Steve M. Blevins

Green Tea minimally affects Biomarkers of Inflammation in Obese Subjects with Metabolic Syndrome

OBJECTIVE Green tea (Camellia sinensis) has shown to exert cardioprotective benefits in observational studies. The objective of this clinical trial was to assess the effects of green tea on features of metabolic syndrome and inflammation in obese subjects. METHODS We conducted a randomized controlled trial in obese subjects with metabolic syndrome. Thirty-five subjects [(mean ± SE) age 42.5 ± 1.7 y, body mass index 36.1 ± 1.3 kg/m(2)] completed the 8-wk study and were randomly assigned to receive green tea (4 cups/d), green tea extract (2 capsules and 4 cups water/d), or no treatment (4 cups water/d). Both the beverage and extract groups had similar dosing of epigallocatechin-3-gallate, the active green tea polyphenol. Fasting blood samples were collected at screening, 4 and 8 wk of the study. RESULTS Green tea beverage or extract supplementation did not significantly alter features of metabolic syndrome or biomarkers of inflammation including adiponectin, C-reactive protein, interleukin-6, interleukin-1β, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, leptin, or leptin:adiponectin ratio. However, both green tea beverage and extracts significantly reduced plasma serum amyloid alpha versus no treatment (P < 0.005). CONCLUSION This study suggests that the daily consumption of green tea beverage or extracts for 8 wk was well tolerated but did not affect the features of metabolic syndrome. However, green tea significantly reduced plasma serum amyloid alpha, an independent cardiovascular disease risk factor, in obese subjects with metabolic syndrome.

Second-Generation Thiazolidinediones and Hepatotoxicity

OBJECTIVE: To report a case of hepatotoxicity probably caused by pioglitazone, summarize case reports of hepatotoxicity induced by rosiglitazone or pioglitazone, and make recommendations regarding routine liver enzyme measurement in patients taking these agents. CASE SUMMARY: A 39-year-old black woman with type 2 diabetes mellitus, hypertension, and congestive heart failure presented to a pharmacist-staffed diabetes comanagement service. She reported fatigue, dark brown urine, nausea, itching, and loss of appetite. Pioglitazone was promptly discontinued because her symptoms were consistent with those of hepatic dysfunction and pioglitazone was identified as a potential cause. The patient was referred to her physician. Liver enzyme levels were checked 13 days after initial presentation and found to be abnormal: alanine aminotransferase 490 U/L, aspartate aminotransferase 360 U/L, alkaline phosphatase 851 U/L, total bilirubin 3.1 mg/dL, direct bilirubin 2.0 mg/dL, and indirect bilirubin 1.1 mg/dL. Within 21/2 months of discontinuing pioglitazone, the patients symptoms resolved and liver enzyme levels returned to normal. DISCUSSION: Troglitazone, a thiazolidinedione (TZD), was removed from the market because of hepatotoxicity. Reported cases involving the newer TZDs, rosiglitazone and pioglitazone, have been few in number and less severe in consequence. Six cases of rosiglitazone-induced hepatotoxicity and 5 of pioglitazone-induced hepatotoxicity have been reported. Most patients improved symptomatically 2–4 weeks following discontinuation of the offending TZD, with normalization of liver enzyme levels in 2 weeks to 6 months following TZD discontinuation. CONCLUSIONS: Although the timeline and extent of liver enzyme elevation in this case are unclear, the Naranjo probability scale suggests that a causal relationship between pioglitazone and liver disease is probable. Patients with previous TZD-induced hepatotoxicity should not be rechallenged. Cases of hepatotoxicity with second generation TZDs, although clearly linked, have been few in number and less severe in consequence when compared to troglitazone. We agree with current package labeling that requires baseline and then periodic measurement of liver enzymes in patients taking pioglitazone or rosiglitazone.

Step-Monitored Home Exercise Improves Ambulation, Vascular Function, and Inflammation in Symptomatic Patients With Peripheral Artery Disease: A Randomized Controlled Trial

Background This prospective, randomized, controlled clinical trial compared changes in primary outcome measures of claudication onset time (COT) and peak walking time (PWT), and secondary outcomes of submaximal exercise performance, daily ambulatory activity, vascular function, inflammation, and calf muscle hemoglobin oxygen saturation (StO2) in patients with symptomatic peripheral artery disease (PAD) following new exercise training using a step watch (NEXT Step) home‐exercise program, a supervised exercise program, and an attention‐control group. Methods and Results One hundred eighty patients were randomized. The NEXT Step program and the supervised exercise program consisted of intermittent walking to mild‐to‐moderate claudication pain for 12 weeks, whereas the controls performed light resistance training. Change scores for COT (P<0.001), PWT (P<0.001), 6‐minute walk distance (P=0.028), daily average cadence (P=0.011), time to minimum calf muscle StO2 during exercise (P=0.025), large‐artery elasticity index (LAEI) (P=0.012), and high‐sensitivity C‐reactive protein (hsCRP) (P=0.041) were significantly different among the 3 groups. Both the NEXT Step home program and the supervised exercise program demonstrated a significant increase from baseline in COT, PWT, 6‐minute walk distance, daily average cadence, and time to minimum calf StO2. Only the NEXT Step home group had improvements from baseline in LAEI, and hsCRP (P<0.05). Conclusions NEXT Step home exercise utilizing minimal staff supervision has low attrition, high adherence, and is efficacious in improving COT and PWT, as well as secondary outcomes of submaximal exercise performance, daily ambulatory activity, vascular function, inflammation, and calf muscle StO2 in symptomatic patients with PAD. Clinical Trial Registration URL: ClinicalTrials.gov. Unique Identifier: NCT00618670.

Calf muscle hemoglobin oxygen saturation characteristics and exercise performance in patients with intermittent claudication

PURPOSE This study was conducted to determine the association between the characteristics of calf muscle hemoglobin oxygen saturation (StO(2)) and exercise performance in patients with intermittent claudication. METHODS The study comprised 39 patients with peripheral arterial disease limited by intermittent claudication. Patients were characterized on calf muscle StO(2) before, during, and after a graded treadmill test, as well as on demographic and cardiovascular risk factors, ankle-brachial index (ABI), ischemic window, initial claudication distance (ICD), and absolute claudication distance (ACD). RESULTS Calf muscle StO(2) decreased 72%, from 55% +/- 18% (mean +/- SD) saturation at rest to the minimum value of 17% +/- 19% saturation attained 459 +/- 380 seconds after the initiation of exercise. After exercise, recovery half-time of calf muscle StO(2) was attained at 129 +/- 98 seconds, whereas full recovery to the resting value was reached at 225 +/- 140 seconds. After adjusting for sex, race, and grouping according to the initial decline constant in calf muscle StO(2) during exercise, the exercise time to minimum calf muscle StO(2) was correlated with the ischemic window (r = -0.493, P = .002), ICD (r = 0.339, P = .043), and ACD (r = 0.680, P < .001). After treadmill exercise, the recovery half-time of calf muscle StO(2) was correlated with the ischemic window (r = 0.531, P < .001), ICD (r = -0.598, P < .001), and ACD (r = -0.491, P = .003). CONCLUSION In patients limited by intermittent claudication, shorter ICD and ACD values are associated with reaching a minimum value in calf muscle StO(2) sooner during treadmill exercise and with having a delayed recovery in calf muscle StO(2) after exercise.

Sex differences in calf muscle hemoglobin oxygen saturation in patients with intermittent claudication

PURPOSES We tested the hypotheses that women have greater impairment in calf muscle hemoglobin oxygen saturation (StO(2)) in response to exercise than men, and that the sex-related difference in calf muscle StO(2) would partially explain the shorter claudication distances of women. METHODS The study comprised 27 men and 24 women with peripheral arterial disease limited by intermittent claudication. Patients were characterized on calf muscle StO(2) before, during, and after a graded treadmill test, as well as on demographic and cardiovascular risk factors, ankle-brachial index (ABI), ischemic window, initial claudication distance (ICD), and absolute claudication distance (ACD). RESULTS Women had a 45% lower ACD than men (296 +/- 268 m vs 539 +/- 288 m; P = .001) during the treadmill test. Calf muscle StO(2) declined more rapidly during exercise in women than in men; the time to reach minimum StO(2) occurred 54% sooner in women (226 +/- 241 vs 491 +/- 426 seconds; P = .010). The recovery time for calf muscle StO(2) to reach the resting value after treadmill exercise was prolonged in women (383 +/- 365 vs 201 +/- 206 seconds; P = .036). Predictors of ACD included the time from start of exercise to minimum calf muscle StO(2), the average rate of decline in StO(2) from rest to minimum StO(2) value, the recovery half-time of StO(2), and ABI (R(2) = 0.70; P < .001). The ACD of women remained lower after adjusting for ABI (mean difference, 209 m; P = .003), but was no longer significantly lower (mean difference, 72 m; P = .132) after further adjustment for the StO(2) variables for the three calf muscles. CONCLUSION In patients limited by intermittent claudication, women have lower ACD and greater impairment in calf muscle StO(2) during and after exercise than men, the exercise-mediated changes in calf muscle StO(2) are predictive of ACD, and women have similar ACD as men after adjusting for calf StO(2) and ABI measures.

GENDER DIFFERENCES IN DAILY AMBULATORY ACTIVITY PATTERNS IN PATIENTS WITH INTERMITTENT CLAUDICATION

OBJECTIVES To compare the pattern of daily ambulatory activity in men and women with intermittent claudication, and to determine whether calf muscle hemoglobin oxygen saturation (StO2) is associated with daily ambulatory activity. METHODS Forty men and 41 women with peripheral arterial disease limited by intermittent claudication were assessed on their community-based ambulatory activity patterns for 1 week with an ankle-mounted step activity monitor and on calf muscle StO2 during a treadmill test. RESULTS Women had lower adjusted daily maximal cadence (mean±SE) for 5 continuous minutes of ambulation (26.2±1.2 strides/min vs 31.0±1.2 strides/min; P=.009), for 1 minute of ambulation (43.1±0.9 strides/min vs 47.2±0.9 strides/min; P=.004), and for intermittent ambulation determined by the peak activity index (26.3±1.2 strides/min vs 31.0±1.2 strides/min; P=.009). Women also had lower adjusted time to minimum calf muscle StO2 during exercise (P=.048), which was positively associated with maximal cadence for 5 continuous minutes (r=0.51; P<.01), maximal cadence for 1 minute (r=0.42; P<.05), and peak activity index (r=0.44; P<.05). These associations were not significant in men. CONCLUSION Women with intermittent claudication ambulate slower in the community setting than men, particularly for short continuous durations of up to 5 minutes and during intermittent ambulation at peak cadences. Furthermore, the daily ambulatory cadences of women are correlated with their calf muscle StO2 during exercise, as women who walk slower in the community setting reach their minimum calf muscle StO2 sooner than those who walk at faster paces. Women with intermittent claudication should be encouraged to not only walk more on a daily basis, but to do so at a pace that is faster than their preferred speed.

Diabetic women are poor responders to exercise rehabilitation in the treatment of claudication

BACKGROUND It is not clear whether subgroups of patients with peripheral artery disease (PAD) and claudication respond more favorably to exercise rehabilitation than others. We determined whether sex and diabetes were factors associated with the response to exercise rehabilitation in patients with claudication. METHODS Eighty patients were randomized to home-based and supervised exercise programs, and 60 finished with complete exercise intervention data. Exercise consisted of intermittent walking to near maximal claudication pain for 3 months. Primary outcome measures included claudication onset time (COT) and peak walking time. Patients were partitioned into diabetic and nondiabetic groups and then further partitioned by sex to form four groups. RESULTS Overall, exercise adherence was high (84%), and there was no significant difference (P > .05) in the amount of exercise completed among the four groups. All groups had significant improvements (P < .05) in COT and peak walking time after exercise rehabilitation, except for diabetic women (P > .05). Only 37% of women with diabetes had an increase in COT compared with 100% of men with diabetes (P < .01), and their risk ratio for nonresponse was 9.2 (P < .0001). CONCLUSIONS Women with PAD and claudication, particularly those with diabetes, represent a vulnerable subgroup of patients who respond poorly to a program of exercise rehabilitation. Diabetic women with PAD and claudication may need a greater dose of exercise or another intervention separate from or in combination with exercise to elicit improvements in claudication measures that are similar to nondiabetic women and to diabetic and nondiabetic men.

Gender and ethnic differences in arterial compliance in patients with intermittent claudication

OBJECTIVE To assess the gender and ethnic differences in arterial compliance in patients with intermittent claudication. METHODS A total of 114 patients participated, including 38 Caucasian men, 32 Caucasian women, 16 African American men, and 28 African American women. Patients were assessed on large artery elasticity index (LAEI), small artery elasticity index (SAEI), age, weight, body mass index, ankle-brachial index (ABI), smoking status, and metabolic syndrome components. RESULTS Group differences were found for LAEI (P = .042), SAEI (P = .019), body mass index (P = .020), prevalence of elevated fasting glucose (P = .001), and prevalence of abdominal obesity (P = .025). Significant covariates for LAEI included age (P = .0002) and elevated triglycerides (P = .0719). LAEI (units = 10 mL x mm Hg) adjusted for age and triglycerides was 39% lower (P = .0005) in African Americans (11.4 +/- .90; mean +/- SE) than in Caucasians (15.8 +/- 0.72), whereas no significant difference (P = .7904) existed between men (13.8 +/- 0.81) and women (13.5 +/- 0.79). Significant covariates for SAEI included age (P = .0001), abdominal obesity (P = .0030), and elevated blood pressure (P = .0067). SAEI (units = 100 mL x mm Hg) adjusted for age, abdominal obesity, and elevated blood pressure was 32% lower (P = .0007) in African-Americans (2.8 +/- 0.3) than in Caucasians 4.1 +/- 0.2), and was 18% lower (P = .0442) in women (3.1 +/- 0.2) than in men (3.8 +/- 0.2). CONCLUSION African American patients with intermittent claudication have more impaired macrovascular and microvascular function than Caucasian patients, and women have more impaired microvascular function than men. These ethnic and gender differences in arterial compliance are evident even though ABI was similar among groups, suggesting that arterial compliance provides unique information to quantify vascular impairment in patients with intermittent claudication.

Walking economy before and after the onset of claudication pain in patients with peripheral arterial disease

PURPOSE To determine the walking economy before and after the onset of claudication pain in patients with peripheral arterial disease (PAD), and to identify predictors of the change in walking economy following the onset of claudication pain. METHODS A total of 39 patients with PAD were studied, in which 29 experienced claudication (Pain group) during a constant load, walking economy treadmill test (speed = 2.0 mph, grade = 0%) and 10 were pain-free during this test (Pain-Free group). Patients were characterized on walking economy (ie, oxygen uptake during ambulation), as well as on demographic characteristics, cardiovascular risk factors, baseline exercise performance measures, and the ischemic window calculated from the decrease in ankle systolic blood pressure following exercise. RESULTS During the constant load treadmill test, the Pain group experienced onset of claudication pain at 323 +/- 195 seconds (mean +/- standard deviation) and continued to walk until maximal pain was attained at 759 +/- 332 seconds. Walking economy during pain-free ambulation (9.54 +/- 1.42 ml x kg(-1) x min(-1)) changed (P < .001) after the onset of pain (10.18 +/- 1.56 ml x kg(-1) x min(-1)). The change in walking economy after the onset of pain was associated with ischemic window (P < .001), hypertension (P < .001), diabetes (P = .002), and height (P = .003). In contrast, the Pain-Free group walked pain-free for the entire 20-minute test duration without a change in walking economy (P = .36) from the second minute of exercise (9.20 +/- 1.62 ml x kg(-1) x min(-1)) to the nineteenth minute of exercise (9.07 +/- 1.54 ml x kg(-1) x min(-1)). CONCLUSION Painful ambulation at a constant speed is associated with impaired walking economy, as measured by an increase in oxygen uptake in patients limited by intermittent claudication, and the change in walking economy is explained, in part, by severity of PAD, diabetes, and hypertension.

ASSOCIATION BETWEEN DAILY AMBULATORY ACTIVITY PATTERNS AND EXERCISE PERFORMANCE IN PATIENTS WITH INTERMITTENT CLAUDICATION

PURPOSE To determine the association between daily ambulatory activity patterns and exercise performance in patients with intermittent claudication. METHODS One hundred thirty-three patients limited by intermittent claudication participated in this study. Patients were assessed on their ambulatory activity patterns for 1 week with a small, lightweight step activity monitor attached to the ankle using elastic velcro straps above the lateral malleolus of the right leg. The step activity monitor recorded the number of strides taken on a minute-to-minute basis and the time spent ambulating. Patients also were characterized on ankle-brachial index (ABI), ischemic window (IW) after a treadmill test, as well as initial claudication distance (ICD), and absolute claudication distance (ACD) during treadmill exercise. RESULTS The patient characteristics (mean +/- SD) were as follows: ABI = 0.71 +/- 0.23, IW = 0.54 +/- 0.72 mm Hg.min.meter(-1), ICD = 236 +/- 198 meters, and ACD = 424 +/- 285 meters. The patients took 3366 +/- 1694 strides/day, and were active for 272 +/- 103 min/day. The cadence for the 30 highest, consecutive minutes of each day (15.1 +/- 7.2 strides/min) was correlated with ICD (r = 0.316, P < .001) and ACD (r = 0.471, P < 0.001), and the cadence for the 60 highest, consecutive minutes of each day (11.1 +/- 5.4 strides/min) was correlated with ICD (r = 0.290, P < .01) and ACD (r = 0.453, P < .001). Similarly, the cadences for the highest 1, 5, and 20 consecutive minutes, and the cadence for the 30 highest, nonconsecutive minutes all were correlated with ICD and ACD (P < .05). None of the ambulatory cadences were correlated with ABI (P > .05) or with ischemic window (P > .05). CONCLUSION Daily ambulatory cadences are associated with severity of intermittent claudication, as measured by ACD and ICD, but not with peripheral hemodynamic measures.