Arie J. Man in 't Veld

A Clinical Prediction Rule for Renal Artery Stenosis

Renal artery stenosis impairs blood flow to the kidney and can consequently cause renovascular hypertension and renal failure [1, 2]. Although the prevalence of this condition among patients with hypertension is low, therapeutic options for relieving renal artery stenosis, such as renal angioplasty and stenting, make the search for renal artery stenosis worthwhile [2-4]. Renal angiography is the gold standard for diagnosing renal artery stenosis, but it is a costly and invasive procedure that can involve serious complications [5, 6]. To diagnose renal artery stenosis efficiently, angiography should be used selectively. Most physicians rely on captopril renal scintigraphy as a selection criterion, but the diagnostic accuracy of this test is low (sensitivity, 65% to 77%; specificity, 90%) [7, 8]. As an alternative, clinical characteristics can be used to select hypertensive patients for angiography [9]. Patients with normal renal function whose blood pressure can be controlled with one or two drugs can be excluded from angiography [9, 10]. In the remaining patients (those with drug-resistant hypertension), such clinical characteristics as atherosclerotic vascular disease, smoking history, and presence of an abdominal bruit can be used to estimate a patients probability of renal artery stenosis [11-14]. This estimate can then be used in selection for angiography. We analyzed the clinical characteristics of 477 patients with drug-resistant hypertension or an increase in serum creatinine concentration during therapy with angiotensin-converting enzyme (ACE) inhibitors who participated in the Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) study [9]. We developed a clinical prediction rule for quantifying the probability of renal artery stenosis [15] and demonstrated the potential consequences of this rule for clinical practice by applying it to our patients. Methods Patients The DRASTIC study is a prospective cohort study conducted at 26 departments of internal medicine with an interest in hypertension throughout the Netherlands [9]. The diagnostic phase of the study was designed to find an optimal strategy for diagnosing renal artery stenosis. In the DRASTIC study, 1133 hypertensive patients 18 to 75 years of age with preserved renal function (serum creatinine concentration 200 mol/L [2.26 mg/dL]) were enrolled. These patients were referred for analysis of hypertension by general practitioners (55%) or hospital specialists (45%), in most cases because their hypertension was difficult to treat with antihypertensive drugs. Sixty percent of patients were from four hospitals. After giving written informed consent, patients were randomly assigned to one of two standard protocols with antihypertensive drugs: amlodipine, 10 mg, plus atenolol, 50 mg, in patients older than 40 years of age or enalapril, 20 mg, plus hydrochlorothiazide, 25 mg, in patients older than 40 years of age. Blood pressure was measured with a standard sphygmomanometer at three consecutive visits at least 1 week apart. Measurements were taken three times per visit after a 5-minute rest with the patient in the sitting position. Patients were selected for diagnostic workup if they had drug-resistant hypertension, defined as a mean diastolic blood pressure per visit of 95 mm Hg or more while receiving the standard drug regimen during all three visits or prescription of an additional drug regardless of blood pressure response. Patients were also selected if the serum creatinine concentration increased 20 mol/L (0.23 mg/dL) or more during therapy with ACE inhibitors. In these patients, intra-arterial digital subtraction angiography and other, noninvasive tests were performed. In accordance with the study protocol, patients who responded well to standard treatment were not evaluated further. The diagnostic phase of the study was followed by a therapeutic phase in which patients with atherosclerotic stenosis were randomly assigned to receive medication or renal angioplasty. Definitions After performing a literature study, we selected 12 clinical characteristics indicative of renovascular disease (predictors) [10, 11, 16-26]: age, sex, ethnicity (black or other), signs and symptoms of atherosclerotic vascular disease (femoral or carotid bruit, angina pectoris, claudication, myocardial infarction, cerebrovascular accident, or vascular surgery), recent onset of hypertension (within the past 2 years), family history of hypertension (parents, siblings, or children with hypertension), smoking history (ever or never), obesity (body mass index 25 kg/m2), abdominal bruit, advanced hypertensive retinopathy (fundus grade III or IV), serum creatinine concentration, and hypercholesterolemia (serum cholesterol level > 6.5 mmol/L [251.35 mg/dL] or use of cholesterol-lowering agents). These characteristics were used to predict the presence of renal artery stenosis. A patient was considered to have renal artery stenosis when the angiogram showed at least one stenosis of 50% or more in a renal artery according to the local-radiologist. Model Development Data are presented as a proportion or as the mean SD. The univariable association between clinical characteristics and presence of renal artery stenosis was studied by computing the value and 95% CI of the odds ratio. In a multivariable analysis, clinical characteristics were combined as predictor variables in a logistic regression model predicting the presence of renal artery stenosis (outcome) [27]. For each patient in the multivariable analysis, the probability of renal artery stenosis was calculated from the regression model (predicted probability). The reliability, discriminative ability, and validity of the model were assessed. The Appendix gives details on model development and evaluation. To enable the use of the regression model in clinical practice, a prediction rule was constructed for predicting renal artery stenosis in future patients with drug-resistant hypertension or an increase in serum creatinine concentration during therapy with ACE inhibitors. For the presence or level of each clinical characteristic in the regression model, a score was calculated on the basis of the regression coefficients (Appendix). These scores were added into a sum score. All possible sum scores and their corresponding predicted probabilities of renal artery stenosis were combined in a graph with 95% CIs of the predicted probabilities. Role of the Funding Source Our funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Statistical Analyses Angiography was performed in 439 patients with drug-resistant hypertension and 39 patients with an increase in serum creatinine concentration during therapy with ACE inhibitors. The procedure failed in 1 patient. For the remaining 477 patients, angiography showed renal artery stenosis in 107 patients (22%), of whom 90 (84%) had atherosclerotic stenosis and 17 (16%) had fibromuscular dysplasia. Bilateral stenoses were found in 27 of 107 affected patients (25%). Renal scintigraphy was performed in 458 patients; it had a sensitivity of 72% and a specificity of 90% for the diagnosis of renal artery stenosis. Table 1 shows the univariable distribution of the clinical characteristics for patients with renal artery stenosis and those with essential hypertension. Most clinical characteristics were indicative of renal artery stenosis (P < 0.05 or borderline significant) except sex, recent onset of hypertension, and presence of advanced hypertensive retinopathy. More young women without signs of atherosclerotic disease were found among patients with fibromuscular dysplasia than among those with atherosclerotic stenosis, but abdominal bruits occurred with the same frequency in both groups (29% and 27%, respectively). Table 1. Associations of Clinical Characteristics with Renal Artery Stenosis The results of multivariable analysis are also shown in Table 1. Advanced hypertensive retinopathy was not studied any further because this clinical characteristic was missing for 43% of the patients. Data on 11 clinical characteristics of 460 patients were considered predictive of renal artery stenosis. Ethnicity and family history of hypertension were removed from the regression model because their contribution to predicting renal artery stenosis was small. Because renal artery stenosis is believed to be more prevalent in young women and old men, interaction between age and sex was tested; this interaction was not statistically significant (P = 0.09). We included an interaction term between age and smoking because this was the only biologically plausible interaction term that was statistically significant (P = 0.01). This interaction term accounts for the fact that the predictive value of increasing age was stronger for patients who never smoked than for current and former smokers. Finally, the type of standard treatment did not provide additional diagnostic information when it was included in the regression model (P > 0.2). The multivariable odds ratios in Table 1 reflect the predictive effect of the individual clinical characteristics while correcting for the other predictors in the multivariable model. For example, the multivariable odds ratio for atherosclerotic vascular disease was lower than the univariable odds ratio because the model also accounted for the effects of age and smoking history. Model Performance Figure 1 shows the agreement between the predicted and the observed probabilities. For 204 patients (44%), the predicted probability of stenosis was 0% to 10%. The predicted probabilities of stenosis obtained from the model agreed well with the observed frequency of stenosis (goodness-of-fit test, P > 0.2). The model discriminated well between patients with renal artery stenosis (predicted probability, 49% 29%) and patients with essential hypertension (predicted probability, 15% 16%); the are

Prognostic value of heart rate variability during long-term follow-up in patients with mild to moderate heart failure

OBJECTIVES We sought to assess the prognostic value of heart rate variability measures, including Poincaré plots, in patients with mild to moderate chronic heart failure. BACKGROUND Mortality is high in patients with heart failure, and many of them die suddenly. However, identification of high risk patients, particularly those with an increased risk for sudden death, has remained difficult. METHODS We studied 95 patients with heart failure (mean [+/- SD] age 60 +/- 8 years, left ventricular ejection fraction 0.29 +/- 0.09, New York Heart Association functional class II [81%] and III [19%]) during up to 4 years of follow-up. Heart rate variability measures and Poincaré plots were obtained from 24-h Holter recordings. RESULTS During follow-up, 17 (18%) of the 95 patients died. In 15 patients, death was cardiac related (11 patients experienced sudden death). None of the conventional time and frequency domain measures of heart rate variability were related to survival. In contrast, abnormal Poincaré plots identified a significantly higher risk for all-cause cardiac death (Cox proportional hazards ratio 5.7, 95% confidence interval [CI] 1.6 to 20.6, univariate analysis) and for sudden cardiac death (hazards ratio 6.8, 95% CI 1.5 to 31.4) compared with those with normal Poincaré plots. Patients with abnormal Poincaré plots were shown to have a lower left ventricular ejection fraction (0.26 +/- 0.10 vs. 0.31 +/- 0.08, p < 0.05) and higher plasma norepinephrine concentrations (506 +/- 207 pg/ml vs. 411 +/- 175 pg/ml, p < 0.05). In multivariate analysis, abnormal Poincaré plots still had independent prognostic value, both for all-cause cardiac mortality and for sudden cardiac death (hazards ratio 5.3, 95% CI 1.2 to 17.1, hazards ratio 4.5, 95% CI 1.0 to 27.5, respectively. CONCLUSIONS Heart rate variability analysis, as assessed by Poincaré plots, has independent prognostic value in patients with mild to moderate chronic heart failure and identifies an increased risk for all-cause and sudden cardiac death in these patients.

Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT).

OBJECTIVES This study was conducted to determine the efficacy and safety of long-term treatment with the orally active dopamine agonist ibopamine in patients with mild to moderate chronic congestive heart failure and to compare the results with those of treatment with digoxin and placebo. BACKGROUND Ibopamine and digoxin are drugs that exert hemodynamic and neurohumoral effects. Because there is accumulating evidence that progression of disease in chronic heart failure is related not only to hemodynamic but also to neurohumoral factors, both drugs might be expected to have a favorable long-term effect. METHODS We studied 161 patients with mild to moderate chronic heart failure (80% in New York Heart Association functional class II and 20% in class III), who were treated with ibopamine (n = 53), digoxin (n = 55) or placebo (n = 53) for 6 months. Background therapy consisted of furosemide (0 to 80 mg); all other drugs for heart failure were excluded. Clinical assessments were made at baseline and after 1, 3 and 6 months. RESULTS Of the 161 patients, 128 (80%) completed the study. Compared with placebo, digoxin but not ibopamine significantly increased exercise time after 6 months (p = 0.008 by intention to treat analysis). Ibopamine was only effective in patients with relatively preserved left ventricular function, as it significantly increased exercise time in this subgroup (for patients with a left ventricular ejection fraction > 0.30; p = 0.018 vs. placebo). No patient receiving digoxin withdrew from the study because of progression of heart failure, compared with six patients receiving ibopamine and two receiving placebo. At 6 months, plasma norepinephrine was decreased with digoxin and ibopamine therapy (-106 and -13 pg/ml, respectively) but increased with placebo administration (+62 pg/ml) (both p < 0.05 vs. placebo). Plasma aldosterone was unaffected, but renin was decreased by both agents after 6 months (p < 0.05 vs. placebo). Total mortality and ambulatory arrhythmias were not significantly affected by the two drugs. CONCLUSIONS Ibopamine and digoxin both inhibit neurohumoral activation in patients with mild to moderate chronic heart failure. However, the clinical effects of these drugs are different and appear to be related to the degree of left ventricular dysfunction.

Plasma semicarbazide-sensitive amine oxidase is elevated in patients with congestive heart failure

OBJECTIVE Semicarbazide-sensitive amine oxidase (SSAO) is present in various mammalian tissues, especially in vascular smooth muscle cells, but also in plasma. The enzyme has been suggested to play a role in vascular endothelial damage through conversion of amines into cytotoxic aldehydes, ammonia and hydrogen peroxide. Endothelial dysfunction is present in diabetes mellitus (DM) and congestive heart failure (CHF). Elevated plasma SSAO activities have been reported in patients with DM, but no data on patients with CHF are as yet available. METHODS AND RESULTS Plasma SSAO was measured in 271 patients with CHF and compared to values in 77 controls. SSAO was found to be elevated in patients with CHF compared to controls (589 +/- 252 vs. 455 +/- 114 mU/l; P < 0.0001). Plasma SSAO was higher in NYHA class III/IV than in class III (662 +/- 288 vs. 555 +/- 226 mU/l; P = 0.004) and also higher in patients with concomitant DM than in those without (706 +/- 248 vs. 557 +/- 245 mU/l; P < 0.0001). Plasma SSAO correlated with plasma atrial natriuretic peptide (r = 0.42; P < 0.0001), with plasma norepinephrine (r = 0.27; P < 0.0001) and with left ventricular ejection fraction (r = -0.13; P = 0.0162). Multiple regression analysis showed atrial natriuretic peptide, norepinephrine, DM and cardiothoracic ratio to be the main determinants of plasma SSAO. CONCLUSION The finding of elevated plasma SSAO in CHF, increasing with severity of the disease and with the concomitant presence of DM, supports the suggestion that SSAO may be involved in the pathogenesis of vascular endothelial damage. Plasma SSAO may be a useful parameter in assessing severity of CHF and in prognostic evaluation. Pharmacologic manipulation of SSAO activity might be an interesting new concept for prevention of vascular endothelial damage in various vascular disease entities.

Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: does it exist and does it affect the antihypertensive response?

Objective To investigate whether the compensatory rise in renin and plasma angiotensin 1 in response to repeated angiotensin converting enzyme (ACE) inhibitor treatment results in a partial escape of ACE inhibition over a 24-h dosing interval. Design A single-blind placebo-controlled study in two parallel groups of eight hypertensive subjects receiving a once-daily dose of the ACE inhibitor, spirapril, of either 12.5 or 25 mg. Detailed 24-h studies were performed at the end of 2 weeks of placebo, and after the first dose and 2 weeks administration of spirapril. Methods Twenty-four-hour ambulatory blood pressure was measured invasively. True* angiotensins I and II were measured by radioimmunoassay after high-performance liquid chromatography separation. Results Both for the the lower and higher doses of spirapril, the time-course of changes of spiraprilat, the active metabolite of spirapril, and ACE activity was similar but the maximal rise in angiotensin I was twofold higher after 2 weeks administration than after the first dose. Angiotensin II after the first dose of spirapril fell rapidly, with lowest values 2 to 4h after dosing. At the end of dosing interval angiotensin II had returned to values seen under placebo with the 12.5-mg dose, but at the end of the 24-h period it was still suppressed with the 25-mg dose. Compared with these first-dose responses the initial maximal degree of angiotensin II suppression after 2 weeks administration of either dose was similar, but during the subsequent hours the degree of angiotensin II suppression tended to be less with the lower and was significantly less with the higher dose of spirapril. With the lower dose of spirapril responses of 24-h ambulatory blood pressure to the first dose and to 2 weeks of administration were almost superimposable, although blood pressures in the second half of the dosing interval tended to be higher during chronic treatment. With the higher dose the response of nocturnal blood pressure after 2 weeks administration was diminished by 8.8 mmHg systolic and 6.8 mmHg diastolic. Conclusions: Repeated ACE inhibitor treatment with once-daily spirapril leads to a partial escape of ACE inhibition, as reflected by a shorter duration of angiotensin II suppression. This escape also affects the antihypertensive response in the second half of the dosing interval.

High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril

OBJECTIVES To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril. BACKGROUND The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect. METHODS In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones. RESULTS At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses. CONCLUSIONS Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.

Time Course and Mechanism of Myocardial Catecholamine Release During Transient Ischemia In Vivo

BACKGROUND Elevated concentrations of norepinephrine (NE) have been observed in ischemic myocardium. We investigated the magnitude and mechanism of catecholamine release in the myocardial interstitial fluid (MIF) during ischemia and reperfusion in vivo through the use of microdialysis. METHODS AND RESULTS In 9 anesthetized pigs, interstitial catecholamine concentrations were measured in the perfusion areas of the left anterior descending coronary artery (LAD) and the left circumflex coronary artery. After stabilization, the LAD was occluded for 60 minutes and reperfused for 150 minutes. During the final 30 minutes, tyramine (154 nmol. kg(-1). min(-1)) was infused into the LAD. During LAD occlusion, MIF NE concentrations in the ischemic region increased progressively from 1. 0+/-0.1 to 524+/-125 nmol/L. MIF concentrations of dopamine and epinephrine rose from 0.4+/-0.1 to 43.9+/-9.5 nmol/L and from <0.2 (detection limit) to 4.7+/-0.7 nmol/L, respectively. Local uptake-1 blockade attenuated release of all 3 catecholamines by >50%. During reperfusion, MIF catecholamine concentrations returned to baseline within 120 minutes. At that time, the tyramine-induced NE release was similar to that seen in nonischemic control animals despite massive infarction. Arterial and MIF catecholamine concentrations in the left circumflex coronary artery region remained unchanged. CONCLUSIONS Myocardial ischemia is associated with a pronounced increase of MIF catecholamines, which is at least in part mediated by a reversed neuronal reuptake mechanism. The increase of MIF epinephrine implies a (probably neuronal) cardiac source, whereas the preserved catecholamine response to tyramine in postischemic necrotic myocardium indicates functional integrity of sympathetic nerve terminals.

Hemodynamic and Biochemical Effects of the AT1 Receptor Antagonist Irbesartan in Hypertension

We studied the hemodynamic, neurohumoral, and biochemical effects of the novel angiotensin type 1 (AT1) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet. According to a double-blind parallel group trial, patients were randomized to a once-daily oral dose of the AT1 receptor antagonist (1, 25, or 100 mg) or placebo after a placebo run-in period of 3 weeks. Randomization medication was given for 1 week. Compared with placebo, 24-hour ambulatory blood pressure did not change with the 1-mg dose, and it fell (mean and 95% confidence interval) by 7.0 (4.2-9.8)/6.1 (3.9-8.1) mm Hg with the 25-mg dose and by 12.1 (8.1-16.2)/7.2 (4.9-9.4) mm Hg with the 100-mg dose. Heart rate did not change during either dose. With the 25-mg dose, the antihypertensive effect was attenuated during the second half of the recording, and with the 100-mg dose, it was maintained for 24 hours. Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated (r = .68, P < .01). Renin did not change with the 1-mg dose, but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration. With the 100-mg dose, renin was still elevated twofold 24 hours after dosing. The changes in renin induced by the AT1 receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II. Aldosterone, despite AT1 receptor blockade, did not fall.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic changes during long-term thiazide treatment of essential hypertension in responders and nonresponders.

Blood pressure, cardiac output, plasma volume, renin, and aldosterone were measured in 13 patients with essential hypertension on placebo and after 1, 4, and 12 wk on hydrochlorothiazide 100 mg daily. In 9 patients the same variables were also measured after 24 and 36 wk. Hydrochlorothiazide lowered mean arterial pressure (p < 0.01). Cardiac output was reduced after 4 and 12 wk of treatment, followed by a return to placebo levels. Stroke volume changed in the same way but heart rate and total peripheral resistance did not differ from placebo values. Plasma volume was reduced after 1 and 24 wk. Renin was permanently elevated (p < 0.01), but aldosterone rose only during the first 12 wk of treatment. A comparison between responders (>10% fall in mean arterial pressure) and nonresponders (<10% fall) revealed different hemodynamic patterns. In responders the initial fall in cardiac output was followed by a return to pretreatment levels, whereas in nonresponders it was permanently reduced. Consequently, total peripheral resistance was lowered only in responders. Nonresponders tended to show a greater degree of plasma volume depletion and greater stimulation of renin and aldosterone, which probably contributed to elevated peripheral resistance. It is concluded that changes in cardiac output are unlikely to be of decisive importance in the ultimate reduction of peripheral resistance in responders to thiazide therapy.

Evaluation of Importance of Central Effects of Atenolol and Metoprolol Measured by Heart Rate Variability During Mental Performance Tasks, Physical Exercise, and Daily Life in Stable Postinfarct Patients

BACKGROUND Physical exercise and mental work cause alterations in cardiac autonomic control. beta-Blockers protect the heart against stress, and this effect may be in part centrally mediated. In this context, the lipophilicity of the drug would be clinically relevant. METHODS AND RESULTS Thirty postinfarct patients were randomized to receive 100 mg atenolol or 200 mg metoprolol CR in a double-blind, crossover manner, each for a 6-week period. Heart rate (HR) variability was used to study autonomic effects during mental and physical stress and to study circadian variations. Mean 24-hour HR decreased from 77 +/- 7 to 60 +/- 6 beats per minute after atenolol and to 62 +/- 6 beats per minute after metoprolol (P = .046). At baseline, mental performance tasks did not affect HR, but decreased HR variability (SDNN index from 51 +/- 26 to 30 +/- 13 milliseconds [ms], P < .001; high-frequency power from 130 +/- 143 to 110 +/- 125 ms2, P = .046; and low-frequency power from 538 +/- 447 to 290 +/- 275 ms2, P < .001). Both beta-blockers decreased HR during mental performance tasks (P < .001) and increased SDNN index and high-frequency power. Before treatment, bicycle exercise decreased HR variability; root-mean-square of successive difference decreased from 21 +/- 8 to 15 +/- 10 ms (P = .004). beta-Blockade could not prevent this decrease. No differences between atenolol and metoprolol were observed for absolute high- and low-frequency power or after adjustment for HR. Vagal blockade with methylatropine during chronic beta-blocker treatment nearly abolished all components of spectral power. HR was found to be the parameter most strongly affected by beta-blockade but not by an influence on vagal tone. No differences were found between atenolol and metoprolol. CONCLUSIONS In stable postinfarct patients, chronic treatment with metoprolol and atenolol attenuates the reduction in HR variability induced by mental performance tasks, but the effects during exercise are limited. beta-Blockers do not appear to increase vagal tone in this stable patient group. The point of action in these patients is mainly a reduction in HR, probably due to a reduction in stress-induced sympathetic activation. Clinically significant differences between atenolol and metoprolol were absent, indicating that the degree of lipophilicity does not distinguish among the beta-blockers what their salutary effects are on HR variability during the specific challenges used.