Relation of Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease to Left Ventricular Diastolic Function and Exercise Tolerance.

The purpose of this study was to determine the relation between liver histology, exercise tolerance, and diastolic function in patients with nonalcoholic fatty liver disease (NAFLD). Myocardial remodeling and diastolic dysfunction have been associated with NAFLD. However, its physiological impact and relationship to the histological severity of NAFLD is not known. Cardiopulmonary exercise testing and stress echocardiography was performed in subjects with biopsy-confirmed NAFLD. Maximal aerobic exercise capacity (peak oxygen consumption [VO2]) was related to diastolic function (mitral annulus Doppler velocity e' and ratio of early diastolic filling pressure [E] to e' [E/e']) at rest and peak exercise. Autonomic dysfunction was determined from heart rate recovery after exercise. Independent predictors of cardiac function and exercise capacity were identified by multivariable regression. Thirty-six subjects (nonalcoholic fatty liver [NAFL  =  15], nonalcoholic steatohepatitis [NASH  =  21]) were enrolled. NASH was associated with impaired exercise capacity compared with NAFL (median peak VO2 17.0 [15.4, 18.9] vs 19.9 [17.4, 26.0], p  =  001); pVO2 declined with increasing fibrosis (F0  =  22.5, F1  =  19.9, F2  =  19.0, F3  =  16.6 ml·kg-1·min-1; p  =  0.01). Similarly, E/e' during exercise increased progressively with increasing fibrosis (F0  =  5.6, F1  =  6.5, F2  =  8.7, F3  =  9.8; P  =  0.02). Finally, heart rate recovery, a marker of autonomic function, was blunted in those with higher fibrosis stages (F0  =  25 [20, 30], F1  =  23 [17.5, 27.0], F2  =  17 [11.8, 21.5], F3  =  11 [8.5, 18.0] beats per minute; p <0.01). Fibrosis was an independent predictor of these functional outcomes. In conclusion, NASH is associated with impaired exercise capacity and diastolic dysfunction compared with NAFL. The severity of impairment is directly related to the severity of fibrosis stage in precirrhotic stages of NAFLD.

Severely Impaired Cardiorespiratory Fitness in Patients With Recently Decompensated Systolic Heart Failure.

Hospital admission for decompensated heart failure marks a critical inflection point in a patient's health. Despite the improvement in signs or symptoms during hospitalization, patients have a high likelihood of readmission, reflecting a lack of resolution of the underlying condition. Surprisingly, no studies have characterized the cardiorespiratory fitness of such patients. Fifty-two patients (38 [73%] male, age 57 [52 to 65] years, left ventricular ejection fraction 31% [24 to 38]) underwent cardiopulmonary exercise testing 4 (1 to 10) days after hospital discharge, when stable and without overt signs of volume overload. Transthoracic Doppler echocardiography, measurement of N-terminal pro-B-natriuretic peptide, and quality of life were also assessed. Aerobic exercise capacity was severely reduced: peak oxygen consumption (pVO2) was 14.1 (11.2 to 16.3) ml/kg/min. Ventilatory inefficiency as indicated by the minute ventilation carbon dioxide production relation (VE/VCO2 slope) >30 and oxygen uptake efficiency slope <2.0 was noted in 41 (77%) and 39 (75%) patients, respectively. Forty-five (87%) patients had 1 of 2 high-risk features (pVO2 < 14 ml/kg/min or VE/VCO2 >30). Perceived functional capacity, measured by the Duke Activity Status Index, was also severely reduced and correlated with pVO2. N-terminal pro-B-natriuretic peptide levels and early transmitral velocity/early mitral annulus velocity (E/e') ratio at echocardiography showed a modest correlation with lower pVO2. In conclusion, patients with recently decompensated systolic heart failure demonstrate severe impairment in cardiorespiratory fitness, severely limiting quality of life.

Usefulness of C-Reactive Protein Plasma Levels to Predict Exercise Intolerance in Patients With Chronic Systolic Heart Failure.

Patients with heart failure (HF) have evidence of chronic systemic inflammation. Whether inflammation contributes to the exercise intolerance in patients with HF is, however, not well established. We hypothesized that the levels of C-reactive protein (CRP), an established inflammatory biomarker, predict impaired cardiopulmonary exercise performance, in patients with chronic systolic HF. We measured CRP using high-sensitivity particle-enhanced immunonephelometry in 16 patients with ischemic heart disease (previous myocardial infarction) and chronic systolic HF, defined as a left ventricular ejection fraction ≤ 50% and New York Heart Association class II-III symptoms. All subjects with CRP >2 mg/L, reflecting systemic inflammation, underwent cardiopulmonary exercise testing using a symptom-limited ramp protocol. CRP levels predicted shorter exercise times (R = -0.65, p = 0.006), lower oxygen consumption (VO2) at the anaerobic threshold (R = -0.66, p = 0.005), and lower peak VO2 (R = -0.70, p = 0.002), reflecting worse cardiovascular performance. CRP levels also significantly correlated with an elevated ventilation/carbon dioxide production slope (R = +0.64, p = 0.008), a reduced oxygen uptake efficiency slope (R = -0.55, p = 0.026), and reduced end-tidal CO2 level at rest and with exercise (R = -0.759, p = 0.001 and R = -0.739, p = 0.001, respectively), reflecting impaired gas exchange. In conclusion, the intensity of systemic inflammation, measured as CRP plasma levels, is associated with cardiopulmonary exercise performance, in patients with ischemic heart disease and chronic systolic HF. These data provide the rationale for targeted anti-inflammatory treatments in HF.

Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study).

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance due to impaired myocardial relaxation and/or increased stiffness. Patients with HFpEF often show signs of chronic systemic inflammation, and experimental studies have shown that interleukin-1 (IL-1), a key proinflammatory cytokine, impairs myocardial relaxation. The aim of the present study was to determine the effects of IL-1 blockade with anakinra on aerobic exercise capacity in patients with HFpEF and plasma C-reactive protein (CRP) >2 mg/L (reflecting increased IL-1 activity). A total of 12 patients were enrolled in a double-blind, randomized, placebo-controlled, crossover trial and assigned 1:1 to receive 1 of the 2 treatments (anakinra 100 mg or placebo) for 14 days and an additional 14 days of the alternate treatment (placebo or anakinra). The cardiopulmonary exercise test was performed at baseline, after the first 14 days, and after the second 14 days of treatment. The placebo-corrected interval change in peak oxygen consumption was chosen as the primary end point. All 12 patients enrolled in the present study and receiving treatment completed both phases and experienced no major adverse events. Anakinra led to a statistically significant improvement in peak oxygen consumption (+1.2 ml/kg/min, p = 0.009) and a significant reduction in plasma CRP levels (-74%, p = 0.006). The reduction in CRP levels correlated with the improvement in peak oxygen consumption (R = -0.60, p = 0.002). Three patients (25%) had mild and self-limiting injection site reactions. In conclusion, IL-1 blockade with anakinra for 14 days significantly reduced the systemic inflammatory response and improved the aerobic exercise capacity of patients with HFpEF and elevated plasma CRP levels.