Parviz Ghahramani

Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population.

Abstract Objective: To examine the accuracy of a new version of the Sheffield table designed to aid decisions on lipids screening and detect thresholds for risk of coronary heart disease needed to implement current guidelines for primary prevention of cardiovascular disease. Design: Comparison of decisions made on the basis of the table with absolute risk of coronary heart disease or cardiovascular disease calculated by the Framingham risk function. The decisions related to statin treatment when coronary risk is ≥years; aspirin treatment when the risk is ≥ 15% over 10 years; and the treatment of mild hypertension when the cardiovascular risk is≥0% over 10 years. Setting: The table is designed for use in general practice. Subjects: Random sample of 1000 people aged 35–64 years from the 1995 Scottish health survey. Main outcome measures: Sensitivity, specificity, and positive and negative predictive values of the table. Results: 13% of people had a coronary risk of ≥15%, and 2.2% a risk of ≥30%, over 10 years. 22% had mild hypertension (systolic blood pressure 140–159 mm Hg). The table indicated lipids screening for everyone with a coronary risk of ≥15% over 10 years, for 95% of people with a ratio of total cholesterol to high density lipoprotein cholesterol of ≥8.0, but for <50% with a coronary risk of <5% over 10 years. Sensitivity and specificity were 97% and 95% respectively for a coronary risk of ≥15% over 10 years; 82% and 99% for a coronary risk of ≥30% over 10 years; and 88% and 90% for a cardiovascular risk of ≥20% over 10 years in mild hypertension. Conclusion: The table identifies all high risk people for lipids screening, reduces screening of low risk people by more than half, and ensures that treatments are prescribed appropriately to those at high risk, while avoiding inappropriate treatment of people at low risk.

Association of panic disorder and panic attacks with hypertension

PURPOSE Previous studies of the association between hypertension and panic disorder were uncontrolled or involved small numbers of patients. PATIENTS AND METHODS We compared the prevalence of panic disorder and panic attacks in 351 patients with documented hypertension who were randomly selected from all hypertensive patients registered in one primary care practice with age- and gender-matched normotensive patients from the same practice and with hypertensive patients attending a hospital clinic. All three groups completed questionnaires for panic disorder based on standard criteria, as well as the Hospital Anxiety and Depression scale. RESULTS The prevalence of current (previous 6 months) panic attacks was significantly greater in primary care patients with hypertension (17%, P <0.05) and hospital-based hypertensive patients (19%, P <0.01) than in normotensive patients (11%). Similar results were seen for lifetime panic attacks (35% versus 39% versus 22%; both P for comparisons with normotensive patients <0.001). The prevalence of panic disorder was significantly greater in primary care patients with hypertension (13%) than normotensive patients (8%, P <0.05). Anxiety scores were significantly higher in both hypertensive groups than in normotensive patients. Depression scores were significantly higher in hospital-based hypertensive patients than in the other two groups. The reported diagnosis of hypertension antedated the onset of panic attacks in a large majority of patients (P <0.01). CONCLUSIONS Physicians caring for patients with hypertension should be aware of the significantly greater prevalence of panic attacks in these patients.

Influence of genetic polymorphisms in the β2-adrenoceptor on desensitization in human lung mast cells

The beta-adrenoceptor agonist, isoprenaline, inhibited the immunoglobulin E-mediated release of histamine from human lung mast cells (HLMC). Long-term (24 h) exposure of HLMC to isoprenaline reduced the subsequent effectiveness of isoprenaline to inhibit histamine release. The extent of this functional desensitization was variable with some HLMC preparations resistant and others highly susceptible. We sought to determine whether the variability in the degree of functional desensitization was influenced by genetic polymorphisms in the beta2-adrenoceptor. HLMC preparations were genotyped at two polymorphic loci, positions 16 (arg to gly) and 27 (gln to glu), and the effect of desensitizing conditions (24 h with 10(-6) M isoprenaline) on the subsequent ability of isoprenaline (10(-7) M) to inhibit histamine release from HLMC was determined (n = 72). In HLMC preparations expressing beta2-adrenoceptors with arg (wild-type) or gly (mutant) at position 16, desensitization was 71 +/- 5% (n = 18) or 43 +/- 5%, (n = 26), respectively, whereas the desensitization was 59 +/- 6% (n = 28) for heterozygotes at this position. In HLMC preparations expressing beta2-adrenoceptors with gln (wild-type) or glu (mutant) at position 27, desensitization was 65 +/- 5% (n = 25) or 28 +/- 7% (n = 17), respectively, whereas the desensitization was 61 +/- 5% (n = 30) for heterozygotes at this position. These data suggest that mutant (gly16 and glu27) forms of the receptor are resistant to desensitization compared to wild-type (arg16 and gln27) forms. However, analyses to determine the relative contributions of positions 16 and 27 suggest that position 27 is more important in influencing the degree of functional desensitization.

Protection by dexamethasone of the functional desensitization to β2‐adrenoceptor‐mediated responses in human lung mast cells

The β‐adrenoceptor agonist, isoprenaline, inhibited the IgE‐mediated release of histamine from human lung mast cells (HLMC) in a dose‐dependent manner. Maximal inhibitory effects were obtained with 0.1 μM isoprenaline. However, the inhibition of histamine release from HLMC by isoprenaline (0.1 μM) was highly variable ranging from 33 to 97% inhibition (mean, 59±3%, n=27). Long‐term (24 h) incubation of HLMC with isoprenaline led to a subsequent reduction in the ability of a second exposure of isoprenaline to inhibit IgE‐mediated histamine release from HLMC. The impairment in the ability of isoprenaline (0.1 μM) to inhibit histamine release following desensitizing conditions (1 μM isoprenaline for 24 h) was highly variable amongst HLMC preparations ranging from essentially negligible levels of desensitization in some preparations to complete abrogation of the inhibitory response in others (mean, 65±6% desensitization, n=27). The ability of HLMC to recover from desensitization was investigated. Following desensitizing conditions (1 μM isoprenaline for 24 h), HLMC were washed and incubated for 24 h in buffer and the effectiveness of isoprenaline (0.1 μM) to inhibit IgE‐mediated histamine release from HLMC was assessed. The extent of recovery was highly variable with some HLMC preparations failing to recover and others displaying a complete restoration of responsiveness to isoprenaline (mean, 40±6% recovery, n=23). The effects of the glucocorticoid, dexamethasone, were also investigated. Long‐term (24–72 h) treatments with dexamethasone (0.1 μM) had no effect on IgE‐mediated histamine release from HLMC. Additionally, long‐term (24–72 h) treatments with dexamethasone (0.1 μM) had no effect on the effectiveness of isoprenaline to inhibit histamine release. However, long‐term (24–72 h) treatments with dexamethasone (0.1 μM) protected against the functional desensitization induced by incubation (24 h) of HLMC with isoprenaline (1 μM). The protective effect was time‐dependent and pretreatment of HLMC with dexamethasone for either 24, 48 or 72 h prevented desensitization by either 15±7, 19±5 or 51±10%, respectively (n=5–7). HLMC preparations which were relatively refractory to isoprenaline even after withdrawal (24 h) from desensitizing conditions responded more effectively to isoprenaline (0.1 μM) if dexamethasone (0.1 μM) was also included during the recovery period (19±9% recovery after 24 h in buffer; 50±8% recovery after 24 h with dexamethasone, n=5). These data indicate that the responses of different HLMC preparations to isoprenaline, the susceptibility of HLMC to desensitization and the ability of HLMC to recover from desensitizing conditions varies markedly. Dexamethasone, which itself has no direct effects on IgE‐mediated histamine release from HLMC, protected HLMC from the functional desensitization to β‐adrenoceptor agonists. Because β2‐adrenoceptor agonists and glucocorticoids are important in the therapeutic management of asthma and as the HLMC is probably important in certain types of asthma, these findings may have wider clinical implications.

Panic disorder, anxiety and depression in resistant hypertension : a case-control study

Background It has been suggested that panic disorder can cause or contribute to hypertension or resistance to antihypertensive drugs. Objective To compare the prevalences of panic disorder, panic attacks, anxiety and depression between patients with resistant hypertension and age- and sex-matched patients with non-resistant hypertension. Design A case–control study of patients attending the Sheffield Hypertension Clinic, using self-completed postal questionnaires to assess panic disorder, anxiety and depression. Patients Cases with resistant hypertension were defined as patients who presently or previously had systolic blood pressure above 160 mmHg or diastolic blood pressure above 90 mmHg despite the use of three or more antihypertensive agents at full dose. For each of 136 cases, one control with non-resistant hypertension, defined as controlled to ≤ 160/90 mmHg by one or two antihypertensive agents, was identified by a bias-free method. Cases and controls were matched for age and sex. Main outcome measures Lifetime and current prevalence of panic attacks, the prevalences of panic disorder, anxiety and depression by Hospital Anxiety and Depression Scale scores, and the severity and frequency of panic attacks. Results Of the resistant hypertensive patients, 33% had experienced a panic attack compared with 39% of the control non-resistant hypertensives (resistant – non-resistant −6%, 95% confidence interval −19 to +7%). Twelve per cent of the resistant patients and 14% of controls fulfilled the criteria for a current or previous diagnosis of panic disorder (resistant – non-resistant −2%, 95% confidence interval −11 to +7%). There were also no significant differences between the groups in the prevalences of current panic attacks, panic attacks rated as moderate or worse, spontaneous panic attacks and in the frequency of panic attacks. There remained no significant difference between the groups for panic attacks and panic disorder when the analysis was limited to those patients who had idiopathic hypertension. The two groups did not differ significantly in scores for anxiety and depression measured by the Hospital Anxiety and Depression Scale. Conclusion We observed no differences in the prevalences of panic, anxiety and depression between patients with resistant hypertension and non-resistant controls. These factors are probably not implicated in resistance to drug treatment. However, the prevalences of panic disorder and panic attacks were remarkably high in both groups of patients attending a hospital hypertension clinic. The relationship between panic disorder and hypertension deserves further study in a general hypertensive population.

Influence of receptor reserve on β-adrenoceptor-mediated responses in human lung mast cells

The effects of the β‐adrenoceptor agonists isoprenaline and salbutamol on IgE‐mediated histamine release from human lung mast cells (HLMC) were evaluated. Both agonists (10−10–10−5 M) inhibited histamine release in a dose‐dependent manner and isoprenaline (pD2, 8.3±0.1, mean±s.e.mean) was more potent than salbutamol (7.3±0.1). Moreover, the mean data indicated that salbutamol was a partial agonist when compared with isoprenaline. However, there was a large degree of inter‐experimental variability because, in 11 of 32 experiments, salbutamol was a full agonist and, in 21 of 32 experiments, a partial agonist relative to isoprenaline. These data suggest that different HLMC preparations possess variable receptor reserves. The effect of the irreversible β‐adrenoceptor antagonist, bromoacetylalprenolol menthane (BAAM), on the inhibition of IgE‐mediated histamine release by both isoprenaline and prostaglandin E2 (PGE2) was assessed. Whereas BAAM (100 nM) antagonized the isoprenaline inhibition of histamine release from activated HLMC, BAAM had no effect on the PGE2 inhibition. Pretreatment of HLMC with the β2‐selective competitive antagonist, ICI 118551 (100 nM), protected against the loss in responsiveness to isoprenaline following treatment with BAAM. Concentrations of 1, 10 and 100 nM of BAAM caused dose‐dependent rightward shifts in the dose‐response curve for the isoprenaline inhibition of histamine release. Furthermore, there was a dose‐dependent reduction in the maximal inhibitory response obtained with isoprenaline following treatments with increasing concentrations of BAAM. Although the rightward shifts in the isoprenaline dose‐response curves, with a given concentration of BAAM, were similar in all experiments, there was some variability in the depression of the maximal response in individual experiments. Thus, in 6 of 16 experiments, BAAM (1 nM) did not depress the maximal response to isoprenaline, whereas in 10 of 16 experiments there was a depression (7 to 49% reduction) in the maximal response. These data suggest that different HLMC preparations possess variable receptor reserves. Isoprenaline was more potent as an inhibitor in those HLMC preparations in which there was a larger receptor reserve (i.e. preparations in which the maximal inhibitory response to isoprenaline was unaffected by pretreatment with 1 nM BAAM). The influence of receptor reserve on the inhibition by salbutamol of histamine release from HLMC was evaluated. There was a good correlation (r=0.77) between receptor reserve and the maximal response (relative to isoprenaline) obtained with salbutamol. Thus, HLMC preparations with larger receptor reserves were more responsive to salbutamol. Receptor reserve influenced the desensitization of β‐adrenoceptor‐mediated responses in HLMC. Cells were incubated (24 h) with isoprenaline (1 μM), washed and then the ability of a second isoprenaline (10−10–10−5 M) exposure to inhibit histamine release was assessed. The pretreatment caused a reduction in the isoprenaline inhibition of histamine release although the extent of desensitization was highly variable, ranging from essentially negligible levels in some preparations to substantial reductions (93% desensitization) in the ability of isoprenaline to inhibit histamine release. There was a reasonable correlation (r=0.59) between receptor reserve and desensitization. Preparations that possessed a larger receptor reserve were more resistant to desensitization. Collectively, these data suggest that a receptor reserve exists for the β‐adrenoceptor‐mediated inhibition of histamine release from HLMC but that the size of this reserve varies between HLMC preparations. Moreover, the size of this receptor reserve may influence the sensitivity of HLMC to β‐adrenoceptor agonists and the susceptibility of individual HLMC preparations to desensitization.

Is coronary risk an accurate surrogate for cardiovascular risk for treatment decisions in mild hypertension? A population validation.

Objective To examine the relationship between coronary (CHD) and cardiovascular (CVD) risk in patients with uncomplicated mild hypertension and to determine the accuracy of using CHD risk ⩾ 15% over 10 years to identify for antihypertensive treatment those patients with CVD risk ⩾ 20% over 10 years as advised in recent British guidelines. Design Comparison of decisions made using CHD risk ⩾ 15% over 10 years calculated by the Framingham risk function and estimated using a simple table with CVD risk ⩾ 20% over 10 years. Setting British population. Subjects People aged 35–64 years with uncomplicated mild systolic hypertension (SBP 140–159 mmHg, n = 624) from the 1995 Scottish Health Survey. Main outcome measures Relationship between CHD and CVD risk. Sensitivity, specificity, positive and negative predictive values (PPV and NPV). Results CHD risk 15% over 10 years was equivalent to CVD risk 21% over 10 years. Exact CHD risk ⩾ 15% over 10 years had sensitivity 79%, specificity 98%, PPV 94% and NPV 93% in detecting CVD risk ⩾ 20% over 10 years. Use of the table to estimate CHD risk ⩾ 15% over 10 years gave sensitivity 88%, specificity 90%, PPV 76% and NPV 95%. Conclusion CHD risk appears acceptably accurate for targeting treatment in mild hypertension. The risk assessment table, which slightly overestimates CHD risk, was more sensitive in identifying patients with CVD risk ⩾ 20% over 10 years and may be preferable to using exact CHD risk. European guidelines which suggest targeting treatment for mild hypertension at CHD risk ⩾ 20% over 10 years are over-conservative compared with British guidelines.

No evidence that panic attacks are associated with the white coat effect in hypertension.

The authors aimed to determine whether hypertensive patients with panic attacks or panic disorder have a larger white coat effect (difference between clinic blood pressure measured under standard conditions and mean daytime ambulatory blood pressure) than hypertensive patients without panic attacks. White coat effect was compared in a hospital hypertension clinic between 24 patients with panic attacks in the previous 6 months (12 with panic disorder) and 23 hypertensive controls. There were no significant differences between cases and controls in clinic blood pressure, mean daytime ambulatory blood pressure, or white coat effect (18/3 vs. 19/6 mm Hg; difference for systolic, −1.9 mm Hg; 95% confidence interval, −15.8 to +12.0; difference for diastolic, −3.0 mm Hg; 95% confidence interval, −10.2 to +4.3). Comparing only patients with panic disorder with controls, there were again no significant differences in clinic blood pressure, mean daytime ambulatory blood pressure, or white coat effect. This study provides no evidence for an exaggerated white coat effect in hypertensive patients who have experienced panic attacks or panic disorder. However, only larger studies could exclude differences in white coat effect <12/4 mm Hg, or an exaggerated white coat effect in a minority of patients with panic attacks.

Protein binding of aspirin and salicylate measured by in vivo ultrafiltration

Methods for measuring protein binding of drugs generally require direct measurement of the concentration of unbound drug and thus may require a highly sensitive assay. In vivo ultrafiltration has been used to determine protein binding of endogenous substances. We have examined its value for measuring protein binding of drugs because it requires measurement of only the concentration of total drug, not unbound drug, in plasma.