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Biomedical subjects

W R Hiatt

Publications and source records attributed to W R Hiatt.

At least 19 recordsLinked to original sources
PubMed2000

Negative impact of cardiac evaluation before vascular surgery.

The optimal preoperative evaluation of cardiac risk in patients with peripheral vascular disease is controversial. In developing a paradigm for preoperative cardiac workup, potential adverse effects of evaluation and cardiac intervention must be considered. This study analyzed the deleterious outcomes of extensive, comprehensive cardiac evaluation and intervention before planned vascular surgery in patients treated at the Denver Department of Veterans Affairs Medical Center. Over a 12-month period between 1994 and 1995, 161 patients were scheduled to undergo major vascular operations; 153 patients came to operation. The decision to pursue a cardiac evaluation was variously made by a combination of surgeons, cardiologists, and anesthesiologists. No defined protocol was followed. Cardiac history, chest X-rays and ECGs were obtained for all patients. Extended cardiac evaluation included these studies plus special tests, including echocardiography (echo), radionuclide ventriculography (RNVG), dipyridamole thallium scintigraphy (DTS), and cardiac catheterization (CC). Extended cardiac evaluations were undertaken in 42 patients. Complications related to percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) were also recorded. Cardiac mortality and morbidity after vascular interventions were itemized in all 153 patients. Forty-two male patients, aged 68 +/- 9 years, underwent extended cardiac evaluations before planned vascular operations. The median elapsed time for cardiac workup was 14 days (mean 30 +/- 59 days). The median and mean times from cardiac workup to vascular surgery were 25 days and 76 +/- 142 days, respectively. Eighteen (43%) patients had echo or RNVG; 22 (52%) patients had DTS; 27 (64%) had CC; 9 (21%) had PTCA; 7 (17%) had CABG. Sixteen (38%) patients had untoward events related to cardiac evaluation. Eight patients (19%: one with cerebrovascular disease, and seven with aortic aneurysms) refused vascular surgery after extended cardiac workup. Complications attributable to CC, PTCA, and CABG included prosthetic graft infection, pseudoaneurysms (two), sternal wound infections (two), renal failure and brain anoxia. Two patients with severe limb ischemia who were candidates for revascularization ultimately required amputations because of delay due to cardiac evaluations. Extensive cardiac evaluation prior to vascular operations can result in morbidity, delays, and refusal to undergo vascular surgery. The underlying indication for vascular operations and the local iatrogenic cardiac complication rates must be considered before ordering special studies.

Aged↗
PubMed2000

Acquired skeletal muscle metabolic myopathy in atherosclerotic peripheral arterial disease.

Peripheral arterial disease (PAD) is associated with an increased risk of overall cardiovascular mortality, and substantial morbidity resulting from claudication. While the initial disease process is clearly the result of atherosclerosis in the arterial circulation of the limb, altered hemodynamics do not completely explain the pathophysiology of claudication. Work from several laboratories has demonstrated secondary changes in the skeletal muscle of patients with PAD which are consistent with the presence of an acquired metabolic myopathy in these patients. Key findings include an alteration in the expression of mitochondrial enzymes, the accumulation of metabolic intermediates, altered regulation of mitochondrial respiration, increased oxidative stress, and the presence of somatic mutations in the mitochondrial genome. Understanding the metabolic changes associated with PAD is important in understanding the pathophysiology of claudication and in the development of novel therapeutic strategies.

Animals↗
PubMed1999

Transatlantic Conference on Clinical Trial Guidelines in Peripheral Arterial Disease: clinical trial methodology. Basel PAD Clinical Trial Methodology Group.

Guidelines for the clinical development of drugs in peripheral arterial disease (PAD) have been issued by the Food and Drug Administration for the United States and by the regulatory agency of the European Union for Europe. With increasing globalization, transatlantic cooperation in drug research and development is essential for the future and would be substantially facilitated by the existence of transatlantic guidelines. A conference was held in Basel, Switzerland, in November 1997 to discuss the scientific background of the existing guidelines on the basis of published evidence and the extensive knowledge of clinical investigators and experienced regulators. The meeting was attended by 52 invited experts from the United States and Europe, as well as by representatives from the 2 regulatory authorities. The main conclusions from the meeting are presented and may serve as a reference for the future development of transatlantic guidelines for the evaluation of pharmacotherapy in PAD.

Clinical Trials as Topic↗
PubMed1999

Skeletal muscle mitochondrial DNA injury in patients with unilateral peripheral arterial disease.

BACKGROUND: Patients with peripheral arterial disease (PAD) have exercise limitation due to claudication-limited pain and metabolic alterations in skeletal muscle. PAD is also associated with oxidative stress, which is a known cause of mitochondrial DNA (mtDNA) injury. The present study was designed to test the hypothesis that PAD is associated with mtDNA injury, as reflected by an increased frequency of a specific 4977-base pair (bp) mtDNA deletion mutation. METHODS AND RESULTS: The deletion frequency was quantified in gastrocnemius muscle of 8 patients with unilateral PAD and 10 age-matched control subjects with the use of polymerase chain reaction methodologies. Muscle from the hemodynamically unaffected (less affected) PAD limb showed an 8-fold increased deletion frequency and the hemodynamically affected (worse affected) PAD limb had a 17-fold increased deletion frequency compared with muscle from control subjects. The frequency of the 4977-bp deletion in the worse-affected limb was positively correlated with the age of the patients but not the claudication-limited exercise performance of the patients. Total mtDNA content, citrate synthase activity, and cytochrome c oxidase activity were not different in the muscle from the 3 limb populations. However, the ratio of citrate synthase to cytochrome c oxidase was higher in the worse- versus less-affected limbs of PAD patients. CONCLUSIONS: The present study demonstrates a large increase in the frequency of the mtDNA 4977-bp deletion in patients with PAD but in a distribution not limited to the hemodynamically affected limb.

Aged↗
PubMed1999

Relationships between muscle mitochondrial DNA content, mitochondrial enzyme activity and oxidative capacity in man: alterations with disease.

Muscle mitochondrial content is tightly regulated, and requires the expression of both nuclear and mitochondrial genes. In addition, muscle mitochondrial content is a major determinant of aerobic exercise capacity in healthy subjects. The current study was designed to test the hypothesis that in healthy humans, muscle mitochondrial DNA (mtDNA) content is correlated with citrate synthase activity (a representative nuclear-encoded mitochondrial enzyme) and aerobic exercise capacity as defined by whole-body peak oxygen consumption (VO2). Furthermore, it was postulated that these relationships might be altered with disease. Twelve healthy and five paraplegic subjects underwent exercise testing and vastus lateralis muscle biopsy sampling. An additional ten healthy subjects and eight patients with unilateral peripheral arterial disease (PAD) underwent exercise testing and gastrocnemius muscle biopsy sampling. Citrate synthase activity and mtDNA content were positively correlated in the vastus lateralis muscles from the healthy subjects. This relationship was similar in muscle from paraplegic subjects. mtDNA content was positively correlated with peak VO2 in the healthy subjects and in the paraplegic subjects in whom peak VO2 had been elicited by functional electrical stimulation of the muscle. In contrast, the PAD subjects demonstrated higher mtDNA contents than would have been predicted based on their claudication-limited peak VO2. Thus, in healthy humans there are strong relationships between muscle mtDNA content and both muscle citrate synthase activity and peak VO2. These relationships are consistent with coordinant nuclear DNA and mtDNA expression, and with mitochondrial content being a determinant of aerobic exercise capacity. The relationships seen in healthy humans are quantitatively similar in paraplegic patients, but not in patients with PAD, a disease which is associated with a metabolic myopathy. The relationships between mtDNA content, mitochondrial enzyme activities and exercise capacity provide insight into the physiologic and pathophysiologic regulation of muscle mitochondrial expression.

Adolescent↗
PubMed1999

Intermediate-term outcome of primary digit amputations in patients with diabetes mellitus who have forefoot sepsis requiring hospitalization and presumed adequate circulatory status.

PURPOSE: The intermediate success and outcome of primary forefoot amputations in patients with diabetes mellitus who have sepsis limited to the forefoot and presumed adequate forefoot perfusion, as determined by means of noninvasive methods, was studied. METHODS: Cases of a university hospital-based practice from January 1984 to April 1998 were retrospectively reviewed. Patients included had diabetes mellitus with forefoot sepsis requiring immediate hospitalization for digit amputations who had adequate arterial circulation for healing based on noninvasive and clinical assessment: palpable pedal pulses (29%), "compressible" ankle pressure of 70 mm Hg or higher (48%), pulsatile metatarsal waveforms (67%), and/or toe pressure higher than 55 mm Hg (36%). All patients underwent a primary single- or multiple-digit amputation (through the interphalangeal joint, metatarsal head, or metatarsal shaft). Additional forefoot procedures (debridement, digit amputation) were performed during the follow-up period as needed for persistent or recurrent infection. The main outcome variables were recurrent or persistent foot infection (defined as requiring rehospitalization for antibiotics, wound care, and/or reoperation), the number of repeat operations and hospitalizations for salvage of limbs with recurrent or persistent infections, and time to complete forefoot healing or foot amputation. RESULTS: Ninety-two patients who had diabetes mellitus with 97 forefoot infections comprised the study group. Ninety-seven primary digit amputations (34 through interphalangeal joints, 28 through metatarsal heads, 35 through metatarsal shafts) were performed. The median length of hospital stay was 10 days. There were no operative deaths. The mean follow-up period was 21 months (range, 3 days to 105 months). The primary amputation healed (without persistent infection) in only 38 limbs (39%), at a mean time of 13 +/- 10 weeks. Twenty-three limbs (24%) had not healed the primary amputation without evidence of persistent infection at last follow-up (mean, 12 weeks). Infection persisted in 35 limbs (36%), and infection recurred in 15 of 38 (40%) healed limbs. An average of 1.0 reoperations (range, 0 to 3) and 1.6 rehospitalizations (range, 1 to 4) were involved in salvage attempts in these recurrent/persistent infections. Five persistent and five recurrent infections ultimately healed (mean, 53 weeks). Complete healing was achieved in only 33 of 97 limbs (34%). Twenty-two foot amputations (20 transtibial, two Syme's) were performed (mean, 49 +/- 74 weeks; 20 for persistent infection). Eighteen persistent/recurrent infections remained unhealed at the last follow-up examination (mean, 105 weeks). CONCLUSION: Patients with diabetes mellitus who have sepsis limited to the forefoot requiring acute hospitalization and undergoing primary digit amputations have a high incidence of intermediate-term, persistent, and recurrent infection, leading to a modest rate of limb loss, despite having apparently salvageable lesions and noninvasive evidence of presumed adequate forefoot perfusion.

Adult↗
PubMed1999

Oxygen uptake kinetics during exercise are slowed in patients with peripheral arterial disease.

Patients with peripheral arterial disease (PAD) have arterial occlusions that limit peripheral blood flow. This study evaluated the dynamic response in O(2) consumption (VO(2)) at the onset of constant-load exercise (VO(2) kinetics) in patients with PAD. Eight patients with bilateral PAD, seven patients with unilateral PAD, nine age-matched nonsmoking controls, and seven smoking controls performed graded treadmill exercise to assess peak VO(2). Subjects also performed constant-load exercise tests at 2.0 miles/h at 0 and 4% grade to determine VO(2) kinetics. Peak VO(2) was reduced 50% in patients with PAD compared with both control groups (P < 0.05). At 4% grade, phase 2 VO(2) kinetics were significantly slowed for the PAD groups compared with controls (60.1 +/- 15.7 and 58.7 +/- 8.3 s, unilateral and bilateral PAD groups, respectively; compared with 28. 4 +/- 19.3 and 27.9 +/- 8.1 s, nonsmoking and smoking controls, respectively; P < 0.05). No relationship was found between VO(2) kinetics and disease severity. These data demonstrate that VO(2) kinetics are markedly slowed in patients with PAD. The impairment in VO(2) kinetics is not related to smoking status or arterial disease severity and therefore may reflect altered control of skeletal muscle metabolism.

Aged↗
PubMed1999

Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded load treadmill protocol.

This study aims to evaluate the reliability of repeated graded workload treadmill testing (G-test; 2 mph; 0% grade, increasing 2% every 2 min) and to compare the reliability of a constant workload treadmill protocol (C-test; 2 mph; 12% grade) versus the graded workload treadmill protocol in patients with intermittent claudication, studied longitudinally. A clinical trial investigating an orally stable prostacycline derivative that included 330 patients with intermittent claudication was performed. The trial employed three active treatment groups and one placebo group. Because there were no significant inter-group differences at baseline or after treatment, data from all groups were pooled for the evaluation of treadmill test reliability. Treadmill data were obtained from a 2-week run-in phase where three G-tests were performed, as well as from the beginning and the end of a 3-month double-blind phase where a G-test and a C-test were performed in random order. Treadmill test reliability was described through test process-related and between-subject variances and also using variance-derived parameters such as the reliability coefficient (RC) and the relative precision (RP). A higher value for the RC and a lower value for the RP indicate that the test variability is predominantly due to between-subject variance and not to test process-related variance. Estimates of variance were described for both the maximal or absolute claudication distance (ACD) and the initial claudication distance (ICD) with each treadmill test. Reliability estimates are reported for the total study sample and for patients with baseline claudication distances < or =300 feet and >300 feet (approximately < or =100 m; >100 m), as measured with the C-test. The cut-off value was empirically chosen to separate severely diseased from mild to moderately diseased claudicants. Theoretical considerations suggest that reliability measures may differ in these subgroups. With repeated testing during the run-in phase for the measure of ACD, the G-test had an RC of 0.952 and an RP of 21.9%. With the comparison of both test protocols in the entire study population for the measurement of ACD, the G-test had an RC of 0.902 and an RP of 31.3%, while the C-test had an RC of 0.876 and an RP of 35.2%. The results for ICD on the G-test were an RC of 0.809 and an RP of 43.7%, while the C-test had an RC of 0.737 and an RP of 51.3%. The reliability of the ACD measurement for RC and RP was numerically superior to those for the ICD for both protocols. In patients with a baseline ACD < or =300 feet, the RC for ACD on the G-test was 0.827 and the RP was 41.4%. In contrast, on the C-test the RC decreased to 0.250 and the RP increased to 86.6%. These changes in RC and RP were due to a marked decrease in the between-subject variance, demonstrating the inability of the C-test to separate appropriately the different claudication distances in populations with highly limited baseline claudication distances. During a run-in phase, the G-test has excellent test characteristics. During the longitudinal phase of a trial, the reliability of G-tests and C-tests are comparable in the entire study population. However, in patients with low claudication distances, the G-test should be given preference over the C-test.

Adult↗
PubMed1999

Effects of exercise training on oxygen uptake kinetic responses in women with type 2 diabetes.

OBJECTIVE: Women with uncomplicated type 2 diabetes have both a decreased maximal oxygen consumption (VO2max) and slowed oxygen uptake (VO2) kinetics at the onset of exercise compared with nondiabetic women. These abnormalities are seen not only at maximal workloads, but also at the onset of low-level exercise. To evaluate the hypothesis that VO2max and VO2 kinetics would improve with exercise training in untrained people with type 2 diabetes, we measured these parameters in premenopausal sedentary women before and after 3 months of supervised exercise training. RESEARCH DESIGN AND METHODS: A total of 8 women with type 2 diabetes, 9 overweight nondiabetic women, and 10 lean nondiabetic women were studied. At baseline and after 3 months of exercise training, subjects underwent bicycle ergometer testing to obtain VO2max and VO2 kinetics data. RESULTS: On entry, women with type 2 diabetes had the lowest VO2max and slowest VO2 kinetics of the three groups. After exercise training, the women with type 2 diabetes improved their VO2max more than the lean and overweight control women: 28 vs. 5 and 8%, respectively (P < 0.05 for the diabetic group vs. both control groups). In the group with diabetes, VO2 kinetics improved by 39 and 22% at 20 and 30 W, respectively. For the control subjects, VO2 kinetics did not improve at any workload in either group. CONCLUSIONS: Despite beginning with the lowest VO2max and slowest VO2 kinetics, subjects with type 2 diabetes benefited more from an exercise training program than did control subjects. These findings suggest that in addition to its known metabolic effects, exercise training in individuals with type 2 diabetes may be an effective therapy to improve the cardiovascular response to exercise and to overcome low-level exercise impairment as reflected by improved VO2max and VO2 kinetics. If the ability to make circulatory adjustments at the beginning of exercise at low workloads is improved by an exercise training program, as suggested by the VO2 kinetics data, the clinical significance of exercise for people with type 2 diabetes is clear.

Adult↗
PubMed1998

The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension.

BACKGROUND: It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study. METHODS: The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension. RESULTS: Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure, > or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5; 95 percent confidence interval, 2.7 to 33.8). CONCLUSIONS: In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.

Adult↗
PubMed1998

Gait characteristics of patients with claudication.

OBJECTIVE: Intermittent claudication of the lower extremity vessels produces pain during walking. This study differentiates walking patterns of patients with claudication from walking patterns of healthy individuals. DESIGN: Nonrandomized case control study performed in a teaching university hospital outpatient setting. PATIENTS: The sample of convenience involved male patients with lower extremity claudication (n = 19) and 11 healthy men of similar ages. INTERVENTIONS: Subjects were asked to walk at self-selected speed for 20 meters on a level, indoor surface. OUTCOME MEASURES: Walking velocity and number of steps were averaged over each of five trials, and step length was calculated from these measures. RESULTS: Patients with claudication walked slower and had decreased step length and decreased cadence compared with controls (p < .001). No positive relationship was found between disease severity, peak walking time, and step length, cadence, or speed. CONCLUSION: All patients with claudication, regardless of disease severity, demonstrated abnormal gait parameters compared with controls. Further studies should evaluate whether the abnormal gait parameters significantly curtail walking ability.

Aged↗
PubMed1998

The role of carnitine and carnitine supplementation during exercise in man and in individuals with special needs.

Carnitine is critical for normal skeletal muscle bioenergetics. Carnitine has a dual role as it is required for long-chain fatty acid oxidation, and also shuttles accumulated acyl groups out of the mitochondria. Muscle requires optimization of both of these metabolic processes during peak exercise performance. Theoretically, carnitine availability may become limiting for either fatty acid oxidation or the removal of acyl-CoAs during exercise. Despite the theoretical basis for carnitine supplementation in otherwise healthy persons to improve exercise performance, clinical data have not demonstrated consistent benefits of carnitine administration. Additionally, most of the anticipated metabolic effects of carnitine supplementation have not been observed in healthy persons. The failure to demonstrate clinical efficacy of carnitine may reflect the complex pharmacokinetics and pharmacodynamics of carnitine supplementation, the challenges of clinical trial design for performance endpoints, or the adequacy of endogenous carnitine content to meet even extreme metabolic demands in the healthy state. In patients with end stage renal disease there is evidence of impaired cellular metabolism, the accumulation of metabolic intermediates and increased carnitine demands to support acylcarnitine production. Years of nutritional changes and dialysis therapy may also lower skeletal muscle carnitine content in these patients. Preliminary data have demonstrated beneficial effects of carnitine supplementation to improve muscle function and exercise capacity in these patients. Peripheral arterial disease (PAD) is also associated with altered muscle metabolic function and endogenous acylcarnitine accumulation. Therapy with either carnitine or propionylcarnitine has been shown to increase claudication-limited exercise capacity in patients with PAD. Further clinical research is needed to define the optimal use of carnitine and acylcarnitines as therapeutic modalities to improve exercise performance in disease states, and any potential benefit in healthy individuals.

Arteriosclerosis↗
PubMed1998

Abnormal oxygen uptake kinetic responses in women with type II diabetes mellitus.

Persons with type II diabetes mellitus (DM), even without cardiovascular complications have a decreased maximal oxygen consumption (VO2 max) and submaximal oxygen consumption (VO2) during graded exercise compared with healthy controls. We evaluated the hypothesis that change in the rate of VO2 in response to the onset of constant-load exercise (measured by VO2-uptake kinetics) was slowed in persons with type II DM. Ten premenopausal women with uncomplicated type II DM, 10 overweight, nondiabetic women, and 10 lean, nondiabetic women had a VO2 max test. On two separate occasions, subjects performed 7-min bouts of constant-load bicycle exercise at workloads below and above the lactate threshold to enable measurements of VO2 kinetics and heart rate kinetics (measuring rate of heart rate rise). VO2 max was reduced in subjects with type II DM compared with both lean and overweight controls (P < 0.05). Subjects with type II DM had slower VO2 and heart rate kinetics than did controls at constant workloads below the lactate threshold. The data suggest a notable abnormality in the cardiopulmonary response at the onset of exercise in people with type II DM. The findings may reflect impaired cardiac responses to exercise, although an additional defect in skeletal muscle oxygen diffusion or mitochondrial oxygen utilization is also possible.

Adult↗