John M. Erikson

Glucocorticoid Dose Thresholds Associated With All-Cause and Cardiovascular Mortality in Rheumatoid Arthritis

To delineate daily and cumulative glucocorticoid dose thresholds associated with increased mortality rates in rheumatoid arthritis (RA).

DITPA (3,5-diiodothyropropionic acid), a thyroid hormone analog to treat heart failure: Phase II trial veterans affairs cooperative study

Background— In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results— This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure–specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (−20%), low-density lipoprotein cholesterol (−30%), and body weight (−11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions— DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.

Radial approach: a new concept in surgical treatment for atrial fibrillation. II. Electrophysiologic effects and atrial contribution to ventricular filling.

BACKGROUND In a previous study the atrial incisions that follow the concept of the radial approach were designed according to the activation sequence during sinus rhythm and the atrial coronary artery anatomy in normal dogs. The purpose of the present study was to determine whether the radial approach provides a more physiologic activation sequence and atrial transport function than the maze procedure. METHODS Ten dogs that had undergone the radial approach (n = 5) or the maze procedure (n = 5) were studied 6 weeks postoperatively. Sinus node function and inducibility of atrial fibrillation were examined before and after operation. The atria were mapped endocardially with 212 electrodes, and atrial activation sequences during sinus rhythm and right atrial pacing were examined. Atrial transport function was assessed by transepicardial Doppler echocardiography. RESULTS No dogs developed sinus node dysfunction postoperatively. Both the radial approach and the maze procedure equally prevented sustained atrial fibrillation. The atrial activation sequence was more synchronous after the radial approach than after the maze procedure. There was no electrically isolated region after the radial approach. The total activation time of the left atrium was significantly shorter after the radial approach than after the maze procedure (53.6+/-9.8 versus 70.5+/-9.6 ms, p<0.05). The ratio of peak flow velocity of the E wave to the A wave (peak E/A) of the transmitral Doppler flow was significantly smaller after the radial approach than after the maze procedure (1.7+/-0.4 versus 3.5+/-1.7, p<0.05). The atrial filling fraction of the transmitral Doppler flow was significantly larger after the radial approach than after the maze procedure (29.9%+/-7.3% versus 14.8%+/-5.0%, p<0.01). There was no significant difference in peak E/A and atrial filling fraction of the transtricuspid Doppler flow between the two procedures. CONCLUSIONS The radial approach provides a more synchronous activation sequence and atrial transport function, and thus may represent a more physiologic alternative to the maze procedure as a surgical treatment for atrial fibrillation.

Exercise training combined with angiotensin II receptor blockade limits post-infarct ventricular remodelling in rats

AIMS Our aim was to test the hypothesis that angiotensin II receptor blockade combined with exercise training after myocardial infarction (MI) could attenuate post-MI left ventricular remodelling and preserve cardiac function. METHODS AND RESULTS Sprague-Dawley rats underwent ligation of the left descending coronary artery, resulting in MI, or a sham operation. Losartan treatment and exercise training were initiated 1 week after infarction and continued for 8 weeks, either as a single intervention or combined. Collagen volume fraction in the sedentary MI (MISed) group was significantly higher than other MI groups treated with exercise training and/or losartan. Compared with MISed group, hearts of rats receiving exercise and/or losartan treatment had lower tissue inhibitor of matrix metalloproteinase (TIMP) 1. Matrix metalloproteinase (MMP) 2 or MMP-9 did not differ among all groups. Additionally, the level of angiotensin II receptor type 1 (AT1) protein significantly decreased in response to exercise training. Furthermore, angiotensin converting enzyme (ACE) binding was markedly lower in hearts receiving exercise training than in the MISed hearts. Cardiac function was preserved in rats receiving exercise training, and the beneficial effect was further improved by exercise combined with losartan treatment in comparison to the MISed group. CONCLUSION Our results suggest that post-MI exercise training and/or AngII receptor blockade reduces TIMP-1 expression and mitigates the expressions of ACE and AT1 receptor. These improvements, in turn, attenuate myocardial fibrosis and preserve post-MI cardiac function.

Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis

Objective To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA). Methods We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use. Results Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression. Conclusions Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.

Effects of the Thyromimetic Agent Diiodothyropropionic Acid on Body Weight, Body Mass Index, and Serum Lipoproteins: A Pilot Prospective, Randomized, Controlled Study

CONTEXT Widespread thyroid hormone actions offer the possibility of developing selective thyromimetic analogs with salutary metabolic properties. Consequently, effects of diiodothyropropionic acid (DITPA) on body weight, serum lipoproteins, and bone metabolism markers were studied in a prospective, controlled, double-blind 24-wk trial, which was primarily designed to assess treatment of stable chronic heart failure. DESIGN Eighty-six patients (aged 66 +/- 11 yr, mean +/- sd) were randomized (1:2) to placebo or an escalating DITPA dose (90 to 180, 270, and 360 mg/d) over 8 wk until serum TSH was less than 0.02 mU/liter. Patients were studied at 2, 4, 6, 8, 16, and 24 wk and after 4 wk off study drug. Only 21 DITPA-treated and 27 placebo patients completed the full 24 wk of therapy. RESULTS DITPA therapy lowered serum TSH levels and, to a lesser extent, serum T(3) and T(4), but there were no differences in clinical manifestations of thyrotoxicosis or hypothyroidism. Serum total and low-density lipoprotein cholesterol levels both decreased on DITPA; there was a transient decrease in triglycerides and no change in high-density lipoprotein cholesterol. DITPA therapy was associated with significant reduction in body weight, 12.5 lb at 24 wk. Increases in serum osteocalcin, N-telopeptide, and deoxypyridinoline levels were consistent with increased bone turnover on DITPA. CONCLUSION This investigation of DITPA actions demonstrated its efficacy in reducing body weight and lowering total and low-density lipoprotein cholesterol levels. However, DITPAs adverse effects at doses used resulted in a high dropout rate and potentially dangerous skeletal actions were observed.

Effect of Post–Myocardial Infarction Exercise Training on the Renin-Angiotensin-Aldosterone System and Cardiac Function

After a myocardial infarction (MI), the injured heart undergoes intensive remodeling characterized by activation of the circulating renin-angiotensin-aldosterone system (RAAS), left ventricular (LV) dilation, and contractile dysfunction. Exercise training may attenuate activation of the RAAS and improve myocardial remodeling. In this study, we investigated whether starting exercise training early or late after MI would have different effect on circulating RAAS and LV dilation and function. Male Sprague-Dawley rats (7 weeks old) underwent surgically induced MI. After surgery, rats were matched for similar infarct sizes and assigned into two major groups, based on the designated starting time of exercise training. Exercise groups started exercise at either 1 or 6 weeks after MI and exercised on a treadmill for 8 weeks. Groups starting exercise 1 week after MI included sham-operated control (1Wk-Sham), MI-ksedentary (1Wk-MI-Sed), and MI-exercise (1Wk-MI-Ex). Groups starting exercise 6 weeks after MI included sham-operated control (6Wk-Sham), MI-sedentary (6Wk-MI-Sed), and MI-exercise (6Wk-MI-Ex). An echocardiogram was performed before and after exercise training. Blood samples were obtained at the end of experiments. The results showed that compared with sedentary rats with MI, exercise training significantly attenuated circulating renin, angiotensin converting enzyme, angiotensin II, and aldosterone. Rats in exercise groups had similar LV end-diastolic diameters compared with their sedentary counterparts and tended to have smaller LV end-systolic diameters, and percent fractional shortening in exercise rats was significantly higher than in sedentary rats. These findings suggest that exercise training does not cause LV dilation and preserves LV function. Post-MI exercise training also normalizes the circulating RAAS, and this effect is independent of timing of post-MI exercise. Exercise starting early or late after MI affects myocardial remodeling and function similarly, suggesting that early exercise training may attenuate activation of the RAAS and preserve cardiac function early after MI.

Endothelin-1 and myocardial preconditioning

This study attempted to define the role of endothelin (ET) in preconditioning. We previously showed that ET Is produced during myocardial ischemia and reperfusion. Because both preconditioning and ET act through protein kinase C, ET could play a role in preconditioning. Dogs were randomized to three groups subjected to 40 minutes of ischemia, with (groups A and B) or without (group C) preconditioning, followed by 4 hours of reperfusion. Groups A and C received saline infusions; group B received continuous infusions of the ETA-selective antagonist FR139317. Both preconditioned groups had smaller infarct sizes (group A, 7.9% +/- 2.5%; group B, 8.4% +/- 2.6%) than the nonpreconditioned group (group C, 16.2% +/- 3.3%). Administration of the ETA antagonist FR139317 did not alter infarct size. This study demonstrated that ETA-receptor blockade did not alter infarct size in preconditioned animals and suggests that endothelin does not play a significant role in this process.

Ultrasound-targeted antisense oligonucleotide attenuates ischemia/reperfusion-induced myocardial tumor necrosis factor-alpha

Ultrasound contrast agents are now emerging as effective vehicles for delivering therapeutic agents to target tissues. In the present study, we used ultrasound-targeted, contrast-bound antisense oligonucleotides to inhibit the expression of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine with negative inotropic effects. We compared the efficacy of left ventricular vs. intravenous administration and determined the optimal time for delivery. WKY rats were treated with perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microspheres incubated with 100 microg of antisense oligonucleotide directed against TNF-alpha. Contrast was infused into either the superior vena cava or the left ventricular cavity along with simultaneous application of ultrasound. Twenty-four hours later, the animals underwent 15 min of ischemia and 2 h reperfusion. Control animals underwent sham operation only, ischemia/reperfusion only, or received PESDA only. A second group received treatment just prior to, or immediately after the onset of ischemia. At the end of the experimental period, hearts were removed and analyzed for TNF-alpha by northern and western blotting. While no TNF-alpha expression was detected in sham-operated animals, robust expression of TNF-alpha mRNA and protein was seen in controls treated with ultrasound and PESDA alone. In contrast, intravenous or left ventricular administration of antisense oligonucleotides significantly inhibited ischemia/reperfusion-induced TNF-alpha expression. Direct delivery into the left ventricular cavity was more effective than intravenous administration, and delivery just prior to ischemia was most effective in attenuating TNF-alpha expression. Furthermore, attenuation of TNF-alpha expression also significantly inhibited other post-ischemic inflammatory mediators including IL-1beta and intercellular adhesion molecule-1 (ICAM-1). Thus, ultrasound-targeted antisense oligonucleotides can effectively attenuate post-ischemic cytokine expression when delivered in a clinically relevant time frame, obviating the need for pretreatment.

Exercise training combined with angiotensin II receptor blockade reduces oxidative stress after myocardial infarction in rats.

An increase in oxidative stress and decrease in antioxidant enzymes have been suggested to be involved in the pathophysiology of myocardial infarction (MI). In this study in rats, treadmill exercise training and losartan treatment began 1 week post‐myocardial infarction (MI) and lasted 8 weeks. We evaluated the changes in the mRNA and protein expressions for the enzymatic antioxidants superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase after exercise and losartan treatment post‐MI. Our results demonstrated that GPx and catalase mRNA levels were comparable among all the groups, while the mRNA level for manganese SOD (MnSOD) was significantly increased in exercise training with/without losartan treatment compared with the sedentary post‐MI group. Moreover, the mRNA level for gp91phox was dramatically decreased by a combination of exercise and losartan treatment. The protein levels for MnSOD were significantly elevated by exercise training in combination with losartan treatment. The protein levels for catalase were significantly increased in response to exercise, and further augmented by exercise together with losartan treatment. Thiobarbituric acid‐reactive substances in plasma were significantly increased in the post‐MI rats, but were decreased by exercise or losartan treatment, indicating that both exercise and losartan may reduce lipid oxidative damage. In addition, catalase and SOD enzymatic activities were significantly enhanced by exercise combined with losartan treatment. Our results suggest that exercise training improves catalase and MnSOD expression and attenuates oxidative stress. These effects are potentiated when combining exercise with angiotensin II receptor blockade.