Arne Westheim

Targeted Anticytokine Therapy in Patients With Chronic Heart Failure Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL)

Background—Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. Methods and Results—Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction ≤0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE (P =0.17) or RECOVER (P =0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P =0.33). Conclusions—The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.

B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study.

Background—We sought to determine the degree to which B-type natriuretic peptide (BNP) adds to clinical judgment in the diagnosis of congestive heart failure (CHF). Methods and Results—The Breathing Not Properly Multinational Study was a prospective diagnostic test evaluation study conducted in 7 centers. Of 1586 participants who presented with acute dyspnea, 1538 (97%) had clinical certainty of CHF determined by the attending physician in the emergency department. Participants underwent routine care and had BNP measured in a blinded fashion. The reference standard for CHF was adjudicated by 2 independent cardiologists, also blinded to BNP results. The final diagnosis was CHF in 722 (47%) participants. At an 80% cutoff level of certainty of CHF, clinical judgment had a sensitivity of 49% and specificity of 96%. At 100 pg/mL, BNP had a sensitivity of 90% and specificity of 73%. In determining the correct diagnosis (CHF versus no CHF), adding BNP to clinical judgment would have enhanced diagnostic accuracy from 74% to 81%. In those participants with an intermediate (21% to 79%) probability of CHF, BNP at a cutoff of 100 pg/mL correctly classified 74% of the cases. The areas under the receiver operating characteristic curve were 0.86 (95% CI 0.84 to 0.88), 0.90 (95% CI 0.88 to 0.91), and 0.93 (95% CI 0.92 to 0.94) for clinical judgment, for BNP at a cutoff of 100 pg/mL, and for the 2 in combination, respectively (P <0.0001 for all pairwise comparisons). Conclusions—The evaluation of acute dyspnea would be improved with the addition of BNP testing to clinical judgment in the emergency department.

Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction

OBJECTIVES This study examines B-type natriuretic peptide (BNP) levels in patients with systolic versus non-systolic dysfunction presenting with shortness of breath. BACKGROUND Preserved systolic function is increasingly common in patients presenting with symptoms of congestive heart failure (CHF) but is still difficult to diagnose. METHODS The Breathing Not Properly Multinational Study was a seven-center, prospective study of 1,586 patients who presented with acute dyspnea and had BNP measured upon arrival. A subset of 452 patients with a final adjudicated diagnosis of CHF who underwent echocardiography within 30 days of their visit to the emergency department (ED) were evaluated. An ejection fraction of greater than 45% was defined as non-systolic CHF. RESULTS Of the 452 patients with a final diagnosis of CHF, 165 (36.5%) had preserved left ventricular function on echocardiography, whereas 287 (63.5%) had systolic dysfunction. Patients with non-systolic heart failure (NS-CHF) had significantly lower BNP levels than those with systolic heart failure (S-CHF) (413 pg/ml vs. 821 pg/ml, p < 0.001). As the severity of heart failure worsened by New York Heart Association class, the percentage of S-CHF increased, whereas the percentage of NS-CHF decreased. When patients with NS-CHF were compared with patients without CHF (n = 770), a BNP value of 100 pg/ml had a sensitivity of 86%, a negative predictive value of 96%, and an accuracy of 75% for detecting abnormal diastolic dysfunction. Using Logistic regression to differentiate S-CHF from NS-CHF, BNP entered first as the strongest predictor followed by oxygen saturation, history of myocardial infarction, and heart rate. CONCLUSIONS We conclude that NS-CHF is common in the setting of the ED and that differentiating NS-CHF from S-CHF is difficult in this setting using traditional parameters. Whereas BNP add modest discriminatory value in differentiating NS-CHF from S-CHF, its major role is still the separation of patients with CHF from those without CHF.

Effects of Group-Based High-Intensity Aerobic Interval Training in Patients With Chronic Heart Failure

The aim of this study was to evaluate the effectiveness of a novel group-based aerobic interval training of high intensity on functional capacity and quality of life in patients with chronic heart failure (CHF) and examine the relation between changes in functional capacity and quality of life. Eighty patients with stable CHF (63 men, 17 women; mean age 70.1 +/- 7.9 [SD] years; left ventricular ejection fraction 30 +/- 8.5%) on optimal medical treatment were randomly assigned to either a 16-week group-based aerobic high-intensity interval training model twice weekly for 65 to 80 minutes/day (n = 40) or a control group (n = 40) that received standard care. Functional capacity was measured using the 6-minute walk test and cycle ergometer test. Quality of life was measured using the Minnesota Living with Heart Failure Questionnaire. After 16 weeks, functional capacity improved significantly in the exercise group compared with the control group measured using the 6-minute walk test (+58 vs -15 meters; p <0.001) and for both workload and time measured using the bicycle ergometer test (+10 vs -1 W; p < 0.001; + 57 vs -8 seconds; p <0.001). Quality of life improved significantly in the exercise group compared with the control group (p = 0.03), and a significant inverse correlation was found between quality of life and functional capacity (r = -0.49, p <0.05). In conclusion, our exercise model significantly improved functional capacity and quality of life compared with the control group in patients with CHF. Improvements in quality of life were significantly related to functional capacity.

High Prevalence of Sleep Apnea in Heart Failure Outpatients: Even in Patients With Preserved Systolic Function

BACKGROUND Sleep-disordered breathing (SDB) is common in patients with reduced ejection fraction (EF). However, little is known about the prevalence of SDB in a general heart failure population including patients with preserved EF (HFPEF). METHODS We prospectively enrolled stable heart failure outpatients from our heart failure clinic to assess the prevalence of SDB independent of systolic left ventricular function. RESULTS Among 115 patients (62% with reduced EF, 38% with preserved EF, New York Heart Association Class II-IV) SDB was present in 81% (27% central sleep apnea, 54% obstructive sleep apnea [OSA]). HFPEF patients had SDB in 80% of the cases, 62% had OSA. This group had significantly more hypertension. CONCLUSIONS This study shows a high prevalence of SDB in a general heart failure population, also in patients with HFPEF. These patients have predominantly OSA. Especially in patients with HFPEF SDB should be kept in mind and referral to a sleep specialist should be considered.

Awareness of high blood pressure increases arterial plasma catecholamines, platelet noradrenaline and adrenergic responses to mental stress

Thirty-six, 19-year-old men within the 95th percentile of mean blood pressure (110 mmHg) at a routine medical screening were randomized into two groups and requested to return for a follow-up visit in 2 weeks. One group was sent a neutral letter, while the other was sent a letter conveying the information that their blood pressures were elevated. After 15 min sitting in the laboratory, there was a significantly higher heart rate (P less than 0.05) in the informed group. Thirteen informed and 13 uninformed subjects were examined further by intra-arterial blood pressure recording and serial sampling of arterial catecholamines during cold pressor and mental stress tests. The study was undertaken examiner-blind. Informing the subjects of high blood pressure increased both baseline plasma noradrenaline (P less than 0.01) and adrenaline (P less than 0.05) and intraplatelet noradrenaline (P less than 0.05). Blood pressure (P less than 0.05) and heart rate (P less than 0.05) increased significantly more in the informed group when the subjects were told of the cold pressor test. In addition, there were exaggerated adrenaline (P less than 0.05) and diastolic blood pressure (P less than 0.05) responses to mental stress in the informed group. Thus, awareness of high blood pressure in young men may increase sympathetic tone and responses as measured in the laboratory. Conclusions from studies on early pathogenesis of essential hypertension should therefore be drawn with more caution when patients are aware of their high blood pressure.

Cardiovascular reactivity, coronary risk factors, and sympathetic activity in young men.

We have previously demonstrated that awareness of high blood pressure may increase blood pressure, plasma catecholamine levels, and stress responses. In the present study, three groups of 19-year-old men, all unaware of their blood pressure status, were selected from the first (group-1, 62 +/- 2 mm Hg, [mean +/- SEM], n = 15), 50th (group-50, 90 +/- 4 mm Hg, n = 15), and 99th (group-99, 123 +/- 5 mm Hg, n = 14) percentiles in causal mean blood pressure at a screening. They were studied (blinded examiners) with intra-arterial blood pressure recordings and multiple measurements of arterial plasma epinephrine and norepinephrine during a mental arithmetic challenge and cold pressor test. Despite high mean blood pressure at the screening, group-99 did not differ from group-50 either in intra-arterial mean blood pressure after 30 minutes of supine rest (89 +/- 3 versus 86 +/- 2 mm Hg) or in serum lipids and resting plasma epinephrine and norepinephrine. However, in group-99 resting plasma epinephrine showed a positive hyperbolic relation to resting diastolic blood pressure (r = .73, P = .004) and a negative hyperbolic relation to the ratio of high-density lipoprotein cholesterol to total cholesterol (r = -.75, P = .002). None of these correlations were present in the two other groups. Furthermore, the three groups differed in heart rate responses (P < .0005) and systolic (P < .0005) and diastolic (P < .05) blood pressure responses to mental arithmetic challenge, group-99 being hyperreactive compared with the other two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-Term Effects of a Group-Based High-Intensity Aerobic Interval-Training Program in Patients With Chronic Heart Failure

Studies on the long-term effects of exercise training programs on functional capacity and the quality of life in patients with chronic heart failure (CHF) are sparse. The aim of this study was to evaluate the long-term effects of group-based, high-intensity interval training on functional capacity and the quality of life in 80 patients with stable CHF (mean age 70.1 +/- 7.9 years) in New York Heart Association classes II to IIIB. Patients were randomized to either an exercise group (n = 40) or a control group (n = 40). The mean ejection fractions at baseline were 31 +/- 8% in the exercise group and 31 +/- 1% in the control group. The exercise group exercised twice a week for 4 months in addition to 4 consultations with a CHF nurse. Six-minute walking distance, workload and exercise time on a cycle ergometer test, and the quality of life were measured at baseline and 4 and 12 months after enrollment. After 4 months, functional capacity (6-minute walking distance +58 vs -15 m, p <0.001) and the quality of life (Minnesota Living With Heart Failure Questionnaire score +10 vs -1 point, p <0.005) improved significantly in the exercise group compared with the control group. After 12 months, the improvements were still significant in the exercise group compared with the control group for all parameters (6-minute walking distance +41 vs -20 m, p <0.001; workload +10 vs -1 W, p = 0.001; exercise time +53 vs -6 seconds, p = 0.003; quality of life +10 vs -6 points, p = 0.003). In conclusion, the results support the implementation of a group-based aerobic interval training program to improve long-term effects on functional capacity and the quality of life in patients with CHF.

Adverse Drug Reactions in Current Antihypertensive Therapy: a General Practice Survey of 2586 Patients in Norway

The objective of this study was to determine the frequency and profile of adverse reactions to antihypertensive drugs in an unselected group of drug-treated hypertensive patients. A questionnaire-based survey was carried out among 2586 drug-treated hypertensive patients who attended a general practitioner for clinical control. Adverse drug reactions reported spontaneously, upon general inquiry, upon specific questioning and as evaluated by a physician were used as the main outcome measures. The study shows that the percentage of patients who reported adverse drug reactions spontaneously, upon general inquiry and upon specific questioning were 16%, 24% and 62% respectively. Users of diuretics reported the lowest frequency of adverse reactions, whereas users of beta-blockers reported the highest frequency. In 7% of the patients, the adverse drug reactions were of such a nature that the physicians considered discontinuing the treatment. As a conclusion, the reported frequency of adverse drug reactions in antihypertensive treatment is high, but with significant differences between the various drug groups. Monotherapy is connected with far fewer adverse drug reactions than combination therapy.

Increased plasma vasopressin in low renin essential hypertension

Baseline plasma vasopressin concentrations were measured in 48 men (all 50 years old) with decreased plasma renin concentration and untreated, sustained essential hypertension and in 29 healthy normotensive men. Mean hypertensive plasma vasopressin concentration was more than twice as high as the corresponding normotensive level (15.7 +/- 2.2 [SE] vs 7.5 +/- 1.0 pg/ml; p less than 0.001). Plasma renin concentration in the hypertensive group was reduced compared with that in the normotensive group (0.28 +/- 0.04 vs 0.46 +/- 0.06 Goldblatt units X 10(-4)/ml). These differences appeared despite virtually identical serum osmolality, creatinine clearance, and urinary sodium excretion in the two groups. In the first 38 hypertensive subjects, arterial plasma epinephrine concentrations were significantly increased over those of the first 28 control subjects (99 +/- 12 vs 68 +/- 6 pg/ml; p less than 0.025). In contrast to those with low renin essential hypertension, 35 men with normal renin essential hypertension (all 40 years old) had normal plasma vasopressin levels that were not significantly different from those in a comparable normotensive control group (3.7 +/- 0.8 vs 3.5 +/- 0.4 pg/ml). Arterial epinephrine concentrations were not significantly different between normal renin subjects and the control group. After 6 weeks of treatment with the nonselective beta-adrenergic receptor blocker oxprenolol in 11 subjects with low renin hypertension, blood pressure was reduced and the plasma vasopressin concentration fell from 27.6 +/- 6.4 to 13.5 +/- 4.2 pg/ml (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)