W. P. Leary

HLA-A, B, DR, and DQ antigens in black patients with severe chronic rheumatic heart disease.

To determine whether genetic factors could be involved in the pathogenesis of rheumatic heart disease, we performed HLA-A and HLA-B typing in 120 black patients with severe chronic rheumatic heart disease requiring cardiac surgery, and HLA-DR and HLA-DQ typing in 103 and 97 of these patients, respectively. The HLA typing was done by a standard microlymphocytotoxicity method. Patients were 12 to 60 years old (mean 27.6 +/- 14.5). No differences in HLA-A, HLA-B, and HLA-DQ frequencies between patients and controls were noted. HLA-DR 1 antigen was present in 12.6% of patients compared with 2.7% of normal control subjects (corrected p less than .045; relative risk = 5.2) and the HLA-DRw6 antigen was present in 31.1% of patients compared with 15% of control subjects (corrected p less than .045; relative risk = 2.6). These findings suggest that genetically determined immune-response factors may play a role in the pathogenesis of severe chronic rheumatic heart disease.

Allopurinol or oxypurinol in heart failure therapy - a promising new development or end of story?

SummaryThe plasma level of the uric acid is frequently elevated in heart failure, due to increased production and/or to reduced renal excretion of this antioxidant metabolite. The transformation of hypoxanthine to xanthine and the conversion of the latter into uric acid, which occur in purine catabolism, are catalysed by xanthine oxidoreductase. The constitutive xanthine dehydrogenase form of this enzyme generally uses NAD+ as an electron acceptor, whereas the post-translational xanthine oxidase form uses molecular oxygen and yields four units of reactive oxygen species per unit of transformed substrate. Allopurinol and oxypurinol inhibit xanthine oxidoreductase and thus diminish the generation of reactive species and decrease plasma uric acid. In a recent study in patients with NHYA class II-III heart failure, add-on treatment with allopurinol 300 mg/day for 3 months lowered plasma uric acid but failed to improve laboratory exercise performance or the distance walked in 6 minutes. In another recent trial, which was carried out in patients with NHYA class III-IV heart failure, add-on treatment with oxypurinol 600 mg/day for 24 weeks decreased plasma uric acid concentration but did not change a composite of patient outcome and state. These results indicate that the reduction in plasma uric acid caused by allopurinol or oxypurinol does not benefit patients with heart failure. Moreover, the hypothesis that the diminution in the renal excretion of the antioxidant uric acid caused by diuretics may be salutary in cardiac failure is strengthened by the study results considered.

The ALLHAT and the Cardioprotection Conferred by Diuretics in Hypertensive Patients: A Connection with Uric Acid?

T he results of the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) show that cardiovascular prognosis in patients suffering from hypertension is improved more effectively by antihypertensive treatment with a diuretic (chlorthalidone at 12.5–25 mg once daily) than by therapy with a calcium antagonist or an angiotensinconverting enzyme inhibitor [1]. Even though these results could have been determined by several factors, including various differential properties of the drug classes that were compared, it can be hypothesized that the added cardiovascular benefit conveyed by antihypertensive therapy with diuretics could be mediated, at least in part, by the elevation in serum uric acid that these agents provoke [2]. The view that increased serum uric acid is an independent cardiovascular risk factor, which stemmed from the early Framingham Study results and changed later when the authors realized that serum uric acid concentration is a correlate of blood pressure [3], has recently been revived amidst inconsistent findings and controversy [4,5]. At variance with the case of established cardiovascular risk factors, no mechanism whereby elevated serum uric acid might impair cardiovascular prognosis in man is readily apparent or has been substantiated by research. Serum uric acid concentration is positively associated not only with blood pressure [3] but also with various conditions that have been confirmed as cardiovascular risk factors and that form part of the so-called metabolic syndrome, including increased reabsorption of filtered sodium in the proximal tubule of the nephron [6], glucose intolerance [7], obesity, and certain derangements in the plasma lipid profile [8]. These associations have lead some to regard hyperuricemia as one of the components of the metabolic syndrome detrimental to cardiovascular health. In fact, the increased fractional reabsorption of sodium in the proximal tubule that is also associated with hypertension [9,10] is accompanied by retention of uric acid at the same nephronal level and therefore by a rise in serum uric acid concentration [6]. This explanation for the link between hypertension and the level at which sodium and, epiphenomenologically, uric acid are handled by the proximal tubule of the nephron is sustained by the fact that hypertension-associated high serum uric acid concentration is due to a lower than usual renal excretion of this metabolite [11]. However, neither the associations described above nor any other statistically defined associations necessarily connote causality. Moreover, elevated uric acid could well be the associated factor at odds with the other components of the metabolic syndrome in terms of cardiovascular consequences. The lack of any causal explanation for the contention that serum uric acid is an independent cardiovascular risk factor is expressly acknowledged by some of those supporters of this view who approach this question through rigorous scientific criteria [4]. The generation of uric acid from xanthine results in the production of hydrogen peroxide and of the superoxide radical, which interact and yield oxygen, the hydroxyl anion and the hydroxyl radical [12]. Nonetheless, uric acid is endowed with powerful oxidant scavenging capacity [13,14], and consequently the balance between the pro-oxidant reactive oxygen species and their antioxidant counterpart that result from the formation of uric acid must be weighed within the context of the total balance between oxidative burden and antioxidant capacity that affects cardiovascular tissues during certain acute pathophysiological circumstances, such as myocardial reperfusion, or in the course of some prolonged situations such as the impairment in the capacity for vasodilatation of the resistance vessels that occurs in heart failure. Avoiding uric acid generation by treatment with allopurinol has beneficial effects in both circumstances [15,16], i.e. it appears that the benefit conveyed by the antioxidant action of newly generated uric acid is surpassed by the damage caused by the co-generation of reactive oxygen species. These findings notwithstanding, it may safely be presumed

Comparison of felodipine and hydrochlorothiazide for the treatment of mild to moderate hypertension in black africans

A double-blind, parallel-group study was performed to assess the antihypertensive effects and tolerability of felodipine and hydrochlorothiazide (HCT) in black patients with mild to moderate uncomplicated hypertension [entry supine diastolic blood pressure (DBP) of 96-116 mm Hg]. The medicines were given as monotherapy and the additional effect of metoprolol was assessed in patients unresponsive to felodipine or HCT alone. After a 4-week placebo period, 45 patients were randomly allocated to treatment with felodipine (21) or HCT (24). Initial doses of felodipine 2.5 mg or HCT 12.5 mg twice daily were doubled after 1 week and doubled again after week 4 in cases with supine DBP above 90 mm Hg. At week 8, metoprolol 100 mg twice daily was added to the regimen of uncontrolled patients (supine DBP greater than 90 mm Hg) and maintained for the remaining 4-week trial period. Felodipine significantly reduced supine and erect systolic BP (SBP) and DBP after 4, 8, and 12 weeks of treatment. Responses to HCT were similar although standing diastolic BP at week 4 and standing SBP at week 8 were not significantly reduced. After 4 weeks, the mean fall in supine DBP was significantly greater for the felodipine than the HCT group. Eight patients on felodipine and 14 in the HCT group required additional metoprolol to achieve BP control. A significantly greater number of adverse effects were associated with HCT than felodipine treatment. Monotherapy with felodipine produced a more rapid control of hypertension, was more frequently effective, and was associated with a lower incidence of side effects than HCT.

Comparative antihypertensive effects of ketanserin and a ketanserin-hydrochlorothiazide combination administered once daily.

The effects of monotherapy with once-daily ketanserin (40 mg) were compared to those of ketanserin (40 mg) plus hydrochlorothiazide (25 mg) once daily in 21 patients with mild essential hypertension. After a placebo run-in period of 4 weeks, medication was randomly allocated. The study was double-blind and the double-dummy technique was used. The measurements of blood pressure during the 3-month treatment period showed a tendency for progressive decreases of the variable. Supine and erect blood pressure mean values were significantly reduced, between pretreatment and the end of week 12, by 17 and 12 mm Hg with ketanserin therapy and by 19 and 16 mm Hg with combination treatment, respectively. A mathematical model used for studying the evolution of erect diastolic blood pressure over time revealed that the combination lowered blood pressure at a higher rate than did ketanserin alone in the first week of treatment, but that thereafter the velocity of change was higher for ketanserin alone. Both treatments had equally effective antihypertensive effects after 12 weeks, although differences existed in the time courses of blood pressure changes. More prolonged studies are required in order to distinguish further between the medications used.