Exercise intolerance is common in people with heart failure and preserved ejection fraction (HFpEF). Right ventricular (RV) dysfunction has been shown at rest in HFpEF but little data are available ...regarding dynamic RV-pulmonary artery (PA) coupling during exercise.
Subjects with HFpEF (n = 50) and controls (n = 24) prospectively underwent invasive cardiopulmonary exercise testing using high-fidelity micromanometer catheters along with simultaneous assessment of RV and left ventricular (LV) mechanics by echocardiography. Compared with controls at rest, subjects with HFpEF displayed preserved RV systolic and diastolic mechanics (RV s' and e'), impaired LV s' and e', higher biventricular filling pressures, and higher pulmonary artery pressures. On exercise, subjects with HFpEF displayed less increase in stroke volume, heart rate, and cardiac output (CO), with blunted increase in CO relative to O
consumption (VO
). Enhancement in RV systolic and diastolic function on exercise was impaired in HFpEF compared with controls. Exercise-induced PA vasodilation was reduced in HFpEF in correlation with greater venous hypoxia. Elevations in biventricular filling pressures and limitations in CO reserve were strongly correlated with abnormal enhancement in ventricular mechanics in the RV and LV during stress.
In addition to limited LV reserve, patients with HFpEF display impaired RV reserve during exercise that is associated with high filling pressures and inadequate CO responses. These findings highlight the importance of biventricular dysfunction in HFpEF and suggest that novel therapies targeting myocardial reserve in both the left and right heart may be effective to improve clinical status.
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:URLhttp://www.clinicaltrials.gov. Unique IdentifierNCT01418248.
CONTEXT Heart failure incidence increases with advancing age, and approximately half of patients with heart failure have preserved left ventricular ejection fraction. Although diastolic dysfunction ...plays a role in heart failure with preserved ejection fraction, little is known about age-dependent longitudinal changes in diastolic function in community populations. OBJECTIVE To measure changes in diastolic function over time and to determine the relationship between diastolic dysfunction and the risk of subsequent heart failure. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort of participants enrolled in the Olmsted County Heart Function Study. Randomly selected participants 45 years or older (N = 2042) underwent clinical evaluation, medical record abstraction, and echocardiography (examination 1 1997-2000). Diastolic left ventricular function was graded as normal, mild, moderate, or severe by validated Doppler techniques. After 4 years, participants were invited to return for examination 2 (2001-2004). The cohort of participants returning for examination 2 (n = 1402 of 1960 surviving 72%) then underwent follow-up for ascertainment of new-onset heart failure (2004-2010). MAIN OUTCOME MEASURES Change in diastolic function grade and incident heart failure. RESULTS During the 4 (SD, 0.3) years between examinations 1 and 2, diastolic dysfunction prevalence increased from 23.8% (95% confidence interval CI, 21.2%-26.4%) to 39.2% (95% CI, 36.3%-42.2%) (P < .001). Diastolic function grade worsened in 23.4% (95% CI, 20.9%-26.0%) of participants, was unchanged in 67.8% (95% CI, 64.8%-70.6%), and improved in 8.8% (95% CI, 7.1%-10.5%). Worsened diastolic dysfunction was associated with age 65 years or older (odds ratio, 2.85 95% CI, 1.77-4.72). During 6.3 (SD, 2.3) years of additional follow-up, heart failure occurred in 2.6% (95% CI, 1.4%-3.8%), 7.8% (95% CI, 5.8%-13.0%), and 12.2% (95% CI, 8.5%-18.4%) of persons whose diastolic function normalized or remained normal, remained or progressed to mild dysfunction, or remained or progressed to moderate or severe dysfunction, respectively (P < .001). Diastolic dysfunction was associated with incident heart failure after adjustment for age, hypertension, diabetes, and coronary artery disease (hazard ratio, 1.81 95% CI, 1.01-3.48). CONCLUSIONS In a population-based cohort undergoing 4 years of follow-up, prevalence of diastolic dysfunction increased. Diastolic dysfunction was associated with development of heart failure during 6 years of subsequent follow-up.
Abstract
A unique and highly versatile technique, stress echocardiography (SE) is increasingly recognized for its utility in the evaluation of non-ischaemic heart disease. SE allows for simultaneous ...assessment of myocardial function and haemodynamics under physiological or pharmacological conditions. Due to its diagnostic and prognostic value, SE has become widely implemented to assess various conditions other than ischaemic heart disease. It has thus become essential to establish guidance for its applications and performance in the area of non-ischaemic heart disease. This paper summarizes these recommendations.
Abstract
Aims
Increases in left ventricular filling pressure are a fundamental haemodynamic abnormality in heart failure with preserved ejection fraction (HFpEF). However, very little is known ...regarding how elevated filling pressures cause pulmonary abnormalities or symptoms of dyspnoea. We sought to determine the relationships between simultaneously measured central haemodynamics, symptoms, and lung ventilatory and gas exchange abnormalities during exercise in HFpEF.
Methods and results
Subjects with invasively-proven HFpEF (n = 50) and non-cardiac causes of dyspnoea (controls, n = 24) underwent cardiac catheterization at rest and during exercise with simultaneous expired gas analysis. During submaximal (20 W) exercise, subjects with HFpEF displayed higher pulmonary capillary wedge pressures (PCWP) and pulmonary artery pressures, higher Borg perceived dyspnoea scores, and increased ventilatory drive and respiratory rate. At peak exercise, ventilation reserve was reduced in HFpEF compared with controls, with greater dead space ventilation (higher VD/VT). Increasing exercise PCWP was directly correlated with higher perceived dyspnoea scores, lower peak exercise capacity, greater ventilatory drive, worse New York Heart Association (NYHA) functional class, and impaired pulmonary ventilation reserve.
Conclusion
This study provides the first evidence linking altered exercise haemodynamics to pulmonary abnormalities and symptoms of dyspnoea in patients with HFpEF. Further study is required to identify the mechanisms by which haemodynamic derangements affect lung function and symptoms and to test novel therapies targeting exercise haemodynamics in HFpEF.
Although right ventricular (RV) dysfunction is a major determinant of outcome in patients with pulmonary hypertension (PH), the optimal measure of RV function is poorly defined. We hypothesized that ...RV strain measured by speckle-tracking echocardiography predicts outcome in PH over a broad range of pulmonary pressures.
Prospective peak RV longitudinal systolic strain measurement was performed on 575 patients (mean age, 56 ± 18 years; 63% women) referred for echocardiography for known or suspected PH. Survival status was assessed over a median of 16.5 (interquartile range, 7.6-20.0) months. There were 406 patients with PH (71%) (74% group 1, 14% group 3, and 12% group 4) and 169 patients without evidence of PH (29%). Among patients with PH, 46% were World Health Organization functional class III-IV. The mean RV strain was -21.2 ± 6.7% for all patients. RV strain declined with worse functional class, shorter 6-minute walk distances, higher N-terminal pro-B-type natriuretic peptide levels, and the presence of right heart failure. RV strain predicted outcome across pulmonary pressures and groups of PH. Eighteen-month survival was 92%, 88%, 85%, and 71% according to RV strain quartile (P<0.001), with a 1.46 higher risk of death (95% confidence interval, 1.05-2.12) per 6.7% decline in RV strain. RV strain predicted survival when adjusted for pulmonary pressure, pulmonary vascular resistance, and right atrial pressure and provided incremental prognostic value over conventional clinical and echocardiographic variables.
Quantitative assessment of RV free-wall systolic strain is feasible and is a powerful predictor of the clinical outcome of patients with known or suspected PH.
Cardiac reserve is depressed in patients with heart failure and preserved ejection fraction (HFpEF). The mechanisms causing this are poorly understood.
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.
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.
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.
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)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to assess whether serial quantitative assessment of right ventricular (RV) function by speckle-based strain imaging is affected by pulmonary hypertension–specific therapies ...and whether there is a correlation between serial changes in RV strain and clinical status. RV longitudinal systolic function was assessed using speckle-tracking echocardiography in 50 patients with pulmonary arterial hypertension (PAH) before and after the initiation of therapy. The mean interval to follow-up was 6 ± 2 months. Subsequent survival was assessed over 4 years. Patients demonstrated a mean increase in RV systolic strain from −15 ± 5 before to −20 ± 7% (p = 0.0001) after PAH treatment. Persistence of or progression to a severe reduction in free wall systolic strain (<−12.5%) at 6 months was associated with greater disease severity (100% were in functional class III or IV vs 42%, p = 0.005), greater diuretic use (86% vs 40%, p = 0.02), higher mean pulmonary artery pressure (67 ± 20 vs 46 ± 17 mm Hg, p = 0.006), and poorer survival (4-year mortality 43% vs 23%, p = 0.002). After adjusting for age, functional class, and RV strain at baseline, patients with ≥5% improvement in RV free wall systolic strain had a greater than sevenfold lower mortality risk at 4 years (hazard ratio 0.13, 95% confidence interval 0.03 to 0.50, p = 0.003). In conclusion, serial echocardiographic assessment of RV longitudinal systolic function by quantitative strain imaging independently predicts clinical deterioration and mortality in patients with PAH after the institution of medical therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In contrast to the wealth of data on isolated systolic hypertension involving the systemic circulation in the elderly, much less is known about age-related change in pulmonary artery systolic ...pressure (PASP) and its prognostic impact in the general population. We sought to define the relationship between PASP and age, to evaluate which factors influence PASP, and to determine whether PASP is independently predictive of mortality in the community.
A random sample of the Olmsted County, Minn, general population (n=2042) underwent echocardiography and spirometry and was followed up for a median of 9 years. PASP was measured from the tricuspid regurgitation velocity. Left ventricular diastolic pressure was estimated with Doppler echocardiography (E/e' ratio), and arterial stiffening was assessed from the brachial artery pulse pressure. Among 1413 subjects (69%) with measurable PASP (age, 63+/-11 years; 43% male), median PASP was 26 mm Hg (25th to 75th percentile, 24 to 30 mm Hg) and increased with age (r=0.31, P<0.001). Independent predictors of PASP were age, pulse pressure, and mitral E/e' (all P< or =0.003). Increasing PASP was associated with higher mortality (hazard ratio, 2.73 per 10 mm Hg; P<0.001). In subjects without cardiopulmonary disease (any heart failure, coronary artery disease, hypertension, diabetes mellitus, or chronic obstructive lung disease), the age-adjusted hazard ratio was 2.74 per 10 mm Hg (P=0.016).
We provide the first population-based evidence of age-related increase in pulmonary artery pressure, its association with increasing left heart diastolic pressures and systemic vascular stiffening, and its negative impact on survival. Pulmonary artery pressure may serve as a novel cardiovascular risk factor and potential therapeutic target.
Aortic stiffening and reduced nitric oxide (NO) availability may contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF).
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.
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.
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.
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)
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