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Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.

ABSTRACT: Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance; however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond what occurs with normal aging and that this contributes to their severe exercise intolerance. Sixty-nine patients ?60 years of age with HFpEF and 62 healthy volunteers (24 young healthy subjects ?30 years and 38 older healthy subjects ?60 years old) were examined. Carotid arterial stiffness was assessed using high-resolution ultrasound, and peak exercise oxygen consumption was measured using expired gas analysis. Peak exercise oxygen consumption was severely reduced in the HFpEF patients compared with older healthy subjects (14.1±2.9 versus 19.7±3.7 mL/kg per minute; P<0.001) and in both was reduced compared with young healthy subjects (32.0±7.2 mL/kg per minute; both P<0.001). In HFpEF compared with older healthy subjects, carotid arterial distensibility was reduced (0.97±0.45 versus 1.33±0.55×10(-3) mm Hg(-1); P=0.008) and Young's elastic modulus was increased (1320±884 versus 925±530 kPa; P<0.02). Carotid arterial distensibility was directly (0.28; P=0.02) and Young's elastic modulus was inversely (-0.32; P=0.01) related to peak exercise oxygen consumption. Carotid arterial distensibility is decreased in HFpEF beyond the changes attributed to normal aging and is related to peak exercise oxygen consumption. This supports the hypothesis that increased arterial stiffness contributes to exercise intolerance in HFpEF and is a potential therapeutic target.

SUBMITTER: Kitzman DW

PROVIDER: S-EPMC3712338 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.

Kitzman Dalane W DW Herrington David M DM Brubaker Peter H PH Moore J Brian JB Eggebeen Joel J Haykowsky Mark J MJ

Hypertension (Dallas, Tex. : 1979) 20121112 1

Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance; however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond what occurs with normal aging and that this contributes to their severe exercise intolerance. Sixty-nine patients ≥60 years of age with HFpEF and 62 ...[more]

PMID: 23150511

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Project description: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).

Project description:OBJECTIVES:This study sought to test the hypothesis that older obese patients with heart failure with preserved ejection fraction (HFpEF) have significantly greater abdominal, cardiac, and intermuscular fat than healthy, age-matched controls, out of proportion to total body fat, and that these abnormalities are associated with objective measurements of physical function. BACKGROUND:Recent studies indicate that excess total body adipose tissue contributes to exercise intolerance in patients with HFpEF. However, the impact of the pattern of regional (abdominal, cardiac, intermuscular) adipose deposition on exercise intolerance in patients with HFpEF is unknown. METHODS:We measured total body adiposity (using dual-energy x-ray absorptiometry) and regional adiposity (using cardiac magnetic resonance), peak oxygen uptake (Vo2), 6-min walk distance (6MWD), short physical performance battery (SPPB), and leg press power in 100 older obese patients with HFpEF and 61 healthy controls (HCs) and adjusted for age, sex, race, and body surface area. RESULTS:Peak Vo2 (15.7 ± 0.4 ml/kg/min vs. 23.0 ± 0.6 ml/kg/min, respectively; p < 0.001), 6MWD (427 ± 7 m vs. 538 ± 10 m, respectively; p < 0.001), SPPB (10.3 ± 0.2 vs. 10.9 ± 0.2, respectively; p < 0.05), and leg power (117 ± 5 W vs. 152 ± 9 W, respectively; p = 0.004) were significantly lower in patients with HFpEF than HCs. Total fat mass, total percent fat, abdominal subcutaneous fat, intra-abdominal fat, and thigh intermuscular fat were significantly higher, whereas epicardial fat was significantly lower in patients with HFpEF than in HC. After we adjusted for total body fat, intra-abdominal fat remained significantly higher, while epicardial fat remained significantly lower in patients with HFpEF. Abdominal subcutaneous fat, thigh subcutaneous fat, and thigh intermuscular fat:skeletal muscle ratio were inversely associated, whereas epicardial fat was directly associated with peak Vo2, 6MWD, SPPB, and leg power. Using multiple stepwise regression, we found intra-abdominal fat was the strongest independent predictor of peak Vo2 and 6MWD. CONCLUSIONS:In metabolic obese HFpEF, the pattern of regional adipose deposition may have important adverse consequences beyond total body adiposity. Interventions targeting intra-abdominal and intermuscular fat could potentially improve exercise intolerance. (Exercise Intolerance in Elderly Patients With Diastolic Heart Failure [SECRET]; NCT00959660).

Project description:BACKGROUND:Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with a pressing shortage of therapies. Exercise intolerance is a cardinal symptom of HFpEF, yet its pathophysiology remains uncertain. METHODS:We investigated the mechanism of exercise intolerance in 134 patients referred for cardiopulmonary exercise testing: 79 with HFpEF and 55 controls. We performed cardiopulmonary exercise testing with invasive monitoring to measure hemodynamics, blood gases, and gas exchange during exercise. We used these measurements to quantify 6 steps of oxygen transport and utilization (the O2 pathway) in each patient with HFpEF, identifying the defective steps that impair each one's exercise capacity (peak Vo2). We then quantified the functional significance of each O2 pathway defect by calculating the improvement in exercise capacity a patient could expect from correcting the defect. RESULTS:Peak Vo2 was reduced by 34±2% (mean±SEM, P<0.001) in HFpEF compared with controls of similar age, sex, and body mass index. The vast majority (97%) of patients with HFpEF harbored defects at multiple steps of the O2 pathway, the identity and magnitude of which varied widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were impaired relative to controls by an average of 27±3% and 36±2%, respectively (P<0.001 for both). Due to interactions between a given patient's defects, the predicted benefit of correcting any single one was often minor; on average, correcting a patient's cardiac output led to a 7±0.5% predicted improvement in exercise intolerance, whereas correcting a patient's muscle diffusion capacity led to a 27±1% improvement. At the individual level, the impact of any given O2 pathway defect on a patient's exercise capacity was strongly influenced by comorbid defects. CONCLUSIONS:Systematic analysis of the O2 pathway in HFpEF showed that exercise capacity was undermined by multiple defects, including reductions in cardiac output and skeletal muscle diffusion capacity. An important source of disease heterogeneity stemmed from variation in each patient's personal profile of defects. Personalized O2 pathway analysis could identify patients most likely to benefit from treating a specific defect; however, the system properties of O2 transport favor treating multiple defects at once, as with exercise training.

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Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.

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Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.

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