OBJECTIVES: The authors hypothesized that quantitative computed tomography (QCT) imaging would reveal subclinical increases in lung congestion in patients with heart failure and preserved ejection fraction (HFpEF) and that this would be related to pulmonary vascular hemodynamic abnormalities. BACKGROUND: Gross evidence of lung congestion on physical examination, laboratory tests, and radiography is typically absent among compensated ambulatory patients with HFpEF. However, pulmonary gas transfer abnormalities are commonly observed and associated with poor outcomes. METHODS: Patients referred for invasive hemodynamic exercise testing who had undergone chest computed tomography imaging within 1 month were identified (N = 137). A novel artificial intelligence QCT algorithm was used to measure pulmonary fluid content. RESULTS: Compared with control subjects with noncardiac dyspnea, patients with HFpEF displayed increased mean lung density (-758 HU [-793, -709 HU] vs -787 HU [-828, -747 HU]; P = 0.002) and a higher ratio of extravascular lung water to total lung volume (EVLWV/TLV) (1.25 [0.80, 1.76] vs 0.66 [0.01, 1.03]; P < 0.0001) by QCT imaging, indicating greater lung congestion. EVLWV/TLV was directly correlated with pulmonary vascular pressures at rest, with stronger correlations observed during exercise. Patients with increasing tertiles of EVLWV/TLV demonstrated higher mean pulmonary artery pressures at rest (34 ± 11 mm Hg vs 39 ± 14 mm Hg vs 45 ± 17 mm Hg; P = 0.0003) and during exercise (55 ± 17 mm Hg vs 59 ± 17 mm Hg vs 69 ± 22 mm Hg; P = 0.0003). CONCLUSIONS: QCT imaging identifies subclinical lung congestion in HFpEF that is not clinically apparent but is related to abnormalities in pulmonary vascular hemodynamics. These data provide new insight into the long-term effects of altered hemodynamics on pulmonary structure and function in HFpEF.

• Keywords
• computed tomography, congestion, exercise, heart failure, hemodynamics,
• MeSH
• Hemodynamics MeSH
• Humans MeSH
• Lung diagnostic imaging   MeSH
• Pulmonary Edema * diagnostic imaging   etiology   MeSH
• Predictive Value of Tests MeSH
• Heart Failure * complications   diagnostic imaging   MeSH
• Stroke Volume MeSH
• Artificial Intelligence MeSH
• Exercise Test MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH

AIMS: Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF). Little is known about the impact of PVD on the pathophysiology of exercise intolerance. METHODS AND RESULTS: Heart failure with preserved ejection fraction patients (n = 161) with elevated pulmonary capillary wedge pressure (≥15 mmHg) at rest were classified into three groups: non-PH-HFpEF (n = 21); PH but no PVD (isolated post-capillary PH, IpcPH; n = 95); and PH with PVD (combined post- and pre-capillary PH, CpcPH; n = 45). At rest, CpcPH-HFpEF patients had more right ventricular (RV) dysfunction and lower pulmonary arterial (PA) compliance compared to all other groups. While right atrial pressure (RAP) and left ventricular transmural pressure (LVTMP) were similar in HFpEF with and without PH or PVD at rest, CpcPH-HFpEF patients demonstrated greater increase in RAP, enhanced ventricular interdependence, and paradoxical reduction in LVTMP during exercise, differing from all other groups (P < 0.05). Lower PA compliance was correlated with greater increase in RAP with exercise. During exercise, CpcPH-HFpEF patients displayed an inability to enhance cardiac output, reduction in forward stroke volume, and blunted augmentation in RV systolic performance, changes that were coupled with marked limitation in aerobic capacity. CONCLUSION: Heart failure with preserved ejection fraction patients with PVD demonstrate unique haemodynamic limitations during exercise that constrain aerobic capacity, including impaired recruitment of LV preload due to excessive right heart congestion and blunted RV systolic reserve. Interventions targeted to this distinct pathophysiology require testing in patients with HFpEF and PVD.

• MeSH
• Pulmonary Artery * MeSH
• Humans MeSH
• Vascular Diseases etiology   MeSH
• Aged MeSH
• Heart Failure complications   physiopathology   MeSH
• Stroke Volume * MeSH
• Pulmonary Veins * MeSH
• Exercise Test * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Cardiac reserve is depressed in patients with heart failure and preserved ejection fraction (HFpEF). The mechanisms causing this are poorly understood. OBJECTIVES: The authors hypothesized that myocardial injury might contribute to the hemodynamic derangements and cardiac reserve limitations that are present in HFpEF. Markers of cardiomyocyte injury, central hemodynamics, ventricular function, and determinants of cardiac oxygen supply-demand balance were measured. METHODS: Subjects with HFpEF (n = 38) and control subjects without heart failure (n = 20) underwent cardiac catheterization, echocardiography, and expired gas analysis at rest and during exercise. Central venous blood was sampled to measure plasma high-sensitivity troponin T levels as an index of cardiomyocyte injury. RESULTS: Compared with control subjects, troponins were more than 2-fold higher in subjects with HFpEF at rest and during exercise (p < 0.0001). Troponin levels were directly correlated with left ventricular (LV) filling pressures (r = 0.52; p < 0.0001) and diastolic dysfunction (r = -0.43; p = 0.002). Although myocardial oxygen demand was similar, myocardial oxygen supply was depressed in HFpEF, particularly during exercise (coronary perfusion pressure-time integral; 44 ± 9 mm Hg × s × min-1 × l × dl-1 vs. 30 ± 9 mm Hg × s × min-1 × l × dl-1; p < 0.0001), and reduced indices of supply were correlated with greater myocyte injury during exercise (r = -0.44; p = 0.0008). Elevation in troponin with exercise was directly correlated with an inability to augment LV diastolic (r = -0.40; p = 0.02) and systolic reserve (r = -0.57; p = 0.0003), greater increases in LV filling pressures (r = 0.55; p < 0.0001), blunted cardiac output response (r = -0.44; p = 0.002), and more severely depressed aerobic capacity in HFpEF. CONCLUSIONS: Limitations in LV functional reserve and the hemodynamic derangements that develop secondary to these limitations during exercise in HFpEF are correlated with the severity of cardiac injury, assessed by plasma levels of troponin T. Further study is warranted to determine the mechanisms causing myocyte injury in HFpEF and the potential role of ischemia, and to identify and test novel interventions targeted to these mechanisms. (EXEC [Study of Exercise and Heart Function in Patients With Heart Failure and Pulmonary Vascular Disease]; NCT01418248).

• Keywords
• HFpEF, biomarkers, exercise, heart failure, hemodynamics, troponin T,
• MeSH
• Exercise physiology   MeSH
• Oxygen blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Coronary Artery Disease physiopathology   MeSH
• Heart Injuries blood   etiology   physiopathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Heart Failure blood   complications   physiopathology   MeSH
• Case-Control Studies MeSH
• Stroke Volume MeSH
• Troponin T blood   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Oxygen MeSH
• Troponin T MeSH

BACKGROUND: Aortic stiffening and reduced nitric oxide (NO) availability may contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: This study compared indices of arterial stiffness at rest and during exercise in subjects with HFpEF and hypertensive control subjects to examine their relationships to cardiac hemodynamics and determine whether exertional arterial stiffening can be mitigated by inorganic nitrite. METHODS: A total of 22 hypertensive control subjects and 98 HFpEF subjects underwent hemodynamic exercise testing with simultaneous expired gas analysis to measure oxygen consumption. Invasively measured radial artery pressure waveforms were converted to central aortic waveforms by transfer function to assess integrated measures of pulsatile aortic load, including arterial compliance, resistance, elastance, and wave reflection. RESULTS: Arterial load and wave reflections in HFpEF were similar to those in control subjects at rest. During submaximal exercise, HFpEF subjects displayed reduced total arterial compliance and higher effective arterial elastance despite similar mean arterial pressures in control subjects. This was directly correlated with higher ventricular filling pressures and depressed cardiac output reserve (both p < 0.0001). With peak exercise, increased wave reflections, impaired compliance, and increased resistance and elastance were observed in subjects with HFpEF. A subset of HFpEF subjects (n = 52) received sodium nitrite or placebo therapy in a 1:1 double-blind, randomized fashion. Compared to placebo, nitrite decreased aortic wave reflections at rest and improved arterial compliance and elastance and central hemodynamics during exercise. CONCLUSIONS: Abnormal pulsatile aortic loading during exercise occurs in HFpEF independent of hypertension and is correlated with classical hemodynamic derangements that develop with stress. Inorganic nitrite mitigates arterial stiffening with exercise and improves hemodynamics, indicating that arterial stiffening with exercise is at least partially reversible. Further study is required to test effects of agents that target the NO pathway in reducing arterial stiffness in HFpEF. (Study of Exercise and Heart Function in Patients With Heart Failure and Pulmonary Vascular Disease [EXEC]; NCT01418248. Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction; NCT01932606. Inhaled Sodium Nitrite on Heart Failure With Preserved Ejection Fraction; NCT02262078).

• Keywords
• HFpEF, aortic stiffness, exercise, heart failure, hypertension,
• MeSH
• Exercise physiology   MeSH
• Nitrates pharmacology   MeSH
• Double-Blind Method MeSH
• Ventricular Function, Left physiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Rest physiology   MeSH
• Prospective Studies MeSH
• Aged MeSH
• Heart Failure drug therapy   physiopathology   MeSH
• Stroke Volume physiology   MeSH
• Vascular Stiffness physiology   MeSH
• Exercise Test MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Nitrates MeSH
• sodium nitrate MeSH Browser

BACKGROUND: Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging and relies largely on demonstration of elevated cardiac filling pressures (pulmonary capillary wedge pressure). Current guidelines recommend use of natriuretic peptides (N-terminal pro-B type natriuretic peptide) and rest/exercise echocardiography (E/e' ratio) to make this determination. Data to support this practice are conflicting. METHODS: Simultaneous echocardiographic-catheterization studies were prospectively conducted at rest and during exercise in subjects with invasively proven HFpEF (n=50) and participants with dyspnea but no identifiable cardiac pathology (n=24). RESULTS: N-Terminal pro-B type natriuretic peptide levels were below the level considered to exclude disease (≤125 pg/mL) in 18% of subjects with HFpEF. E/e' ratio was correlated with directly measured pulmonary capillary wedge pressure at rest (r=0.63, P<0.0001) and during exercise (r=0.57, P<0.0001). Although specific, current guidelines were poorly sensitive, identifying only 34% to 60% of subjects with invasively proven HFpEF on the basis of resting echocardiographic data alone. Addition of exercise echocardiographic data (E/e' ratio>14) improved sensitivity (to 90%) and thus negative predictive value, but decreased specificity (71%). CONCLUSIONS: Currently proposed HFpEF diagnostic guidelines on the basis of resting data are poorly sensitive. Adding exercise E/e' data improves sensitivity and negative predictive value but compromises specificity, suggesting that exercise echocardiography may help rule out HFpEF. These results question the accuracy of current approaches to exclude HFpEF on the basis of resting data alone and reinforce the value of exercise testing using invasive and noninvasive hemodynamic assessments to definitively confirm or refute the diagnosis of HFpEF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01418248.

• Keywords
• diagnosis, exercise, exercise test, heart failure,
• MeSH
• Echocardiography MeSH
• Ventricular Function, Left physiology   MeSH
• Hemodynamics MeSH
• Middle Aged MeSH
• Humans MeSH
• Natriuretic Peptide, Brain analysis   MeSH
• Peptide Fragments analysis   MeSH
• Prospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Heart Failure diagnosis   diagnostic imaging   MeSH
• Stroke Volume physiology   MeSH
• Exercise Test MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Natriuretic Peptide, Brain MeSH
• Peptide Fragments MeSH
• pro-brain natriuretic peptide (1-76) MeSH Browser