A comparison of programmable and nonprogrammable compression devices for treatment of lymphoedema using an administrative health outcomes dataset.

BACKGROUND: Patients with lymphoedema experience lifelong swelling and recurrent cellulitis despite use of complete decongestive therapy. Pneumatic compression devices (PCDs), including nonprogrammable and programmable devices that meet individual patient needs, support long-term self-care in the home. OBJECTIVES: Patients with either a nonprogrammable device (NP-PCD) or a dynamic pressure programmable device [P-PCD; Flexitouch® (Tactile Medical, Minneapolis, MN, U.S.A.)] were evaluated to compare associated clinical and health utilization outcomes pre-/postdevice acquisition. METHODS: Retrospective analysis of deidentified administrative claims from 2007 through 2013 of a large U.S. insurer. Outcome variables included rates of lymphoedema-related cellulitis, manual therapy use, outpatient services and inpatient hospitalizations. Multivariate regression analysis was performed to (i) compare outcomes for the 12 months pre- and postdevice acquisition and (ii) compare these two device types for their treatment-associated benefits. RESULTS: The sample consisted of 1013 NP-PCD and 718 P-PCD recipients. Compared with the NP-PCD group, P-PCD patients' baseline cellulitis rate was higher, whereas their postdevice cellulitis rate was lower. In the cancer cohort, the NP-PCD group had a 53% reduction in episodes of cellulitis (from 17·9% to 8·5%), compared with a greater 79% reduction in the P-PCD group (from 23·7% to 5·0%) (P < 0·001). In the noncancer cohort, the P-PCD group also experienced a larger 76% decline (from 31·0% to 7·4%) vs. 54% decline (from 22·9% to 10·6%) in cellulitis rates (P = 0·003). Outpatient service use reduced in both device groups, with greater reductions observed in the P-PCD group. Both device groups experienced reductions in manual therapy use. Inpatient hospitalizations were largely stable with reductions observed only in the noncancer cohort of the P-PCD group. CONCLUSIONS: P-PCD receipt was associated with superior lymphoedema-related health outcomes and reductions in cellulitis.

Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia.

VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 ± 17.8 versus 36.6 ± 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.

Characterizing axillary web syndrome: ultrasonographic efficacy.

The aim of this study was to determine if ultrasound could successfully characterize axillary web syndrome (AWS) and clarify the pathophysiologic basis of AWS as a vascular or lymphatic abnormality, or an abnormal tissue structure. This prospective study evaluated women who developed AWS following breast cancer surgery. Using an 18 MHz ultrasound transducer, images were taken of the AWS cord and compared to mirror images on the contralateral side. A blinded radiologist assessed the ultrasound characteristics of and structural changes in the skin and subcutaneous tissue and formulated an opinion as to the side in which AWS was located. Seventeen subjects participated in the study. No structure or abnormality consistent with AWS could be identified by ultrasound. There were no statistical differences between the ipsilateral and contralateral side in skin thickness; subcutaneous reflector thickness, number or disorganization; or subcutaneous tissue echodensity (p>0.05). The radiologist correctly identified the side with AWS in 12 of 17 subjects (=0.41). A distinct ultrasonographic structure or abnormality could not be identified in subjects with AWS using 18 MHz ultrasound. The inability to identify a specific structure excludes the possibility that AWS is associated with vein thrombosis or a fascial abnormality, and supports the theory that AWS may be pathology that is not visible with 18 MHz ultrasound, such as microlymphatic stasis or binding of fibrin or other proteins in the interstitial space.

Pneumatic compression device treatment of lower extremity lymphedema elicits improved limb volume and patient-reported outcomes.

OBJECTIVES: Examine the effectiveness of an advanced pneumatic compression device (APCD) in reducing limb volume (LV), and to evaluate clinician and patient-reported outcomes. DESIGN: Device registry study. MATERIALS AND METHODS: Data were collected prospectively for 196 lower extremity lymphedema patients prescribed an APCD. Baseline and post-treatment LVs were calculated and clinical outcomes (skin changes, pain, and function) were assessed. Patient-reported outcomes and satisfaction utilizing a pre- and post-treatment survey were also evaluated. RESULTS: 90% of APCD-treated patients experienced a significant reduction in LV with 35% enjoying a reduction >10%. Mean LV reduction was 1,150 mL or 8% (p < .0001). Greater baseline LV and BMI were strong predictors of LV reduction (p < .0001). Clinician assessment indicated that the majority of patients experienced improvement in skin fibrosis and function. Patient-reported outcomes showed a significant increase in ability to control lymphedema through APCD treatment, with an increase in function and a reduction in the interference of pain. 66% were "very satisfied" with the APCD treatment. CONCLUSION: APCD use is associated with consistent reductions in LV, with favorable patient-reported outcomes. Results demonstrate that reduction in LV and pain, combined with functional improvement and patient satisfaction can be achieved, providing tangible benefit for lower extremity patients.

Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease.

Peripheral artery disease is a progressive disease. Primary ischemic leg symptoms are muscle fatigue, discomfort or pain during ambulation, known as intermittent claudication. The most severe manifestation of peripheral artery disease is critical limb ischemia (CLI). The long-term safety of gene therapy in peripheral artery disease remains unclear. This four center peripheral artery disease registry was designed to evaluate the long-term safety of the intramuscular non-viral fibroblast growth factor-1 (NV1FGF), a plasmid-based angiogenic gene for local expression of fibroblast growth factor-1 versus placebo in patients with peripheral artery disease who had been included in five different phase I and II trials. Here we report a 3-year follow-up in patients suffering from CLI or intermittent claudication. There were 93 evaluable patients, 72 of them in Fontaine stage IV (47 NV1FGF versus 25 placebo) and 21 patients in Fontaine stage IIb peripheral artery disease (15 NV1FGF versus 6 placebo). Safety parameters included rates of non-fatal myocardial infarction (MI), stroke, death, cancer, retinopathy and renal dysfunction. At 3 years, in 93 patients included this registry, there was no increase in retinopathy or renal dysfunction associated with delivery of this angiogenic factor. There was also no difference in the number of strokes, MI or deaths, respectively, for NV1FGF versus placebo. In the CLI group, new cancer occurred in two patients in the NV1FGF group. Conclusions that can be drawn from this relatively small patient group are limited because of the number of patients followed and can only be restricted to safety. Yet, data presented may be valuable concerning rates in cancer, retinopathy, MI or strokes following angiogenesis gene therapy in the absence of any long-term data in angiogenesis gene therapy. It may take several years until data from larger patient populations will become available.

Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study.

We aimed to evaluate in a phase I dose-escalation study, the safety of intramuscular injections of a novel non-viral plasmid DNA expressing two isoforms of human hepatocyte growth factor (HGF) (VM202) in patients with critical limb ischemia (CLI). In total, 12 patients with CLI and unsuitable for revascularization were consecutively assigned to increasing doses (2 to 16 mg) of VM202 administered into the ischemic calf muscle at days 1 and 15. Patients were evaluated for safety and tolerability, changes in ankle- and toe brachial index (ABI and TBI), and pain severity score using a visual analog scale (VAS) throughout a 12-month follow-up period. Median age was 72 years and 53% of the patients were male. VM202 was safe and well tolerated with no death during the 12-month follow-up. Median ABI and TBI significantly increased from 0.35 to 0.52 (P=0.005) and from 0.15 to 0.24 (P=0.01) at 12 months follow-up. Median VAS decreased from 57.5 to 16.0 mm at 6 months follow-up (P=0.03). In this first human clinical trial, VM202, which expresses two isoforms of human HGF, appear to be safe and well tolerated with encouraging clinical results and thus supports the performance of a phase II randomized controlled trial.

Worse blood pressure control in patients with cerebrovascular or peripheral arterial disease compared with coronary artery disease.

OBJECTIVES: Poor blood pressure (BP) control is common amongst patients with symptomatic atherothrombotic disease. It is unclear whether BP control and management differ across atherothrombotic disease subtypes. METHODS: We analysed the baseline data of 44,984 patients with documented coronary artery disease (CAD) only (n = 30,414), cerebrovascular disease (CVD) only (n = 11,359) and peripheral arterial disease (PAD) only (n = 3211) from the international REduction of Atherothrombosis for Continued Health Registry and investigated the impact of atherothrombotic disease subtype on BP control and use of antihypertensive drugs. RESULTS: The proportion of patients with BP controlled (<140/90 mmHg) was higher in CAD (58.1%) than in CVD (44.8%) or PAD (38.9%) patients (P < 0.001). Amongst patients with treated hypertension, CAD patients were more likely to have BP controlled than were CVD patients [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 1.59-1.75] or PAD (OR = 2.30; 95% CI = 2.10-2.52). These differences were smaller in women than in men and decreased with age. Amongst treated patients, CAD patients were more likely to receive > or =3-drug combination therapies than were CVD (OR = 1.73; 95% CI = 1.64-1.83) or PAD (OR = 1.64; 95% CI = 1.49-1.80) patients. Adjustment for age, gender, waist obesity, diabetes, education level and world region did not alter the results. CONCLUSIONS: Coronary artery disease patients are more likely than CVD or PAD patients to have BP controlled and to receive antihypertensive drugs, particularly combination therapies. Promotion of more effective BP control through combination antihypertensive therapies could improve secondary prevention and therefore prevent complications in CVD and PAD patients.

The next 10 years in the management of peripheral artery disease: perspectives from the 'PAD 2009' Conference.

OBJECTIVES: To briefly inform on the conclusions from a conference on the next 10 years in the management of peripheral artery disease (PAD). DESIGN OF THE CONFERENCE: International participation, invited presentations and open discussion were based on the following issues: Why is PAD under-recognised? Health economic impact of PAD; funding of PAD research; changes of treatment options? Aspects on clinical trials and regulatory views; and the role of guidelines. RESULTS AND CONCLUSIONS: A relative lack of knowledge about cardiovascular risk and optimal management of PAD patients exists not only among the public, but also in parts of the health-care system. Specialists are required to act for improved information. More specific PAD research is needed for risk management and to apply the best possible evaluation of evidence for treatment strategies. Better strategies for funding are required based on, for example, public/private initiatives. The proportion of endovascular treatments is steadily increasing, more frequently based on observational studies than on randomised controlled trials. The role of guidelines is therefore important to guide the profession in the assessment of most relevant treatment.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Vasopressin-mediated forearm vasodilation in normal humans. Evidence for a vascular vasopressin V2 receptor.

Arginine vasopressin (AVP) is a potent vasopressor and antidiuretic neurohormone. However, when administered intravenously to humans, AVP causes forearm vasodilation. This effect has been attributed to sympathetic withdrawal, secondary to AVP-induced sensitization of baroreceptors. The possibility that AVP also causes forearm vasodilation directly has not been examined. Accordingly, the direct effect of AVP was determined by studying the forearm blood flow (FBF) response to intraarterial (IA) AVP infusion (0.01-1.0 ng/kg per min). Infusion of IA AVP increased FBF (96%) in the infused arm, but not the control arm, in a dose-dependent manner. The role of specific AVP V1 receptors in mediating this FBF response was determined before and after pretreatment with a V1 antagonist (AVP-A). AVP-A alone had no effect on FBF, but coadministration of AVP and AVP-A potentiated the vasodilatory response (223%). IA infusion of the V2 agonist, 1-desamino[8-D-arginine] vasopressin, caused a dose-dependent increase in FBF. These findings suggest that AVP causes direct, dose-dependent vasodilation in the human forearm that may be mediated by V2 vasopressinergic receptors. In contrast, AVP infusion caused digital vasoconstriction that was blocked by AVP-A, whereas dDAVP did not affect digital blood flow. Thus, AVP induces regionally selective vascular effects, with concurrent forearm vasodilation and digital vasoconstriction.

Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation.

We compared the activity and physiologic effects of cardiac angiotensin converting enzyme (ACE) using isovolumic hearts from male Wistar rats with left ventricular hypertrophy due to chronic experimental aortic stenosis and from control rats. In response to the infusion of 3.5 X 10(-8) M angiotensin I in the isolated buffer perfused beating hearts, the intracardiac fractional conversion to angiotensin II was higher in the hypertrophied hearts compared with the controls (17.3 +/- 4.1% vs 6.8 +/- 1.3%, P less than 0.01). ACE activity was also significantly increased in the free wall, septum, and apex of the hypertrophied left ventricle, whereas ACE activity from the nonhypertrophied right ventricle of the aortic stenosis rats was not different from that of the control rats. Northern blot analyses of poly(A)+ purified RNA demonstrated the expression of ACE mRNA, which was increased fourfold in left ventricular tissue obtained from the hearts with left ventricular hypertrophy compared with the controls. In both groups, the intracardiac conversion of angiotensin I to angiotensin II caused a comparable dose-dependent increase in coronary resistance. In the control hearts, angiotensin II activation had no significant effect on systolic or diastolic function; however, it was associated with a dose-dependent depression of left ventricular diastolic relaxation in the hypertrophied hearts. These novel observations suggest that cardiac ACE is induced in hearts with left ventricular hypertrophy, and that the resultant intracardiac activation of angiotensin II may have differential effects on myocardial relaxation in hypertrophied hearts relative to controls.

Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure.

The intrarenal renin-angiotensin system (RAS) may contribute to the pathophysiology of heart failure by the generation of angiotensin II at local sites within the kidneys. Angiotensin II may directly influence renal hemodynamics, glomerular contractility, and tubular sodium reabsorption, thereby promoting sodium and fluid retention in this syndrome. In the present study, we examined components of the circulating RAS as well as the intrarenal expressions of renin and angiotensinogen mRNA in rats with stable compensated heart failure (HF) 12 wk after experimental myocardial infarction. Renal angiotensinogen mRNA level in vehicle-treated HF rats increased 47%, as compared with sham control rats (P = 0.001). The increase in angiotensinogen mRNA levels was more pronounced in animals with medium (46%, P < 0.05) and large (66%, P < 0.05) infarcts than in those with small infarcts (31%, P = NS). There were no differences in liver angiotensinogen mRNA, circulating angiotensinogen, angiotensin II, plasma renin concentration (PRC), kidney renin content (KRC), and renal renin mRNA level between sham and HFv. In addition, in a separate group of rats with heart failure, we demonstrated that renal angiotensin II concentration increased twofold (P < 0.05) as compared with that of age-matched sham operated controls. A parallel group of heart failure rats (HFe, n = 11) was treated with enalapril (25 mg/kg per d) in drinking water for 6 wk before these measurements. Blood pressure decreased significantly during treatment (91 vs. 103 mm Hg, P < 0.05). Enalapril treatment in HF rats increased renin mRNA level (2.5-fold, P < 0.005), KRC (5.6-fold, P = 0.005), and PRC (15.5-fold, P < 0.005). The increase in renal angiotensinogen mRNA level observed in HFv rats was markedly attenuated in enalapril treated HF rats (P < 0.001), suggesting a positive feedback of angiotensin II on renal angiotensinogen synthesis. These findings demonstrate an activation of intrarenal RAS, but no changes in the circulating counterpart in this model of experimental heart failure, and they support the concept that the intrinsic renal RAS may contribute to the pathophysiology in this syndrome.

Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery.

BACKGROUND: After coronary artery bypass surgery, patients have a high cumulative rate of graft closure and recurrent ischemic events. We sought to determine whether antiplatelet therapy with clopidogrel would be more effective than aspirin, the accepted standard, in these patients. METHODS AND RESULTS: The event rates for all-cause mortality, vascular death, myocardial infarction, stroke, and rehospitalization were determined for the 1480 patients with a history of cardiac surgery randomized to either clopidogrel or aspirin in a trial of 19 185 patients. The event rate per year of vascular death, myocardial infarction, stroke, or rehospitalization was 22.3% in the 705 patients randomized to aspirin and 15.9% in the 775 patients randomized to clopidogrel (P:=0.001). A risk reduction was also seen in each of the individual end points examined, including a 42.8% relative risk reduction in vascular death in patients on clopidogrel versus aspirin (P:=0.030). In a multivariate model incorporating baseline clinical characteristics, clopidogrel therapy was independently associated with a decrease in vascular death, myocardial infarction, stroke, or rehospitalization in patients with a history of cardiac surgery, with a 31.2% relative risk reduction (95% CI, 15.8 to 43.8; P:=0.0003). Although clopidogrel therapy was efficacious in the entire Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) population, multivariate analysis demonstrated that patients with previous cardiac surgery derived particular benefit (P:=0.015). CONCLUSION: Compared with aspirin, clopidogrel therapy results in a striking reduction in the elevated risk for recurrent ischemic events seen in patients with a history of prior cardiac surgery, along with a decreased risk of bleeding.

Responsiveness of atrial natriuretic factor to reduction in right atrial pressure in patients with chronic congestive heart failure.

In patients with congestive heart failure, atrial natriuretic factor may serve as a counter-regulatory hormone, offsetting the vasoconstrictive and volume-retentive effects of the sympathetic nervous system, the renin-angiotensin-aldosterone system and vasopressin. Indeed, the plasma levels of atrial natriuretic factor and the vasoconstrictor hormones are often simultaneously elevated in these patients. It is not known, however, whether atrial natriuretic factor remains responsive to sudden reductions in atrial pressure in patients with chronic heart failure, or is unresponsive like the vasoconstrictor systems. To examine this issue, the plasma concentrations of atrial natriuretic factor and the vasoconstrictor hormones were measured in 20 normal subjects and 12 patients with chronic congestive heart failure during incremental lower body negative pressure, an intervention that lowers atrial pressure. In the normal subjects, incremental lower body negative pressure at -10, -20 and -40 mm Hg decreased central venous pressure and pulse pressure. At maximal lower body negative pressure, plasma atrial natriuretic factor levels decreased from 51 +/- 5 to 27 +/- 3 pg/ml (p less than 0.01), whereas increases occurred in plasma levels of norepinephrine (194 +/- 11 to 385 +/- 70 pg/ml, p less than 0.01), renin activity (1.4 +/- 0.2 to 3.9 +/- 0.1 ng/ml per h, p less than 0.01) and vasopressin (1.3 +/- 0.1 to 6.4 +/- 2.4 pg/ml, p less than 0.05). In the patients with congestive heart failure, lower body negative pressure also reduced central venous pressure. Baseline plasma atrial natriuretic factor levels were markedly elevated, averaging 438 +/- 138 pg/ml, and decreased to 317 +/- 87 pg/ml at maximal lower body negative pressure (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium depresses arterial baroreceptor reflex function in normotensive humans.

Sodium may contribute to the pathogenesis of hypertension by impairing arterial baroreceptor reflex function. The objectives of this study were to 1) determine whether a high sodium diet depresses arterial baroreceptor reflex function in normotensive humans, and 2) determine whether alterations in baroreceptor reflex function are related to changes in arterial compliance. Seventeen normotensive men, aged 30 +/- 2 years, received 10 and 200 meq sodium per day diets, each for 5 days, in a randomized crossover trial. Carotid baroreceptor reflex function was assessed by measuring the blood pressure response to sequential neck suction (0, -10, -20, and -30 mm Hg) and neck pressure (0, +10, +20, and +30 mm Hg). Forearm vascular resistance was determined by venous occlusion plethysmography. Arterial compliance was evaluated by calculating the quotient of the diastolic blood pressure decay time constant and forearm vascular resistance. Blood pressure averaged 124 +/- 3/62 +/- 2 mm Hg on the low sodium diet and 122 +/- 3/60 +/- 2 mm Hg on the high sodium diet (p = NS). Baroreceptor reflex slopes representing the systolic and diastolic blood pressure responses to changes in neck chamber pressure were steeper in the subjects when randomly assigned to low sodium diet than to high sodium diet. Diastolic blood pressure decay time and forearm arterial compliance were similar during low and high sodium intake. We conclude that short-term exposure to a high sodium diet depresses carotid baroreceptor reflex function in normotensive humans. This observation cannot be attributed to changes in the arterial compliance.

Effect of bilateral nephrectomy on active renin, angiotensinogen, and renin glycoforms in plasma and myocardium.

In an attempt to clarify the relationship of the circulating and myocardial renin-angiotensin systems, active renin concentration, its constituent major glycoforms (active renin glycoforms I through V), and angiotensinogen were measured in plasma and left ventricular homogenates from sodium-depleted rats under control conditions or 2 minutes, 3 hours, 6 hours, and 48 hours after bilateral nephrectomy (BNX). Control myocardial renin concentration was 1.4+/-0.1 ng angiotensin I (Ang I) per gram myocardium per hour and plasma renin concentration was 6.7+/-1.1 ng Ang I per milliliter plasma per hour. Control myocardial angiotensinogen was 0.042+/-0.004 micromol/kg myocardium and plasma angiotensinogen was 1.5 micromol/L plasma. Two minutes after BNX and corresponding stimulation of renin secretion by anesthesia and surgery, plasma renin concentration was increased disproportionately compared with myocardial renin. Three, 6, and 48 hours after BNX, renin decay occurred significantly faster from the plasma than from the myocardium. Forty-eight hours after BNX, myocardial renin concentrations had fallen to 15% of control values, while myocardial angiotensinogen concentrations had increased 12-fold and plasma angiotensinogen concentrations had increased by only 3.5-fold. Myocardial renin glycoform proportions were identical in myocardial homogenates and plasma in control animals. At 6 hours BNX, the proportions of plasma active renin glycoforms I+II fell, while those in the myocardium significantly increased. We conclude that in control rats, active renin and active renin glycoforms are distributed as if in diffusion equilibrium between plasma and the myocardial interstitial space. After BNX, myocardial renin concentration falls dramatically, suggesting that most cardiac renin is derived from plasma renin of renal origin. After BNX, renin glycoforms I+II are preferentially cleared from the plasma but preferentially retained by the myocardium. Control myocardial angiotensinogen concentrations are too low to result from simple diffusion equilibrium between plasma and the myocardial interstitium.

Calcium channel blockers as antihypertensive agents.

Because of their unique action on the cardiovascular system, the calcium channel blockers have generated a great deal of excitement among pharmacologists, physiologists, and clinicians. One obvious potential application for these drugs is in antihypertensive therapy and, although experience with these agents for this indication is limited in the United States, it is considerable in Europe and Japan. These agents' ultimate role in antihypertensive therapy, however, has not been established. Since the available calcium channel blockers are structurally diverse, it is uncertain whether they will have comparable effects in hypertension. The rationale for the use of calcium channel blockers in treating hypertension and the relevant pharmacologic actions of these agents is discussed, along with a summary of some of the clinical trials, observations from our own experience with these drugs, and speculation about their future role in antihypertensive therapy.

Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication.

PURPOSE: We tested the hypothesis that propionyl-L-carnitine would improve peak walking time in patients with claudication. Secondary aims of the study were to evaluate the effects of propionyl-L-carnitine on claudication onset time, functional status, and safety. SUBJECTS AND METHODS: In this double-blind, randomized, placebo-controlled trial, 155 patients with disabling claudication from the United States (n = 72) or Russia (n = 83) received either placebo or propionyl-L-carnitine (2g/day orally) for 6 months. Subjects were evaluated at baseline and 3 and 6 months after randomization with a graded treadmill protocol at a constant speed of 2 miles per hour, beginning at 0% grade, with increments in the grade of 2% every 2 minutes until maximal symptoms of claudication forced cessation of exercise. Questionnaires were used to determine changes in functional status. RESULTS: At baseline, peak walking time was 331 +/- 171 seconds in the placebo group and 331 +/- 187 seconds in the propionyl-L-carnitine group. After 6 months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 +/- 222 seconds (a 54% increase) as compared with an improvement of 75 +/- 191 seconds (a 25% increase) for those on placebo (P <0.001). Similar improvements were observed for claudication onset time. Propionyl-L-carnitine treatment significantly improved walking distance and walking speed (by the Walking Impairment Questionnaire), and enhanced physical role functioning, reduced bodily pain, and resulted in a better health transition score (by the Medical Outcome Study SF-36 Questionnaire). The incidence of adverse events and study discontinuations were similar in the two treatment groups. CONCLUSIONS: Propionyl-L-carnitine safely improved treadmill exercise performance and enhanced functional status in patients with claudication.

The economic survival of pediatric practice.

Many aspects of pediatric practice in the future are unclear. Among them is how pediatricians will be reimbursed. Based on trends established during the past 10 years, capitation is a likely mechanism. The advantages and disadvantages of capitation as a reimbursement mechanism--particularly as it compares with fee for service--are discussed, and a simplified description of how capitation rates are set is included.