Obokata, Masaru

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

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: Anemia is associated with increased mortality, cardiovascular events, and decreased quality of life in patients with heart failure with preserved ejection fraction (HFpEF). Iron deficiency may contribute to disease severity independent of effects on red cell mass. The hemodynamic consequences of anemia and iron deficiency in HFpEF remain unclear. Methods: We analyzed a cohort of 313 consecutive subjects with HFpEF diagnosed by invasive hemodynamic assessment, and compared echocardiographic and hemodynamic characteristics of anemic versus non-anemic subjects. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Iron deficiency was defined as ferritin <100 ug/L. Results: Compared to patients without anemia, HFpEF patients with anemia displayed higher NT-proBNP, elevated pulmonary artery (PA) pressures at rest and at peak exercise, and lower oxygen consumption at peak exercise (Table). There was no difference in pulmonary capillary wedge pressure (PCWP). Patients with iron deficiency were more likely to be women. At rest, patients with iron deficiency displayed lower left ventricular (LV) mass, higher resting SVRI and lower cardiac index (CI), but there were not significant differences with exercise. Conclusions: Anemia in HFpEF is associated with greater evidence of congestion and more severe pulmonary hypertension, contributing to reduced exercise capacity. Iron deficiency in HFpEF is more common in women and associated with lower cardiac output at rest, but hemodynamics are otherwise similar. Further study is required to understand the mechanisms by which anemia and iron deficiency influence cardiac function and outcomes in HFpEF.

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 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.

Abstract Aims Lung congestion in patients with heart failure (HF) has traditionally been treated using interventions that reduce pulmonary capillary hydrostatic pressure. The transient receptor potential vanilloid 4 (TRPV4) channel regulates fluid transit across the pulmonary capillary-interface, and represents a novel target to reduce lung water, independent of pulmonary capillary hypertension. This pilot study examined the safety and potential efficacy of TRPV4 blockade as a novel treatment for HF. Methods and results In this randomized, double-blind, placebo-controlled crossover pilot trial, 11 subjects with chronic, compensated HF were treated with a novel TRPV4 antagonist (GSK2798745) or placebo. The primary endpoint was lung diffusing capacity for carbon monoxide (DLCO) after 7 days of treatment with GSK2798745 as compared to placebo. Secondary endpoints included additional diffusion parameters, spirometry and safety assessments. Compared to placebo, treatment with GSK2798745 resulted in a trend to improvement in DLCO (placebo: −0.336 mL/mmHg/min; GSK2798745: +0.458 mL/mmHg/min; treatment difference: +0.793 mL/mmHg/min; 95% confidence interval: −0.925 to 2.512) that was not statistically significant. GSK2798745 was well-tolerated with no serious adverse events. Conclusion In this pilot trial, GSK2798745 was found to be safe and well-tolerated, with a trend toward improved gas transfer. Further investigation is warranted in larger studies to determine whether treatment with TRPV4 antagonists or alternative treatments targeting capillary permeability might be effective to improve lung congestion, pulmonary gas transfer and clinical status in patients with acute or chronic HF.

Abstract Aims Patient-reported quality of life (QOL) is a highly prognostic and clinically relevant endpoint in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The relationships between QOL and different markers of HF severity remain unclear, particularly as they relate to functional capacity and directly measured activity levels. We hypothesized that QOL would demonstrate a stronger relationship with measures of exercise capacity and adiposity compared to other disease measures. Methods and results This is a secondary analysis of the National Heart, Lung, and Blood Institute-sponsored RELAX, NEAT-HFpEF and INDIE-HFpEF trials to determine the relationships between QOL (assessed by the Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire) and different domains reflecting HF severity, including maximal aerobic capacity (peak oxygen consumption), submaximal exercise capacity (6-min walk distance), volume of daily activity (accelerometry), physician-estimated functional class, resting echocardiography, and plasma natriuretic peptide levels. A total of 408 unique patients with chronic HFpEF were split into tertiles of QOL scores defined as QOLworst, QOLintermediate, QOLbest. The QOLworst HFpEF group was youngest, with a higher body mass index, greater prevalence of class II obesity and diabetes, and the lowest N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. After adjustment for age, sex and body mass index, poorer QOL was associated with worse physical capacity and activity levels, assessed by peak oxygen consumption, 6-min walk distance and actigraphy, but was not associated with NT-proBNP or indices from resting echocardiography. QOL was similarly reduced in patients with and without prior HF hospitalization. Conclusions Quality of life in HFpEF is poorest in patients who are young, obese and have diabetes, and is more robustly tied to measures reflecting functional capacity and daily activity levels rather than elevations in NT-proBNP or prior HF hospitalization. These findings have major implications for the understanding of QOL in HFpEF and for the design of future clinical trials targeting symptom improvement in HFpEF. Clinical Trial Registration: RELAX, NCT00763867; NEAT-HFpEF, NCT02053493; INDIE-HFpEF, NCT02742129.

Background: Patients with vascular stiffening may display increased arterial afterload that is out of proportion to systolic blood pressure (SBP). Since vascular and endothelial dysfunction develop in patients with coarctation of aorta (COA), we hypothesized that for any SBP, patients with mild COA (COA peak velocity <2 m/s) will have a higher arterial afterload and increased left ventricular mass index (LVMI) compared with controls, and that Doppler-derived arterial load indices would be a better predictor of LVMI compared with SBP alone. Methods: We studied 204 COA patients (age 35±12 y) and 204 matched controls. Doppler-derived arterial afterload was assessed using effective arterial elastance index and total arterial compliance index. Results: Despite similar SBP, the mild COA group displayed higher arterial afterload as evidenced by a higher elastance index (3.3±0.9 versus 2.9±0.7 mm Hg/mL·m 2 ; P <0.001) and lower total arterial compliance index (0.8±0.3 versus 1.2±0.5 mL/mm Hg·m 2 ; P <0.001). This was associated with higher LVMI in COA (109±35 versus 93±32, g/m 2 ; P <0.001). Compared with SBP (β=0.24 [95% CI, 0.02–0.45]), elastance index (β=20.2 [95% CI, 15.8–44.1]) and total arterial compliance index (β=−32.5 [95% CI, −43.8 to −123.6]) were better predictors of LVMI. Elastance index (but not SBP) was predictive of longitudinal increases in LVMI ( r =0.43, P <0.001). Conclusions: COA patients had higher arterial afterload compared with controls with similar SBP. In comparison to SBP, Doppler-derived arterial load indices correlate more strongly with LV hypertrophy. These data suggest that SBP may underestimate LV afterload in this population. This has important clinical implications since titration of antihypertensive therapy is currently based on SBP.

ABSTRACT Aims Mild to moderate functional mitral regurgitation (MR) is common in patients with heart failure and preserved ejection fraction (HFpEF) where it is usually considered as an innocent bystander. We hypothesized that MR in HFpEF reflects greater left atrial (LA) myopathy, leading to more adverse haemodynamics and poorer exercise reserve. Methods and results Patients with HFpEF (n = 280) with and without MR underwent echocardiography, invasive haemodynamic exercise testing, and expired gas analysis. As compared to non-MR-HFpEF (n = 163), patients with MR-HFpEF (n = 117; 78 mild and 39 moderate, central jet in 90%) were older, more likely female, with lower body mass and higher prevalence of atrial fibrillation (AF). HFpEF patients with MR displayed greater LA volume, reduced LA strain and compliance, and greater mitral annular dilatation, which was strongly correlated with LA dilatation (r = 0.63, P &lt; 0.0001) but was only weakly related to left ventricular remodelling (r = 0.37). Patients with MR-HFpEF displayed worse biventricular function, more adverse pulmonary haemodynamics, impaired pulmonary vasodilatation, blunted right ventricular reserve, and reduced cardiac output with exercise as compared to non-MR-HFpEF. Importantly, these findings were maintained after excluding patients with HFpEF and AF, suggesting a role for LA myopathy in contributing to MR in HFpEF, independent of rhythm. Conclusions Functional MR in patients with HFpEF reflects LA myopathy, even in the absence of AF, and is associated with greater haemodynamic severity of disease and poorer functional capacity. Further study is required to better define causal mechanisms and potential treatments for MR and LA dysfunction in patients with HFpEF.

Abstract Background Coronary microvascular inflammation is hypothesized to play a fundamental role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). No study has directly evaluated both endothelium-dependent and independent coronary microvascular function in HFpEF. Methods and results Consecutive patients with HFpEF undergoing invasive coronary physiologic testing and echocardiography were examined. Endothelial function was quantified by the increase in coronary blood flow in response to intracoronary infusion of acetylcholine (10−6–10−4 mol/L) using a Doppler flow wire with quantitative angiography. Endothelium-independent coronary microvascular function was assessed by the hyperaemic increase in coronary flow reserve in response to adenosine infusion. Among 162 HFpEF patients (67% women), coronary microvascular function was abnormal in 117 (72%). Isolated endothelium-dependent microvascular dysfunction was present in 47 patients (29%), isolated endothelium-independent microvascular dysfunction in 53 patients (33%), and combined microvascular dysfunction in 17 patients (10%). The presence of coronary microvascular dysfunction was not identifiable from medical co-morbidities or other clinical characteristics. As compared to patients with normal endothelium-independent function, HFpEF patients with endothelium-independent coronary microvascular dysfunction displayed lower diastolic relaxation velocities (7.0 ± 1.8 vs. 8.4 ± 2.9 cm/s, P = 0.002) and higher estimated filling pressures (E/e’ 13.1 ± 4.1 vs. 9.6 ± 3.4, P &lt; 0.001). There were no relationships between left ventricular structure, function, or haemodynamics and endothelium-dependent coronary vasodilatation. Endothelium-independent microvascular dysfunction was associated with increased mortality. Conclusions Coronary microvascular dysfunction is common in patients with HFpEF and is caused equally by endothelium-dependent and independent mechanisms, but the presence of microvascular dysfunction cannot be identified from clinical markers and co-morbidities alone. Patients with HFpEF and endothelium-independent microvascular dysfunction display worse diastolic dysfunction and outcomes.