mortality in patients with suspected heart failure with preserved ejection fraction.

AIMS: In patients with suspected heart failure with preserved ejection fraction (HFpEF), invasive exercise testing may be considered when measurements at rest are inconclusive. However, the prognostic impact of invasive exercise testing is uncertain, so far. METHODS AND RESULTS: We retrospectively analysed mortality in 355 patients [mean age 61.2 ± 11.3 years, 235 (66.2%) women] with unexplained dyspnoea and suspected HFpEF. During an invasive haemodynamic stress test pulmonary capillary wedge pressure (PCWP) at rest and the PCWP response to exercise, expressed as the ratio of PCWP at peak exercise to workload normalized to body weight [PCWL (mmHg/W/kg)], were recorded. Both PCWP at rest and PCWL were significant and independent predictors of long-term mortality. Adding PCWL to PCWP at rest improved reclassification of patients into survivors or non-survivors with a net reclassification improvement (NRI) of 0.56 (95% CI: 0.29-0.83; P < 0.001). Ten-year mortality was 6.6% in subjects with low PCWP at rest (≤ 12 mmHg) and low PCWL (≤ 25.5 mmHg/W/kg); 28.2% in patients with low PCWP and high PCWL and 35.2% in those with high PCWP and high PCWL. Compared with patients with low PCWP and low PCWL, the adjusted hazard ratio for mortality was 2.37 (95% CI: 1.09-5.17; P = 0.029) for the low-PCWP/high-PCWL group and 4.75 (95% CI: 1.90-11.84; P < 0.001) for patients with high PCWP/high PCWL. CONCLUSION: In patients with suspected HFpEF, invasive exercise testing substantially improves prediction of long-term mortality. An excessive rise of PCWP during exercise despite normal PCWP at rest is associated with increased mortality and may be considered as early HFpEF.

Non-invasive prediction of pulmonary vascular disease-related exercise intolerance and survival in non-group 1 pulmonary hypertension.

AIMS: The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved. METHODS AND RESULTS: We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular-pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660-0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656-0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference -0.072, 95% CI -0.123 to -0.020, p = 0.006, and -0.043, 95% CI -0.067 to -0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all). CONCLUSIONS: Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH.

Right ventricular outflow tract diameter change with exercise: a prospective exercise echocardiography and invasive CPET study.

While cardiac output reserve with exercise predicts outcomes in cardiac and pulmonary vascular disease, precise quantification of exercise cardiac output requires invasive cardiopulmonary testing (iCPET). To improve the accuracy of cardiac output reserve estimation with transthoracic echocardiography (TTE), this prospective study aims to define changes in right ventricular outflow tract diameter (RVOTd) with exercise and its relationship with invasively measured haemodynamics. Twenty subjects underwent simultaneous TTE and iCPET, with data collected at rest, leg-raise, 25 W, 50 W (n = 16), 75 W (n = 14), and 100 W (n = 6). This was followed by a second exercise study with real-time RV pressure-volume loops at similar stages (except leg-raise). The overall cohort included heart failure with preserved ejection fraction (n = 12), pulmonary arterial hypertension (n = 5), and non-cardiac dyspnoea (n = 3). RVOTd was reverse engineered from the TTE-derived RVOT velocity time integral (VTI) and iCPET-derived stroke volume, using the formula: Fick stroke volume = RVOT VTI × RVOT area (wherein RVOT area = π × [RVOTd/2]2). RVOTd increased by nearly 3-4% at every 25 W increment. Using linear regression models, where each subject is treated as a categorical variable and adjusting for subject intercept, RVOTd was correlated with haemodynamic variables (cardiac output, heart rate, pulmonary artery and RV pressures). Of all the predictor haemodynamic variables, cardiac output had the highest r2 model fit (adjusted r2 = 0.68), with a unit increase in cardiac output associated with a 0.0678 increase in RVOTd (P < 0.001). Our findings indicate that RVOTd increases by 3-4% with every 25 W increment, predominantly correlated with cardiac output augmentation. These results can improve the accuracy of cardiac output reserve estimation by adjusting for RVOTd with graded exercise during non-invasive CPET and echocardiogram. However, future studies are needed to define these relationships for left ventricular outflow tract diameter.

Obesity in heart failure with preserved ejection fraction: Insights from the REDUCE LAP-HF II trial.

AIMS: Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF. METHODS AND RESULTS: The REDUCE LAP-HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m2 . As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score) and 6-min walk distance worsened. More severe obesity was associated with lower natriuretic peptide levels despite more cardiac remodelling, higher cardiac filling pressures, and higher cardiac output. Lower cut points for E/e' were needed to identify elevated PCWP in more obese patients. Strain measurements in all four chambers were maintained as BMI increased. Pulmonary vascular resistance at rest and exercise decreased with higher BMI. Obesity was associated with more first and recurrent heart failure events. However, there was no significant interaction between obesity and treatment effects of the atrial shunt. CONCLUSIONS: Increasing severity of obesity was associated with greater cardiac remodelling, higher right and left ventricular filling pressures, higher cardiac output and increased subsequent heart failure events. Despite significant obesity, many HFpEF patients have preserved right heart and pulmonary vascular function and thus, may be appropriate candidates for atrial shunt therapy.

Physiological mechanisms behind respiratory variations in right atrial pressure in pulmonary hypertension.

Impaired respiratory variation of right atrial pressure (RAP) in severe pulmonary hypertension (PH) suggests difficulty tolerating increased preload during inspiration. Our study explores whether this impairment links to specific factors: right ventricular (RV) diastolic function, elevated RV afterload, systolic RV function, or RV-pulmonary arterial (PA) coupling. We retrospectively evaluated respiratory RAP variation in all participants enrolled in the EXERTION study. Impaired respiratory variation was defined as end-expiratory RAP - end-inspiratory RAP ≤ 2 mm Hg. RV function and afterload were evaluated using conductance catheterization. Impaired diastolic RV function was defined as end-diastolic elastance (Eed) ≥ median (0.19 mm Hg/mL). Seventy-five patients were included; PH was diagnosed in 57 patients and invasively excluded in 18 patients. Of the 75 patients, 31 (41%) had impaired RAP variation, which was linked with impaired RV systolic function and RV-PA coupling and increased tricuspid regurgitation and Eed as compared to patients with preserved RAP variation. In backward regression, RAP variation associated only with Eed. RAP variation but not simple RAP identified impaired diastolic RV function (area under the receiver operating characteristic curve [95% confidence interval]: 0.712 [0.592, 0.832] and 0.496 [0.358, 0.634], respectively). During exercise, patients with impaired RAP variation experienced greater RV dilatation and reduced diastolic reserve and cardiac output/index compared with patients with preserved RAP variation. Preserved RAP variation was associated with a better prognosis than impaired RAP variation based on the 2022 European Society of Cardiology/European Respiratory Society risk score (chi-square P = 0.025) and survival free from clinical worsening (91% vs 71% at 1 year and 79% vs 50% at 2 years [log-rank P = 0.020]; hazard ratio: 0.397 [95% confidence interval: 0.178, 0.884]). Subgroup analyses in patients with group 1 and group 4 PH demonstrated consistent findings with those observed in the overall study cohort. Respiratory RAP variations reflect RV diastolic function, are independent of RV-PA coupling or tricuspid regurgitation, are associated with exercise-induced haemodynamic changes, and are prognostic in PH.Trial registration. NCT04663217.

Central haemodynamic abnormalities and outcome in patients with unexplained dyspnoea.

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) (<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 (<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.

Left atrial enlargement is associated with pulmonary vascular disease in heart failure with preserved ejection fraction.

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.

Prognostic impact of invasive exercise haemodynamics in patients with severe mitral regurgitation.

OBJECTIVES: Abnormal invasive exercise haemodynamics in asymptomatic patients with severe mitral regurgitation were associated with higher regurgitation burden. We analysed the association between parameters of invasive exercise testing with mortality and valve surgery compared to guideline defined non-invasive criteria. METHODS: This single centre, retrospective cohort study assesses the association of invasive exercise haemodynamics and mortality with and without surgery in patients with severe mitral regurgitation and normal ejection fraction (≥55%) as primary outcome. The secondary outcome was the need for mitral valve surgery in 113 asymptomatic patients primarily managed conservatively. RESULTS: We identified 314 patients [age 59 years (standard deviation 13), 27% female] with available exercise haemodynamics with a median follow-up of 8.2 (interquartile range 5.2-11.2) years. Five-year survival rate was 93.0%. Pulmonary capillary wedge pressure at maximum exercise >30 mmHg was the only parameter independently associated with mortality after adjustment for age and guideline criteria [hazard ratio (HR) 2.7 (1.3-5.6), P = 0.007]. In the 113 patients primarily managed conservatively, maximum pulmonary capillary wedge pressure was independently associated with mitral valve surgery during follow-up in multivariable analysis (HR 2.10 (1.32-3.34), P = 0.002; after adjustment for workload and weight: HR 1.31 (1.14-1.52), P < 0.001], whereas systolic pulmonary artery pressure and current guideline criteria were not. Adding maximum pulmonary capillary wedge pressure >25 mmHg improved the predictive power of current guideline criteria for surgery (area under the curve 0.61-0.68, P = 0.02). CONCLUSIONS: Invasive exercise haemodynamics predict mortality and improve prognostic information about surgery during follow-up derived from current guideline criteria in asymptomatic patients with severe mitral regurgitation.

Coronary microvascular dysfunction is associated with exertional haemodynamic abnormalities in patients with heart failure with preserved ejection fraction.

AIMS: This study uniquely explored the relationship between coronary microvascular function and exercise haemodynamics using concurrent invasive testing. METHODS AND RESULTS: Fifty-one consecutive patients with unexplained cardiac exertion symptoms, non-obstructive coronary artery disease and normal left ventricular ejection fraction (>50%) underwent haemodynamic exercise assessment and concurrent coronary reactivity testing. Heart failure with preserved ejection fraction (HFpEF) was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg at rest and/or ≥25 mmHg at peak exercise. Endothelium-independent coronary microvascular dysfunction (CMD) was defined as a coronary flow reserve (CFR) ≤2.5, while endothelium-dependent CMD was defined as ≤50% increase in coronary blood flow (CBF) in response to intracoronary acetylcholine infusions. Patients with HFpEF (n = 22) had significantly lower CFR (2.5 ± 0.6 vs. 3.2 ± 0.7; P = 0.0003) and median %CBF increase in response to intracoronary acetylcholine [1 (-35; 34) vs. 64 (-4; 133); P = 0.002] compared to patients without HFpEF (n = 29). PAWP was significantly higher in patients with endothelium-independent CMD compared to controls during both rest and exercise. This significant elevation was only present during exercise in patients with endothelium-dependent CMD compared to controls. CFR had significant inverse correlations with PAWP at rest (r = -0.31; P = 0.03) and peak exercise (r = -0.47, P = 0.001). CFR also had positive correlations with maximal exercise capacity (in W/kg) (r = 0.33, P = 0.02). CONCLUSIONS: Coronary microvascular function is inversely associated with filling pressures, particularly during exercise. Both types of CMD are associated with higher filling pressures at peak exercise. These findings underscore the potential mechanism and therapeutic target for CMD and HFpEF.

Left atrial strain and compliance in the diagnostic evaluation of heart failure with preserved ejection fraction.

AIMS: Left atrial (LA) function is impaired in heart failure with preserved ejection fraction (HFpEF) and predicts disease severity and risk of adverse outcome. We sought to evaluate whether LA strain could enhance diagnosis of HFpEF. METHODS AND RESULTS: Consecutive patients with unexplained exertional dyspnoea and image quality suitable for measuring LA strain underwent invasive cardiopulmonary exercise testing to ascertain the presence of HFpEF or non-cardiac causes of dyspnoea (NCD). LA reservoir strain was measured in all patients, while LA conduit and booster strain were measured in patients with sinus rhythm. LA strain was measurable in 363 of 378 examinations (96.5%; HFpEF: 238, NCD: 125). LA reservoir strain (29 ± 16% vs. 40 ± 13%, P < 0.0001) and conduit strain (18 ± 10% vs. 22 ± 10%, P = 0.0001) were significantly impaired in HFpEF compared to NCD. Of all echocardiographic indices, LA reservoir strain best discriminated HFpEF from NCD [area under the curve (AUC) 0.719, P < 0.0001], outperforming E/e' (AUC difference +0.117, P < 0.0001), LA enlargement (+0.090, P = 0.001), tricuspid regurgitation velocity > 2.8 m/s (+0.082, P = 0.0085), left ventricular hypertrophy (+0.0159, P < 0.0001) and left ventricular global longitudinal strain (+0.0198, P < 0.0001). Indexing LA reservoir strain to estimated LA pressure (E/e') as a surrogate for LA compliance further improved diagnostic performance (AUC 0.772, P < 0.0001; +0.053 compared to LA reservoir strain alone, P = 0.003). CONCLUSION: Left atrial reservoir strain may provide enhanced diagnostic accuracy beyond conventional echocardiographic measures to discriminate HFpEF from NCD. Further study is required to verify the diagnostic utility of LA strain.

Prognostic value of exercise myocardial deformation and haemodynamics in long-term heart-transplanted patients.

AIMS: The study evaluated exercise left ventricular global longitudinal strain (LVGLS) and invasive haemodynamics for major adverse cardiac events (MACE) prediction in heart-transplanted (HTx) patients. METHODS AND RESULTS: The study comprised 74 stable consecutive HTx patients who were followed at the Department of Cardiology, Aarhus University Hospital, Denmark, from August 2013 to January 2017. All patients were transplanted a minimum of 12 months before study entry and were included at the time of their routine annual coronary angiography. A symptom-limited haemodynamic exercise test with simultaneous echocardiographic study was performed. The primary endpoint was MACE during follow-up defined as heart failure hospitalization, treated rejection episodes, coronary event, or cardiac death. The median time since transplant was 5 years [1:12] and the median follow-up was 1095 days [391;1506]. Thirty patients (41%) experienced MACE during follow-up. Patients who suffered MACE had an impaired resting and peak exercise systolic function in form of a lower LV ejection fraction (Rest: 56 ± 12% vs. 65 ± 7%, P < 0.001; Peak 64 ± 13% vs. 72 ± 6%, P < 0.01) and LVGLS (Rest: 13 ± 4% vs. 16 ± 2%, P < 0.01; Peak: 15 ± 6% vs. 20 ± 4%, P = 0.0001) than patients without MACE episodes. In contrast, resting diastolic filling patterns were comparable between patients suffering from MACE and patients without MACE. At rest, pulmonary capillary wedge pressure (mPCWP) and cardiac index did not predict MACE, whereas increased right atrial pressure (mRAP) was associated with increased MACE risk. Patients with peak exercise mPCWP >23 mmHg [hazard ratio (HR) 2.5, 95% confidence interval (CI): 1.2-5.4], cardiac index <5.9 L/min/m2 (HR 2.7, 95% CI: 1.0-6.3), or mRAP >13 mmHg (HR 2.7, 95% CI: 1.1-6.3) had increased MACE risk. Patients with exercise-induced LVGLS increase <3.5% and peak exercise cardiac index <5.9 L/min/m2 [HR 6.1 (95% CI: 2.2-17.1)] or mPCWP >23 mmHg [HR 6.1 (95% CI: 2.1-17.5)] or mRAP >13 mmHg [HR 7.5 (95% CI: 2.3-23.9)] had the highest MACE risk. CONCLUSIONS: Resting haemodynamic parameters were poor MACE predictors in long-term HTx patients. In contrast, peak exercise mPCWP, mRAP, and CI were significant MACE predictors. LVGLS both at rest and during exercise were significant MACE predictors, and the combined model with peak exercise LVGLS and peak exercise mPCWP, mRAP, and CI clearly identified high-risk HTx patients in relation cardiovascular endpoints independently of time since HTx.