Elevations in C-reactive protein and endothelin-1 system activity in humans.

AIMS: C-reactive protein (CRP) is an inflammatory cytokine that has been shown to be an independent predictor of future atherothrombotic events. Hyperactivity of endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by the endothelium, is linked with cardiovascular disease development and progression. ET-1 is sensitive to inflammatory stimuli, though the influence of CRP on ET-1 system activity is unknown. We tested the hypothesis that ET-1-mediated vasoconstrictor tone is enhanced in adults with elevated plasma CRP concentrations. MATERIALS AND METHODS: Sixty non-obese adults (43-70years) were studied: 20 with hsCRP<1.0mg/L (low CRP; 0.5±0.1mg/L); 20 with hsCRP 1.0-3.0mg/L (moderate CRP; 2.0±0.1mg/L); and 20 with hsCRP>3.0mg/L (high CRP; 6.3±0.5mg/L). Forearm blood flow (FBF; plethysmography) was determined in response to intra-arterial infusions of ET-1 (5pmol/min for 20min) and selective ETA receptor blockade (BQ-123, 100nmol/min for 60min). KEY FINDINGS: In response to ET-1, FBF decreased ~10% in the low (-10.0±2.3%), moderate (-10.7±4.0%), and high (-6.6±5.2%) CRP groups, with no significant differences between groups. Additionally, all groups demonstrated a marginal, though significant (~10%), vasodilator response to BQ-123; however, there were no differences in the FBF response to BQ-123 across CRP groups. There were no significant correlations between plasma CRP concentrations and peak FBF response to either ET-1 or BQ-123. SIGNIFICANCE: These results indicate that ET-1 system activity is not influenced by elevations in CRP. Enhanced ET-1 system activity may not be involved in the increased cardiovascular disease risk associated with elevations in plasma CRP concentrations.

Neutrophil gelatinase-associated lipocalin and cystatin C for the prediction of clinical events in patients with advanced heart failure and after ventricular assist device placement.

BACKGROUND: Progressive renal dysfunction develops in patients with advanced HF. We evaluated neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C compared with established markers of renal function in patients with heart failure (HF) because they might improve prognostic assessment of patients with HF. METHODS: Serum samples were collected from 40 patients with stable HF (age: 58 ± 8 years, body mass index [BMI]: 28.4 ± 6.4 kg/m(2)), 40 HF patients undergoing ventricular assist device (VAD) implantation (age: 53 ± 11 years, BMI: 26.8 ± 5.5 kg/m(2)), 40 patients undergoing VAD removal at cardiac transplantation, and 24 controls (age: 48 ± 7 years, BMI: 29.4 ± 4.2 kg/m(2)). Clinical data were collected from institutional medical records. NGAL and cystatin C levels were measured by enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease formula. RESULTS: Patients with stable HF showed elevated NGAL and cystatin C levels compared with controls (NGAL: 114.9 ± 48.3 ng/mL vs 72.0 ± 36.6 ng/mL, p < 0.0001; cystatin C: 1490.4 ± 576.1 ng/mL vs 954.7 ± 414.2 ng/mL, p = 0.0026). Unlike cystatin C, NGAL increased in advanced HF patients requiring VAD implantation (158.7 ± 74.8 ng/mL, p < 0.001). On VAD support, NGAL levels decreased (127.1 ± 80.4 ng/mL, p = 0.034). NGAL was higher in patients who developed right ventricular failure (187.8 ± 66.0 vs 130.9 ± 67.0 ng/mL, p = 0.03) and irreversible renal dysfunction (190.0 ± 73.8 ng/mL vs 133.8 ± 54.2 ng/mL, p < 0.05), whereas cystatin C, creatinine, and eGFR were not different. NGAL correlated with eGFR (r = -0.2188, p = 0.01). CONCLUSIONS: NGAL levels correlate with HF severity and hemodynamic improvement after VAD placement. Our findings suggest a role of this novel biomarker as a marker of severity and prognosis in patients with HF.

Metabolic syndrome and endothelin-1 mediated vasoconstrictor tone in overweight/obese adults.

OBJECTIVE: To determine whether endothelin (ET)-1 vasoconstrictor tone is greater in overweight and obese adults with the metabolic syndrome (MetS). MATERIALS/METHODS: Forty overweight/obese middle-aged and older adults (age: 43-71 years; BMI: 25.1-36.9 kg/m²) were studied: 20 without MetS (13 M/7 F) and 20 with MetS (13 M/7 F). MetS was established according to NCEP ATP III guidelines. Forearm blood flow (FBF; plethysmography) responses to intra-arterial infusion of selective ET(A) receptor blockade (BQ-123; 100 nmol/min; for 60 min) and non-selective ET(A/B) receptor blockade (BQ-123 + BQ-788 [50 nmol/min for 60 min]) were determined. RESULTS: In response to the selective ET(A) antagonism, there was a significant increase in forearm blood flow from baseline in both groups. However, the increase in forearm blood flow was significantly higher (P=0.03; ~45%) in the overweight/obese group with MetS than the group without MetS. In contrast, there were no significant group differences in FBF responses to non-selective ET(A/B) receptor blockade. Peak vasodilator responses to nonselective ET(A/B) blockade were ~50% higher than baseline blood flow in the overweight/obese groups without and with MetS. CONCLUSION: MetS is associated with higher ET-1 vasoconstrictor tone in overweight/obese adults. The enhanced ET-1 vasoconstrictor activity with MetS is mediated by the ET(A) receptor subtype.

Reduced handgrip strength as a marker of frailty predicts clinical outcomes in patients with heart failure undergoing ventricular assist device placement.

BACKGROUND: Heart failure (HF) is associated with the derangement of muscle structure and metabolism, contributing to exercise intolerance, frailty, and mortality. Reduced handgrip strength is associated with increased patient frailty and higher morbidity and mortality. We evaluated handgrip strength as a marker of muscle function and frailty for prediction of clinical outcomes after ventricular assist device (VAD) implantation in patients with advanced HF. METHODS AND RESULTS: Handgrip strength was measured in 72 patients with advanced HF before VAD implantation (2.3 ± 4.9 days pre-VAD). We analyzed dynamics in handgrip strength, laboratory values, postoperative complications, and mortality. Handgrip strength correlated with serum albumin levels (r = 0.334, P = .004). Compared with baseline, handgrip strength increased post-VAD implantation by 18.2 ± 5.6% at 3 months (n = 29) and 45.5 ± 23.9% at 6 months (n = 27). Patients with a handgrip strength <25% of body weight had an increased risk of mortality, increased postoperative complications, and lower survival after VAD implantation. CONCLUSION: Patients with advanced HF show impaired handgrip strength indicating a global myopathy. Handgrip strength <25% of body weight is associated with higher postoperative complication rates and increased mortality after VAD implantation. Thus, the addition of measures of skeletal muscle function underlying the frailty phenotype to traditional risk markers might have incremental prognostic value in patients undergoing evaluation for VAD placement.

Impaired fasting blood glucose is associated with increased endothelin-1 vasoconstrictor tone.

AIM/HYPOTHESIS: The experimental aim of this study was to determine whether ET-1-mediated vasoconstrictor tone is elevated in adult humans with impaired fasting blood glucose concentrations, independent of other cardiovascular risk factors. METHODS: Forearm blood flow (FBF: plethysmography) responses to intra-arterial infusion of selective ETA receptor blockade (BQ-123: 100 nmol/min for 60 min) and non-selective ETA/B blockade (BQ-123 + BQ-788: 50 nmol/min for 60 min) were determined in 28 middle-aged, sedentary adults (17 M/11 F): 14 with normal fasting blood glucose (age: 57 ± 2 yr; 6 F/8 M; BMI: 29.2 ± 0.9 kg/m(2); glucose: 4.9 ± 0.1 mmol/L) and 14 impaired fasting blood glucose (58 ± 1 yr; 5 F/9 M; 29.6 ± 1.1 kg/m(2); 5.8 ± 0.1 mmol/L) concentrations. RESULTS: Selective ETA receptor blockade elicited a significantly greater (∼20%) increase in FBF in the impaired fasting glucose adults compared with the normoglycemia controls. ETA/B blockade resulted in a further 2-fold increase (P < 0.05) in FBF above that elicited by ETA receptor antagonism in the impaired fasting glucose but not normal fasting glucose adults. There was a positive correlation between fasting blood glucose levels and the peak vascular responses to ETA (r = 0.44; P < 0.05) and ETA/B (r = 0.62; P < 0.05) blockade. No other anthropometric, hemodynamic or metabolic variable was correlated with the blood flow responses to ET-1 receptor blockade. CONCLUSIONS/INTERPRETATION: ET-1-mediated vasoconstrictor tone is elevated in adults with impaired fasting blood glucose concentrations, independent of other cardiometabolic risk factors. Enhanced ET-1 system activity may underlie endothelial vasomotor dysfunction and increased cardiovascular risk in adults with impaired fasting blood glucose concentrations.

Effects of the left ventricular assist device on the compliance and distensibility of the carotid artery.

We investigated the impact of continuous-flow left ventricular assist devices (LVAD) on the carotid elastic properties. Carotid artery parameters (diameter distensibility (DD), cross-sectional distensibility (CSD), diameter compliance (DC), cross-sectional compliance (CSC), and incremental elastic modulus (IEM)) were measured in a cross-sectional study using a standard ultrasound with a 10-MHz linear array probe. Measurements (mean ± SEM) were made in separate groups at various clinical time points: prior to LVAD surgery (baseline; 13 male/3 female; age 48 ± 3 years), 1 week following LVAD placement (acute; 12 male/2 female; age 47 ± 3 years), approximately 24 weeks following LVAD surgery (chronic; 13 male/2 female; age 52 ± 3 years), and in a group of healthy subjects (controls; 9 male/1 female; age 51 ± 4 years). Distensibility properties were lower (P < 0.05) in the acute (DD 2.3 % ± 0.4 %; CSD 4.7 % ± 0.8 %) and chronic (DD 2.2 % ± 0.4 %; CSD 4.5 ± 0.9 %) compared with the baseline (DD 5.9 % ± 0.7 %; CSD 12.2 % ± 1.5 %) and control (DD 5.8 % ± 0.6 %; CSD 11.9 % ± 1.3 %) groups. Compliance properties were lower (P < 0.05) in the chronic (DC 4.4 ± 0.7 mm/mmHg × 10(-3); CSC 1.2 ± 0.2 mmHg(-1) × 10(-3)) compared with acute (DC 9.0 ± 1.6 mm/mmHg × 10(-3); CSC 2.6 ± 0.4 mmHg(-1) × 10(-3)) and baseline (DC 11.1 ± 1.1 mm/mmHg × 10(-3); CSC 3.3 ± 0.4 mmHg(-1) × 10(-3)) groups. The compliance properties in the control (DC 8.3 ± 0.8 mm/mmHg × 10(-3); CSC 2.4 ± 0.2 mmHg(-1) × 10(-3)) group were not different from any of the patient groups. The IEM was higher (P < 0.05) in the chronic (6908 ± 1269 mmHg) compared with acute (2739 ± 412 mmHg), baseline (1849 ± 177 mmHg), and control (2349 ± 241 mmHg) groups. Chronic continuous-flow LVAD support is associated with lower carotid artery compliance and distensibility, which may place further strain on the left ventricle.

Effects of continuous flow left ventricular assist device support on microvascular endothelial function.

The effects of continuous flow left ventricular assist device (CF-LVAD) support on microvascular endothelial function in New York Heart Association (NYHA) class IV heart failure (HF) patients are currently unknown. Microvascular endothelial function was assessed by beat-to-beat plethysmographic measurement of finger arterial pulse wave signal changes for 5 min following reactive hyperemia. A group of seven NYHA class IV HF patients was evaluated before CF-LVAD placement (HF), and a second group of six NYHA class IV HF patients was evaluated 1-4 months following CF-LVAD placement (CF-LVAD). Additionally, a third group of seven age-matched healthy subjects served as controls (control). There was no significant (P > 0.05) difference among the three groups in age, weight, or height. Systolic blood pressure (BP) was significantly higher in the control group (120 ± 2 mmHg) as compared to that in the HF (97 ± 8 mmHg, P = 0.005) and CF-LVAD (106 ± 4 mmHg, P = 0.003) groups. Diastolic BP was significantly lower in the HF group (57 ± 5 mmHg) as compared to that in the control (71 ± 2 mmHg, P = 0.012) and CF-LVAD (80 ± 7 mmHg, P = 0.008) groups. The reactive hyperemic index (RHI), a measure of endothelial function, was significantly higher in the control group (2.373 ± 0.274) than in both the HF (1.543 ± 0.173, P = 0.013) and CF-LVAD (1.355 ± 0.163, P = 0.004) groups; however, there was no significant (P = 0.223) difference in RHI between the HF and CF-LVAD groups. The results of the present study demonstrate that while 1-4 months of CF-LVAD support do not negatively affect microvascular endothelial function, 1-4 months of CF-LVAD support do not significantly improve vascular function in resistance vessels.

Lower relative bone mineral content in obese adolescents: role of non-weight bearing exercise.

We assessed relative bone mineral content (BMC) in normal-weight (BMI < 85th percentile), overweight (BMI ≥ 85th---< 95th percentile), and obese (BMI ≥ 95th percentile) adolescents and evaluated the impact of nonweight bearing stationary cycle exercise training in a subset of obese participants. Obese and overweight adolescents had higher (p = .001) BMC than normal-weight counterparts, but after adjusting for total body mass the overweight and obese adolescents had a significantly lower (p < .001) BMC than normal-weight subjects. Although aerobic training such as cycling would seem optimal for caloric expenditure in obese adolescents, this study showed that eight weeks of cycle training did not improve BMC in obese adolescents. Weight-bearing aerobic exercise would be a better option for optimizing bone health in this population.