Contrasting effects of verapamil and amlodipine on cardiovascular stress responses in hypertension.

AIMS: To compare the effects of two long-acting calcium antagonists of different types on cardiovascular stress responses in hypertension. METHODS: One-hundred and forty-five patients with mild to moderate hypertension and a mean (+/- s.e.mean) age of 51 +/- 0.9 years received for 8 weeks the phenylalkylamine verapamil sustained release (240 mg) and the dihydropyridine amlodipine (5 mg) in a double-blind cross-over design, both after 4 weeks of placebo. Blood pressure, heart rate and plasma noradrenaline were monitored during 3 min of sustained isometric handgrip and 2 min of cold pressor. RESULTS: Blood pressure was equally reduced by both drugs. After 3 min handgrip, systolic blood pressure, heart rate and rate-pressure product were lower with verapamil compared with amlodipine. Verapamil attenuated the increases in systolic blood pressure (25 +/- 2 vs 30 +/- 2 mmHg, difference 4.6, 95% CI (1.0, 8.1), P < 0.01) and rate-pressure product (3.1 +/- 0.2 vs 3.6 +/- 0.3 x 10(3) mmHg x beats min(-1), difference 0.5, 95% CI (0.1, 0.9), P < 0.01) during handgrip compared with amlodipine. Similar results were observed during cold pressor. Plasma noradrenaline levels were lower with verapamil compared with amlodipine at rest and after both tests, but the increases in plasma noradrenaline were not significantly different. CONCLUSIONS: Verapamil is more effective in reducing blood pressure and rate-pressure product responses to stress compared with amlodipine. Although plasma noradrenaline is lower with verapamil at rest and after stress, the increase during stress is not different.

[Long-term follow-up of 100 patients with acute myocardial infarction treated with angioplasty]. / Langtidsresultater etter primaer angioplastikk hos 100 pasienter med akutt hjerteinfarkt.

BACKGROUND: There is little information available on long-term follow up of patients treated with primary angioplasty for acute myocardial infarction. MATERIAL AND METHODS: 100 consecutive patients with acute ST-elevation myocardial infarction and symptoms of less than six hours' duration were treated with primary angioplasty. Clinical examination was performed in 97 patients and exercise stress test in 74 patients 11-37 months (mean 20 months) later. Patients were observed for survival up to 48 months. RESULTS: 24 patients had been rehospitalized, 16 because of chest pain. 77 patients were treated with beta blocker, 83 with statins, and 95 with antithrombotic medication. 84 patients were in NYHA (New York's Heart Association's classification's) class I at follow-up examination. Three patients died. 11 patients had a serious event, reinfarction (n = 3) or need for revascularization (n = 8) during the first 13 months. Total cumulative mortality rates after one and three years were 3% (95% CI 1-8) and 11% (95% CI 6-19). INTERPRETATION: The good initial results in primary angioplasty are maintained in long-term follow-up. This is in accordance with reports from centres abroad.

The effects of dihydropyridine and phenylalkylamine calcium antagonist classes on autonomic function in hypertension: the VAMPHYRE study.

The aim of the present study was to compare the effects of a long-acting dihydropyridine (amlodipine) and a nondihydropyridine (verapamil) on autonomic function in patients with mild to moderate hypertension. A total of 145 patients with a diastolic blood pressure (BP) between 95 and 110 mm Hg received 8 weeks of verapamil sustained release (240 mg) and amlodipine (5 mg) in a prospective randomized, double blind, cross-over study, both after 4 weeks of placebo. The 24-h autonomic balance was measured by analysis of 24-h heart rate variability and short-term autonomic control of BP by baroreflex sensitivity measurements. Plasma norepinephrine was sampled at rest. Blood pressure was equally reduced from 153/100 mm Hg to 139/91 mm Hg with verapamil and 138/91 mm Hg with amlodipine, P = .50/.59. The low- to high-frequency ratio (LF/HF), reflecting sympathovagal balance, was higher with amlodipine than with verapamil (4.66 v 4.10; P = .001). Baroreflex function was improved by both treatments; however, baroreflex sensitivity (BRS) was significantly higher with verapamil than with amlodipine (8.47 v 8.06 msec/mm Hg; P = .01). Plasma norepinephrine (NE) level was higher with amlodipine than with verapamil (1.59 v 1.32 nmol/L; P < .0001). Amlodipine induces a shift in sympathovagal balance, as measured by heart rate variability indices and plasma NE, toward sympathetic predominance compared with vagal predominance with verapamil. Short-term autonomic control of BP, as assessed by BRS, is more effectively improved by verapamil than by amlodipine. These contrasting effects on autonomic function suggest that the nondihydropyridine calcium antagonist verapamil may have additional beneficial effects beyond lowering BP compared with the dihydropyridine amlodipine.

Low molecular weight heparin prevents activation of coagulation in a hypobaric environment.

It is commonly thought that people are at increased risk of venous thrombosis during air flights, but the magnitude of the risk is unknown. Suggested risk factors are hypobaric hypoxia, stasis, and dehydration. In a previous experimental study, we found immediate activation of coagulation as determined by the levels of prothrombin fragments 1 + 2 (F(1 + 2)) and thrombin-antithrombin complex (TAT) after rapid exposure to a hypobaric and hypoxic environment (76 kPa). The aim of the present study was to examine the ability of low molecular weight heparin (LMWH) to prevent such activation. Twelve healthy male volunteers were given 40 mg enoxaparin as a single subcutaneous injection 1 h prior to exposure from 96.3 to 76 kPa. We found no activation of coagulation as judged by F(1 + 2) or TAT. Anti-activated factor X activity levels and release of tissue factor pathway inhibitor was normal. We conclude that high prophylactic doses of a LMWH most probably prevent activation of coagulation in a hypobaric environment.

Less adrenergic response to mental task during verapamil compared to amlodipine treatment in hypertensive subjects.

We compared the effects of amlodipine and verapamil slow release on autonomic responses to a 5-min mental arithmetic test (MST) in patients with mild to moderate hypertension. Twenty subjects received 8 weeks of verapamil slow release 240 mg or amlodipine 10 mg in a double-blind crossover design, both after 4 weeks' placebo. Heart rate (HR) and blood pressure (BP) were continuously monitored. Venous plasma catecholamines were analysed by a radioenzymatic assay. Baroreflex sensitivity (BRS) was estimated with the transfer function technique. Calculations of the area under the curve (AUC) were used to estimate average HR, BP and catecholamine concentrations. The reactivity to MST was estimated as percent change from the basal AUC. A paired t-test was performed. Data are means +/-SEM. Compared to verapamil, amlodipine increased average noradrenaline (NA) concentrations (245 +/- 23 vs 191 +/- 17 pg/l, respectively, p = 0.005), NA reactivity (14.0 +/- 5.5% vs -2.9 +/- 3.3, p = 0.004), average HR (65 +/- 2 vs 61 +/- 2 beats/min, p < 0.001) and HR reactivity (2.5 +/- 1.0 vs 0.1 +/- 0.9%, p = 0.056). BP did not differ significantly. BRS correlated with average and baseline HR on both medications (r = -0.53 and -0.63, p < or = 0.03). We conclude that adrenergic responses to MST are blunted on treatment with verapamil compared to amlodipine in hypertensive patients.

Autonomic function in hypertensive and normotensive subjects: the importance of gender.

Baroreceptor reflex sensitivity (BRS) has been found lower and heart rate variability (HRV) parasympathetic markers have been found higher in healthy women than in healthy men. Thus, in the present study we hypothesized gender differences in the autonomic function among hypertensive subjects. Forty-one hypertensive patients and 34 normotensive subjects, age 53+/-1 years, were examined. Four weeks after cessation of antihypertensive therapy, HRV was assessed in 24-hour Holter ECGs, and BRS was calculated with the transfer technique. A t test was performed after log transformation of spectral values. Resting blood pressure and heart rate in the hypertensive and the normotensive groups were 150+/-2/100+/-1 (mean+/-SEM) and 121+/-2/81+/-1 mm Hg, respectively, and 68+/-1 and 60+/-1 bpm, respectively (P<0.0005). Compared with normotensive controls, hypertensive patients had lower total power (1224+/-116 versus 1797+/-241 ms(2); P=0.03), lower low frequency power (550+/-57 versus 813+/-115 ms(2); P=0.04), lower high frequency power (141+/-23 versus 215+/-38 ms(2); P=0.06), lower root mean square successive difference (28.7+/-2.7 versus 35.7+/-3.0 ms; P=0.03), and PNN50 (4.9+/-0.6% versus 9.8+/-1.5%; P=0.003). BRS was also lower in the hypertensive subjects (7.6+/-0.6 versus 10.4+/-0.8 ms/mm Hg; P=0.005). When comparing the same parameters between normotensive subjects and hypertensive subjects within the same gender group, we found significant reduction (P<0.05) only within the female group. The difference in BRS within the female group was twice that within the male group. Stepwise multiple regression analysis revealed gender, age, HDL cholesterol, and blood pressure as independent explanatory variables of BRS and HRV. Our results suggest that gender is an important determinant of BRS and HRV. Autonomic function parameters were especially impaired in hypertensive women compared with hypertensive men.

Reduced autonomic activity during stepwise exposure to high altitude.

Several studies have shown increased sympathetic activity during acute exposure to hypobaric hypoxia. In a recent field study we found reduced plasma catecholamines during the first days after a stepwise ascent to high altitude. In the present study 14 subjects were exposed to a simulated ascent in a hypobaric chamber to test the hypothesis of a temporary reduction in autonomic activity. The altitude was increased stepwise to 4500 m over 3 days. Heart rate variability (HRV) was assessed continuously in seven subjects. Baroreceptor reflex sensitivity (BRS) was determined in eight subjects with the 'Transfer Function' method at baseline, at 4500 m and after returning to baseline. Resting plasma catecholamines and cardiovascular- and plasma catecholamine- responses to cold pressor- (CPT) and mental stress-test (MST) were assessed daily in all and 12 subjects, respectively. Data are mean +/- SEM. Compared with baseline at 4500 m there were lower total power (TP) (35 457 +/- 26 302 vs. 15 001 +/- 11 176 ms2), low frequency (LF) power (3112 +/- 809 vs. 1741 +/- 604 ms2), high frequency (HF) power (1466 +/- 520 vs. 459 +/- 189 ms2) and HF normalized units (46 +/- 0.007 vs. 44 +/- 0.006%), P < or = 0.001. Baroreceptor reflex sensitivity decreased (15.6 +/- 2.1 vs. 9.5 +/- 2.6 ms mmHg(-1), P = 0.015). Resting noradrenaline (NA) decreased (522 +/- 98 vs. 357 +/- 60 pmol L(-1), P = 0.027). The increase in systolic blood pressure (SBP) and NA during mental stress was less pronounced (21 +/- 4 vs. 10 +/- 2% and 25 +/- 9 vs. -2 +/- 8%, respectively, P < 0.05). The increase in SBP during cold pressor test decreased (16 +/- 3 vs. 1 +/- 6%, P = 0.03). Diastolic blood pressure, HR and adrenaline displayed similar tendencies. We conclude that a transient reduction in parasympathetic and sympathetic activity was demonstrated during stepwise exposure to high altitude.

[Measurements of heart rate variability and baroreflex sensitivity]. / Undersøkelser av hjertefrekvensvariabilitet og baroreflekssensitivitet.

BACKGROUND: Heart rate variability and baroreflex sensitivity are used to assess the activity in the autonomic nervous system. Heart rate variability is a measure of the tonic autonomic heart rate control, whereas baroreflex sensitivity measures the dynamic autonomic heart rate control. MATERIAL AND METHODS: On the basis of relevant literature and our own research, this article reviews the most commonly used techniques for measuring heart rate variability and baroreflex sensitivity, as well as results from selected studies. RESULTS: Reduced heart rate variability and reduced baroreflex sensitivity may be related to increased risk for malignant ventricular arrhythmias and sudden death in patients with coronary artery disease. These parameters are also distorted in patients with hypertension. Furthermore, heart rate variability has been suggested as a tool for monitoring anaesthesia depth. INTERPRETATION: Even though these methods are useful in pathophysiological studies of the autonomic nervous system, results from clinical studies have been diverging. Further investigation is required before these methods may be incorporated in clinical practice.

Association between acute hypobaric hypoxia and activation of coagulation in human beings.

The risk of venous thrombosis is thought to be increased by flying. In a study of 20 healthy male volunteers who were suddenly exposed to a hypobaric environment similar to that encountered within aeroplane cabins, markers of activated coagulation transiently Increased by two-fold to eight-fold. We suggest that hypobaric hypoxia, with sedentariness and dehydration, may cause this increased risk of venous thrombosis.

Blood pressure and heart rate responses to cold pressor test in patients admitted to hospital due to chest pain.

Cardiovascular hyperreactivity to stress may be a risk factor for future cardiovascular events. In this study we hypothesized increased cardiovascular responses to a cold pressor test (CPT) in coronary patients admitted to hospital due to chest pain compared with patients admitted with chest pain with suspected, but not later confirmed, coronary artery disease (CAD). A total of 20 patients were included in the study. All were admitted due to chest pain. None of the patients suffered from myocardial infarction. In 10 patients (CAD+) CAD was confirmed by positive exercise ECG or coronary angiography. In the other 10 patients (CAD-) all tests were negative. The two groups did not differ significantly in resting blood pressure, body mass index (BMI), age, gender or smoking status. A 1 min CPT was performed after 15 min supine rest. Blood pressure (BP) and heart rate (HR) responses were registered. There were significantly larger heart rate (p < 0.001) and systolic blood pressure (p < 0.01) responses to a cold pressure test in patients with chest pain and coronary heart disease than in patients with chest pain only. Percentage increases in HR and systolic BP also differed significantly. Cardiovascular responses to a cold pressor test were significantly larger in CAD patients admitted to hospital due to chest pain than in patients admitted with chest pain and suspected, but not later confirmed, CAD.