The arrhythmogenic effects of flecainide in atrial fibrillation and flutter were assessed in a co... more The arrhythmogenic effects of flecainide in atrial fibrillation and flutter were assessed in a consecutive material of 100 patients without severe heart failure (NYHA class I or II). Severe arrhythmogenic events occurred in 9% (4-16%) of the patients: within the first 5 days of treatment in seven patients, and in two patients after 60 and 240 days of flecainide treatment. Patients with proarrhythmic events tended to be older and to have a longer QRS duration. Following flecainide therapy conversion to sinus rhythm was achieved in 21 of 43 patients (49%) with atrial fibrillation and in 10 of 29 (34%) with atrial flutter. It is concluded that flecainide, although an effective antiarrhythmic drug, has potential proarrhythmic effects and therefore cautious use of this drug is mandatory.
In a retrospective, consecutive case-control study, the psychosocial work environment of 52 men y... more In a retrospective, consecutive case-control study, the psychosocial work environment of 52 men younger than 55 years, who had survived an acute myocardial infarction, was analysed with respect to workload and work quality using a comprehensive self-administered questionnaire. Patients more frequently reported exhaustion after work, had less responsibility at their job, held less well esteemed positions, and had less possibility of social contact during working hours. These differences bore no simple relationship to social class or conventional risk factor distribution, although higher workloads were associated with a significantly higher frequency of smoking. The study suggests that the ideal cardioprotective job is a well esteemed job at a certain responsibility level with good conditions for social interaction during working hours, in which the experienced job demands are reasonable, and where extra resources are available if needed.
Currently, no pharmacological treatment can modify the natural history of aortic valve stenosis (... more Currently, no pharmacological treatment can modify the natural history of aortic valve stenosis (AS). This underlines the critical need to explore novel treatment strategies, which could postpone or prevent the need for aortic valve replacement in patients with asymptomatic AS. The objectives of this study were to investigate whether metoprolol reduce the hemodynamic and metabolic burden imposed by AS. In a double-blinded design, 40 patients with moderate-severe asymptomatic AS (aortic valve area, 0.5±0.1 cm(2)/m(2); peak gradient, 53±19 mm Hg) were randomized to placebo or metoprolol treatment for 22 weeks. Patients were evaluated by echocardiography, cardiovascular magnetic resonance, and (11)C-acetate positron emission tomography. Compared with placebo, metoprolol (100±53 mg/d) decreased heart rate; mean difference (95% confidence interval) -8 minute(-)(1) (-13, -3; P=0.003) and increased ejection time 26 ms (2, 50; P=0.03). Furthermore, metoprolol reduced aortic valve peak -7 mm...
Journal of the American Heart Association, Jan 6, 2017
Myocardial oxygen consumption (MVO2) and its coupling to contractile work are fundamentals of car... more Myocardial oxygen consumption (MVO2) and its coupling to contractile work are fundamentals of cardiac function and may be involved causally in the transition from compensated left ventricular hypertrophy to failure. Nevertheless, these processes have not been studied previously in patients with aortic valve stenosis (AS). Participants underwent (11)C-acetate positron emission tomography, cardiovascular magnetic resonance, and echocardiography to measure MVO2 and myocardial external efficiency (MEE) defined as the ratio of left ventricular stroke work and the energy equivalent of MVO2. We studied 10 healthy controls (group A), 37 asymptomatic AS patients with left ventricular ejection fraction ≥50% (group B), 12 symptomatic AS patients with left ventricular ejection fraction ≥50% (group C), and 9 symptomatic AS patients with left ventricular ejection fraction <50% (group D). MVO2 did not differ among groups A, B, C, and D (0.105±0.02, 0.117±0.024, 0.129±0.032, and 0.104±0.026 mL/m...
ABSTRACT The role of the type-A behavioral pattern (TABP) and psychic vulnerability (PV) as risk ... more ABSTRACT The role of the type-A behavioral pattern (TABP) and psychic vulnerability (PV) as risk factors in coronary heart disease (CHD) was investigated in 54 male acute myocardial infarction survivors less than 55 years old and 77 age-matched healthy controls. No significant difference between patients and controls was found in TABP, as assessed by Jenkins Activity Survey. The frequency of PV was surprisingly high among both patients and controls, but with no difference between groups. However, patients responded positively significantly more often to questions concerning the frequent occurrence of headaches, unexplained rapid heart beat, faintness, or spells of complete exhaustion, unhappiness, a sense of bodily deterioration, depression, anger, extreme shyness or sensitivity, or preference for loneliness. TABP and PV were present simultaneously in 13% of both patients and controls. Twenty-three per cent of patients and 46% of controls exhibited neither PV nor TABP (p&lt;0.01). It is concluded that psychic vulnerability occurs predominantly among subjects not exhibiting the type-A behavioral pattern. Absence of these two behavioral traits is associated with low risk of CHD, whereas liability to negative emotions may prove to be associated with increased coronary risk.
Untreated essential hypertension is associated with left ventricular hypertrophy (LVH) and struct... more Untreated essential hypertension is associated with left ventricular hypertrophy (LVH) and structural changes in resistance vessels. The aim of this study was to establish the effect of perindopril based antihypertensive therapy on media thickness to lumen diameter (media:lumen) ratio of peripheral resistance vessels and left ventricular mass in essential hypertension. Twenty-five patients with newly diagnosed or poorly regulated essential hypertension were treated with perindopril. Insufficient treatment response (DBP &gt; 90 mmHg) led to addition of isradipine, and hydralazine was used as a tertiary drug if necessary. Gluteal subcutaneous biopsies were taken surgically at baseline and after 9 months of successful treatment. Two small resistance arteries were isolated and mounted in a small vessel myograph, and media:lumen ratio (%) was measured under standardized conditions. Left ventricular mass was determined by echocardiography. Mean (SD) media:lumen ratio decreased from 9.8 (2.6) % to 7.8 (1.9) % (p &lt; 0.05), while left ventricular mass decreased from 299 (75) g to 199 (53) g (p &lt; 0.001). Correlation was found between changes in left ventricular mass index and media:lumen ratio (r = 0.62, p &lt; 0.01). It is concluded that a perindopril based regimen efficiently normalizes resistance artery structure and left ventricular hypertrophy in essential hypertension within one year of treatment. The impact of these findings on the excess cardiovascular morbidity and mortality in arterial hypertension remains to be investigated.
In essential hypertension, cardiovascular structure is believed to be influenced by hormonal and ... more In essential hypertension, cardiovascular structure is believed to be influenced by hormonal and by hemodynamic factors. The objective of the present study was, in essential hypertensives, to investigate the relationship between blood pressure (BP) level as well as circulating hormones on the one hand and cardiovascular structure on the other. Seventy-nine untreated essential hypertensives were examined by 24-h ambulatory BP monitoring, echocardiography, microscopy of subcutaneous resistance vessels and analyzes of plasma for angiotensin II (P-Ang II), aldosterone, atrial natriuretic factor and 24-h urinary excretion of catecholamines. Multiple regression analysis showed a statistically significant correlation between P-Ang II and the end diastolic interventricular septal diameter (IVSDd) (R = 0.32, P = .005) and a weak correlation between P-Ang II and the left ventricular posterior wall diameter (R = 0.22, P = .049). These correlations were closer in the subgroup of patients (N = 5...
ABSTRACT The role of the type-A behavioral pattern (TABP) and psychic vulnerability (PV) as risk ... more ABSTRACT The role of the type-A behavioral pattern (TABP) and psychic vulnerability (PV) as risk factors in coronary heart disease (CHD) was investigated in 54 male acute myocardial infarction survivors less than 55 years old and 77 age-matched healthy controls. No significant difference between patients and controls was found in TABP, as assessed by Jenkins Activity Survey. The frequency of PV was surprisingly high among both patients and controls, but with no difference between groups. However, patients responded positively significantly more often to questions concerning the frequent occurrence of headaches, unexplained rapid heart beat, faintness, or spells of complete exhaustion, unhappiness, a sense of bodily deterioration, depression, anger, extreme shyness or sensitivity, or preference for loneliness. TABP and PV were present simultaneously in 13% of both patients and controls. Twenty-three per cent of patients and 46% of controls exhibited neither PV nor TABP (p&lt;0.01). It is concluded that psychic vulnerability occurs predominantly among subjects not exhibiting the type-A behavioral pattern. Absence of these two behavioral traits is associated with low risk of CHD, whereas liability to negative emotions may prove to be associated with increased coronary risk.
Structural abnormality of resistance arteries is a characteristic pathophysiological phenomenon i... more Structural abnormality of resistance arteries is a characteristic pathophysiological phenomenon in essential hypertension and can be assessed in vitro as an increase in the media: lumen ratio (M: L) of isolated small arteries. We have investigated whether M: L is a risk predictor in uncomplicated essential hypertensive patients. Recently, high M: L was demonstrated as a prognostic marker in patients at high cardiovascular risk, including normotensive type 2 diabetic patients. Since diabetes is associated with pressure-independent changes in M: L, the relevance of this finding to essential hypertension has been uncertain. We conducted a follow-up survey of 159 essential hypertensive patients, who had previously been submitted to a M: L evaluation while participating in a clinical trial. They composed a homogeneous moderate-risk group, with no concomitant diseases, and represented 1661 years of follow-up. Thirty patients suffered a documented predefined cardiovascular event during follow-up. Increased relative risk (RR) was associated with M: L &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or= 0.083 (mean level of the hypertensive cohort), RR = 2.34 [95% confidence interval (CI) 1.11-4.95], and with M: L &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or= 0.098 (mean level of a normotensive control group + 2SD), RR = 2.49 (95% CI 1.21-5.11). Both results remained significant (RR = 2.19, 95% CI 1.04-4.64, and RR = 2.20, 95% CI 1.06-4.56, respectively) when adjusted for Heart Score level (10-year mortality risk-estimate, integrating age, gender, systolic blood pressure, cholesterol and smoking). Abnormal resistance artery structure independently predicts cardiovascular events in essential hypertensive patients at moderate risk.
Structural changes of small resistance arteries occur early in the disease process of essential h... more Structural changes of small resistance arteries occur early in the disease process of essential hypertension and predict cardiovascular events in previously untreated patients. We investigated whether on-treatment small artery structure also identifies patients at elevated risk despite normalization of blood pressure (BP). We conducted a long-term follow-up survey of cardiovascular events in 134 moderate-risk patients with 9-12 months of well treated essential hypertension. All participants underwent subcutaneous biopsies with determination of small artery structure in terms of media to lumen ratio (M : L) before and during treatment. After 9-12 months of treatment SBP was lowered from 164 ± 15 to 134 ± 14 mmHg (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) and M : L reduced from 0.084 ± 0.028 to 0.075 ± 0.024 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Mean follow-up hereafter was 15 years representing a total of 2035 years for the entire cohort. During this period 47 patients suffered a predefined cardiovascular event. For patients with on-treatment M : L above the mean value of the cohort (≥0.075), the hazard ratio was 2.14 [95% confidence interval (CI) 1.19-3.84, P = 0.01] and also those with M : L above mean +2SD of a normotensive population (≥0.098) had an elevated risk (hazard ratio 2.99, 95% CI 1.60-5.58, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Both results were adjusted for heart score (a 10-year mortality risk estimate integrating age, sex, smoking status, cholesterol level and SBP). Analysis of changes in M : L during treatment showed significantly higher event rates among patients with increased M : L and vice versa (hazard ratio 1.36 per 25% change, 95% CI 1.07-1.73, P = 0.013). On-treatment small artery structure identifies individuals still at increased cardiovascular risk despite long-term BP normalization and may be an additional target for therapy to prevent cardiovascular events.
Apolipoprotein E (apoE) phenotypes were determined in a random sample of 466 Danish men born in 1... more Apolipoprotein E (apoE) phenotypes were determined in a random sample of 466 Danish men born in 1948. The frequencies of the common alleles of the apoE gene were (with 95% confidence intervals) epsilon 2 = 0.085 (0.068-0.105), epsilon 3 = 0.741 (0.712-0.769), and epsilon 4 = 0.174 (0.150-0.200). These frequencies were compared to findings in 45 other study populations around the world (n greater than 100). The Danish population was found to cluster with populations from Iceland, Norway, Iceland, Scotland, the Netherlands, Germany, France (Paris), and Caucasian populations in Canada and the USA. The compiled data further show that dissimilarities in apoE allele frequencies among Caucasian populations are comparable to dissimilarities between some Caucasian and Asian populations. Notably, the frequency of epsilon 4 appears to be higher in northern regions of Europe (the Nordic countries, Scotland, Germany, and the Netherlands) than in southern regions (Switzerland, Tyrol, France [Nancy], Italy, and Spain).
The study comprised 83 patients, mean (+/-SD) age 47 +/- 8 years, with essential hypertension. Sy... more The study comprised 83 patients, mean (+/-SD) age 47 +/- 8 years, with essential hypertension. Systolic and diastolic blood pressure at inclusion were 171 +/- 16 and 110 +/- 7 mm Hg, respectively. Two small resistance arteries were dissected from a subcutaneous gluteal biopsy and mounted in an isometric small vessel myograph for measurement of the media:lumen ratio. Left ventricular mass (LVM) was estimated by echocardiography, and the occurrence of ventricular arrhythmias was assessed by ambulatory ECG for 48 h. Left ventricular hypertrophy (LVH) occurred in 67% of the patients. Systolic function was generally unimpaired. ST depression was found in 75%, and ventricular arrhythmias in 45%. Twenty-two patients had permanent ST depression, and they had also greater LVM and more frequent ventricular arrhythmias than those without permanent ST depression. The area under the ST trend curve of all significant ST depressions was correlated to the LVM (r = 0.42, p &lt; 0.001). Patients with arrhythmias had significantly greater area under the ST trend curve of all significant ST depressions than patients without arrhythmias (p &lt; 0.05). In patients with LVH and permanent ST depression, the media:lumen ratio of the peripheral vessels was greater than that of patients with LVH but without permanent ST depression (11.6 +/- 2.9 vs. 9.8 +/- 2.0, p &lt; 0.01). This suggests that hypertensive structural changes similar to those observed in peripheral vessels might occur in the walls of myocardial resistance arteries.
The aim of this study was to describe the renal function (renal hemodynamics, water and sodium ha... more The aim of this study was to describe the renal function (renal hemodynamics, water and sodium handling) and its relation to cardiovascular structural changes in a population of essential hypertensive patients before and after antihypertensive treatment. Glomerular filtration rate and renal plasma flow were measured by a constant infusion technique. The reference substances used were [131I]iodohippurate (Hippuran) and [125I]iothalamate. The lithium clearance method was used for measuring renal water and sodium handling. Microalbuminuria was measured. A subcutaneous gluteal biopsy was taken and the media thickness to lumen diameter ratio of small resistance vessels was determined. Left ventricular mass index was determined by echocardiography. Thirty-seven patients with newly diagnosed or poorly controlled essential hypertension were randomized to treatment with regimens based upon either isradipine, perindopril or hydrochlorothiazide-amiloride. Atenolol and hydralazine were added as secondary and tertiary drugs, respectively, when needed for normalization of diastolic blood pressure. Investigations were performed before and after 9 months of normalization of blood pressure. Renal function in untreated hypertensive patients was characterized by increased renal vascular resistance, decreased renal blood flow, normal glomerular filtration fraction and normal serum creatinine. No association was found between peripheral resistance vessel structure in subcutaneous vessels and renal hemodynamic parameters. Patients with severe left ventricular hypertrophy (left ventricular mass &gt;360 g) had lower glomerular filtration fraction, greater renal vascular resistance, lower renal blood flow and increased microalbuminuria in comparison with patients with less pronounced cardiac changes. After 1 year of treatment, which had a profound effect on heart and vessel structure, renal hemodynamics were unchanged in patients receiving antihypertensive treatment regimens based on the ACE inhibitor perindopril or the Ca-antagonist isradipine, whereas renal plasma flow was reduced, glomerular filtration rate preserved and filtration fraction significantly increased in those treated with a regimen based on diuretics. The serum creatinine concentration was decreased in the former group, whereas it was unchanged in the latter two. Significantly detrimental effect on uric acid homeostasis was only found in patients treated with a regimen based on diuretics.
Immunoreactive endothelin (ir-ET) was measured in peripheral venous plasma in 12 patients with re... more Immunoreactive endothelin (ir-ET) was measured in peripheral venous plasma in 12 patients with renovascular hypertension (RVH) due to unilateral renal arterial stenosis, in 12 patients with essential hypertension (EH), and in 12 control subjects (C). In the patients with RVH, ir-ET was also measured in the aorta and in both renal veins before and 1 h after 25 mg of captopril was given orally. In peripheral venous plasma, ir-ET was the same in RVH (median 1.02 pmol/l (range 0.53-1.65)) as in EH (0.96 pmol/l (0.76-1.32)) and in C (1.00 pmol/l (0.77-1.16)). In RVH, the concentrations of ir-ET decrease from the aorta to the renal vein of both the affected (0.88 pmol/l (0.54-1.28) vs 0.68 (0.51-1.24), p &amp;amp;lt; 0.01) and in the unaffected kidney (0.85 pmol/l (0.62-1.38) vs 0.78 pmol/l (0.36-1.25), p &amp;amp;lt; 0.01). Renal extraction of ir-ET was the same on the affected side (15.1% (-3.7-33.2)) and on the unaffected side (11.2% (0.5-46.4)). In the aorta, ir-ET was significantly lower than in peripheral venous plasma (p &amp;amp;lt; 0.05). The renal handling of ir-ET did not change in response to captopril in either the affected or unaffected kidney. It is concluded that circulating levels of ir-ET are normal in renovascular hypertension associated with unilateral renal artery stenosis and in essential hypertension. There is significant renal extraction of ir-ET which is unaffected by renal artery stenosis and captopril.
In a double-blind parallel-group randomized study, 28 patients with essential hypertension (World... more In a double-blind parallel-group randomized study, 28 patients with essential hypertension (World Health Organization class I/II) were allocated in equal numbers to one of two groups for treatment with either isradipine 5 to 20 mg twice daily or atenolol 50 to 100 mg once daily. At the end of the study, 12 patients were evaluable in the isradipine group and nine in the atenolol group. Assessments at baseline and after 20 weeks of treatment included arterial and venous compliance, mean peripheral perfusion pressure, heart rate, and digital vascular resistance using photoplethysmography. Isradipine had a direct relaxing effect on the arterioles, revealed by a significant increase in arterial compliance and a concomitant normalization of the digital vascular resistance. Atenolol had no significant effect on these parameters but, as expected, it lowered the heart rate, which was not affected by isradipine in the long term. The venous compliance remained low in both groups and, since isradipine--unlike atenolol--is known to have venodilating properties in vitro, its lack of effect in vivo is most likely due to reflex activation of sympathetically mediated venous tone. Because of the preference of isradipine for the arterial side of the peripheral vascular tree, the mean peripheral perfusion pressure remained higher in this group than in the atenolol group, although central systemic blood pressure was lowered equally and satisfactorily in both groups.
The arrhythmogenic effects of flecainide in atrial fibrillation and flutter were assessed in a co... more The arrhythmogenic effects of flecainide in atrial fibrillation and flutter were assessed in a consecutive material of 100 patients without severe heart failure (NYHA class I or II). Severe arrhythmogenic events occurred in 9% (4-16%) of the patients: within the first 5 days of treatment in seven patients, and in two patients after 60 and 240 days of flecainide treatment. Patients with proarrhythmic events tended to be older and to have a longer QRS duration. Following flecainide therapy conversion to sinus rhythm was achieved in 21 of 43 patients (49%) with atrial fibrillation and in 10 of 29 (34%) with atrial flutter. It is concluded that flecainide, although an effective antiarrhythmic drug, has potential proarrhythmic effects and therefore cautious use of this drug is mandatory.
In a retrospective, consecutive case-control study, the psychosocial work environment of 52 men y... more In a retrospective, consecutive case-control study, the psychosocial work environment of 52 men younger than 55 years, who had survived an acute myocardial infarction, was analysed with respect to workload and work quality using a comprehensive self-administered questionnaire. Patients more frequently reported exhaustion after work, had less responsibility at their job, held less well esteemed positions, and had less possibility of social contact during working hours. These differences bore no simple relationship to social class or conventional risk factor distribution, although higher workloads were associated with a significantly higher frequency of smoking. The study suggests that the ideal cardioprotective job is a well esteemed job at a certain responsibility level with good conditions for social interaction during working hours, in which the experienced job demands are reasonable, and where extra resources are available if needed.
Currently, no pharmacological treatment can modify the natural history of aortic valve stenosis (... more Currently, no pharmacological treatment can modify the natural history of aortic valve stenosis (AS). This underlines the critical need to explore novel treatment strategies, which could postpone or prevent the need for aortic valve replacement in patients with asymptomatic AS. The objectives of this study were to investigate whether metoprolol reduce the hemodynamic and metabolic burden imposed by AS. In a double-blinded design, 40 patients with moderate-severe asymptomatic AS (aortic valve area, 0.5±0.1 cm(2)/m(2); peak gradient, 53±19 mm Hg) were randomized to placebo or metoprolol treatment for 22 weeks. Patients were evaluated by echocardiography, cardiovascular magnetic resonance, and (11)C-acetate positron emission tomography. Compared with placebo, metoprolol (100±53 mg/d) decreased heart rate; mean difference (95% confidence interval) -8 minute(-)(1) (-13, -3; P=0.003) and increased ejection time 26 ms (2, 50; P=0.03). Furthermore, metoprolol reduced aortic valve peak -7 mm...
Journal of the American Heart Association, Jan 6, 2017
Myocardial oxygen consumption (MVO2) and its coupling to contractile work are fundamentals of car... more Myocardial oxygen consumption (MVO2) and its coupling to contractile work are fundamentals of cardiac function and may be involved causally in the transition from compensated left ventricular hypertrophy to failure. Nevertheless, these processes have not been studied previously in patients with aortic valve stenosis (AS). Participants underwent (11)C-acetate positron emission tomography, cardiovascular magnetic resonance, and echocardiography to measure MVO2 and myocardial external efficiency (MEE) defined as the ratio of left ventricular stroke work and the energy equivalent of MVO2. We studied 10 healthy controls (group A), 37 asymptomatic AS patients with left ventricular ejection fraction ≥50% (group B), 12 symptomatic AS patients with left ventricular ejection fraction ≥50% (group C), and 9 symptomatic AS patients with left ventricular ejection fraction <50% (group D). MVO2 did not differ among groups A, B, C, and D (0.105±0.02, 0.117±0.024, 0.129±0.032, and 0.104±0.026 mL/m...
ABSTRACT The role of the type-A behavioral pattern (TABP) and psychic vulnerability (PV) as risk ... more ABSTRACT The role of the type-A behavioral pattern (TABP) and psychic vulnerability (PV) as risk factors in coronary heart disease (CHD) was investigated in 54 male acute myocardial infarction survivors less than 55 years old and 77 age-matched healthy controls. No significant difference between patients and controls was found in TABP, as assessed by Jenkins Activity Survey. The frequency of PV was surprisingly high among both patients and controls, but with no difference between groups. However, patients responded positively significantly more often to questions concerning the frequent occurrence of headaches, unexplained rapid heart beat, faintness, or spells of complete exhaustion, unhappiness, a sense of bodily deterioration, depression, anger, extreme shyness or sensitivity, or preference for loneliness. TABP and PV were present simultaneously in 13% of both patients and controls. Twenty-three per cent of patients and 46% of controls exhibited neither PV nor TABP (p&lt;0.01). It is concluded that psychic vulnerability occurs predominantly among subjects not exhibiting the type-A behavioral pattern. Absence of these two behavioral traits is associated with low risk of CHD, whereas liability to negative emotions may prove to be associated with increased coronary risk.
Untreated essential hypertension is associated with left ventricular hypertrophy (LVH) and struct... more Untreated essential hypertension is associated with left ventricular hypertrophy (LVH) and structural changes in resistance vessels. The aim of this study was to establish the effect of perindopril based antihypertensive therapy on media thickness to lumen diameter (media:lumen) ratio of peripheral resistance vessels and left ventricular mass in essential hypertension. Twenty-five patients with newly diagnosed or poorly regulated essential hypertension were treated with perindopril. Insufficient treatment response (DBP &gt; 90 mmHg) led to addition of isradipine, and hydralazine was used as a tertiary drug if necessary. Gluteal subcutaneous biopsies were taken surgically at baseline and after 9 months of successful treatment. Two small resistance arteries were isolated and mounted in a small vessel myograph, and media:lumen ratio (%) was measured under standardized conditions. Left ventricular mass was determined by echocardiography. Mean (SD) media:lumen ratio decreased from 9.8 (2.6) % to 7.8 (1.9) % (p &lt; 0.05), while left ventricular mass decreased from 299 (75) g to 199 (53) g (p &lt; 0.001). Correlation was found between changes in left ventricular mass index and media:lumen ratio (r = 0.62, p &lt; 0.01). It is concluded that a perindopril based regimen efficiently normalizes resistance artery structure and left ventricular hypertrophy in essential hypertension within one year of treatment. The impact of these findings on the excess cardiovascular morbidity and mortality in arterial hypertension remains to be investigated.
In essential hypertension, cardiovascular structure is believed to be influenced by hormonal and ... more In essential hypertension, cardiovascular structure is believed to be influenced by hormonal and by hemodynamic factors. The objective of the present study was, in essential hypertensives, to investigate the relationship between blood pressure (BP) level as well as circulating hormones on the one hand and cardiovascular structure on the other. Seventy-nine untreated essential hypertensives were examined by 24-h ambulatory BP monitoring, echocardiography, microscopy of subcutaneous resistance vessels and analyzes of plasma for angiotensin II (P-Ang II), aldosterone, atrial natriuretic factor and 24-h urinary excretion of catecholamines. Multiple regression analysis showed a statistically significant correlation between P-Ang II and the end diastolic interventricular septal diameter (IVSDd) (R = 0.32, P = .005) and a weak correlation between P-Ang II and the left ventricular posterior wall diameter (R = 0.22, P = .049). These correlations were closer in the subgroup of patients (N = 5...
ABSTRACT The role of the type-A behavioral pattern (TABP) and psychic vulnerability (PV) as risk ... more ABSTRACT The role of the type-A behavioral pattern (TABP) and psychic vulnerability (PV) as risk factors in coronary heart disease (CHD) was investigated in 54 male acute myocardial infarction survivors less than 55 years old and 77 age-matched healthy controls. No significant difference between patients and controls was found in TABP, as assessed by Jenkins Activity Survey. The frequency of PV was surprisingly high among both patients and controls, but with no difference between groups. However, patients responded positively significantly more often to questions concerning the frequent occurrence of headaches, unexplained rapid heart beat, faintness, or spells of complete exhaustion, unhappiness, a sense of bodily deterioration, depression, anger, extreme shyness or sensitivity, or preference for loneliness. TABP and PV were present simultaneously in 13% of both patients and controls. Twenty-three per cent of patients and 46% of controls exhibited neither PV nor TABP (p&lt;0.01). It is concluded that psychic vulnerability occurs predominantly among subjects not exhibiting the type-A behavioral pattern. Absence of these two behavioral traits is associated with low risk of CHD, whereas liability to negative emotions may prove to be associated with increased coronary risk.
Structural abnormality of resistance arteries is a characteristic pathophysiological phenomenon i... more Structural abnormality of resistance arteries is a characteristic pathophysiological phenomenon in essential hypertension and can be assessed in vitro as an increase in the media: lumen ratio (M: L) of isolated small arteries. We have investigated whether M: L is a risk predictor in uncomplicated essential hypertensive patients. Recently, high M: L was demonstrated as a prognostic marker in patients at high cardiovascular risk, including normotensive type 2 diabetic patients. Since diabetes is associated with pressure-independent changes in M: L, the relevance of this finding to essential hypertension has been uncertain. We conducted a follow-up survey of 159 essential hypertensive patients, who had previously been submitted to a M: L evaluation while participating in a clinical trial. They composed a homogeneous moderate-risk group, with no concomitant diseases, and represented 1661 years of follow-up. Thirty patients suffered a documented predefined cardiovascular event during follow-up. Increased relative risk (RR) was associated with M: L &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or= 0.083 (mean level of the hypertensive cohort), RR = 2.34 [95% confidence interval (CI) 1.11-4.95], and with M: L &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or= 0.098 (mean level of a normotensive control group + 2SD), RR = 2.49 (95% CI 1.21-5.11). Both results remained significant (RR = 2.19, 95% CI 1.04-4.64, and RR = 2.20, 95% CI 1.06-4.56, respectively) when adjusted for Heart Score level (10-year mortality risk-estimate, integrating age, gender, systolic blood pressure, cholesterol and smoking). Abnormal resistance artery structure independently predicts cardiovascular events in essential hypertensive patients at moderate risk.
Structural changes of small resistance arteries occur early in the disease process of essential h... more Structural changes of small resistance arteries occur early in the disease process of essential hypertension and predict cardiovascular events in previously untreated patients. We investigated whether on-treatment small artery structure also identifies patients at elevated risk despite normalization of blood pressure (BP). We conducted a long-term follow-up survey of cardiovascular events in 134 moderate-risk patients with 9-12 months of well treated essential hypertension. All participants underwent subcutaneous biopsies with determination of small artery structure in terms of media to lumen ratio (M : L) before and during treatment. After 9-12 months of treatment SBP was lowered from 164 ± 15 to 134 ± 14 mmHg (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) and M : L reduced from 0.084 ± 0.028 to 0.075 ± 0.024 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Mean follow-up hereafter was 15 years representing a total of 2035 years for the entire cohort. During this period 47 patients suffered a predefined cardiovascular event. For patients with on-treatment M : L above the mean value of the cohort (≥0.075), the hazard ratio was 2.14 [95% confidence interval (CI) 1.19-3.84, P = 0.01] and also those with M : L above mean +2SD of a normotensive population (≥0.098) had an elevated risk (hazard ratio 2.99, 95% CI 1.60-5.58, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Both results were adjusted for heart score (a 10-year mortality risk estimate integrating age, sex, smoking status, cholesterol level and SBP). Analysis of changes in M : L during treatment showed significantly higher event rates among patients with increased M : L and vice versa (hazard ratio 1.36 per 25% change, 95% CI 1.07-1.73, P = 0.013). On-treatment small artery structure identifies individuals still at increased cardiovascular risk despite long-term BP normalization and may be an additional target for therapy to prevent cardiovascular events.
Apolipoprotein E (apoE) phenotypes were determined in a random sample of 466 Danish men born in 1... more Apolipoprotein E (apoE) phenotypes were determined in a random sample of 466 Danish men born in 1948. The frequencies of the common alleles of the apoE gene were (with 95% confidence intervals) epsilon 2 = 0.085 (0.068-0.105), epsilon 3 = 0.741 (0.712-0.769), and epsilon 4 = 0.174 (0.150-0.200). These frequencies were compared to findings in 45 other study populations around the world (n greater than 100). The Danish population was found to cluster with populations from Iceland, Norway, Iceland, Scotland, the Netherlands, Germany, France (Paris), and Caucasian populations in Canada and the USA. The compiled data further show that dissimilarities in apoE allele frequencies among Caucasian populations are comparable to dissimilarities between some Caucasian and Asian populations. Notably, the frequency of epsilon 4 appears to be higher in northern regions of Europe (the Nordic countries, Scotland, Germany, and the Netherlands) than in southern regions (Switzerland, Tyrol, France [Nancy], Italy, and Spain).
The study comprised 83 patients, mean (+/-SD) age 47 +/- 8 years, with essential hypertension. Sy... more The study comprised 83 patients, mean (+/-SD) age 47 +/- 8 years, with essential hypertension. Systolic and diastolic blood pressure at inclusion were 171 +/- 16 and 110 +/- 7 mm Hg, respectively. Two small resistance arteries were dissected from a subcutaneous gluteal biopsy and mounted in an isometric small vessel myograph for measurement of the media:lumen ratio. Left ventricular mass (LVM) was estimated by echocardiography, and the occurrence of ventricular arrhythmias was assessed by ambulatory ECG for 48 h. Left ventricular hypertrophy (LVH) occurred in 67% of the patients. Systolic function was generally unimpaired. ST depression was found in 75%, and ventricular arrhythmias in 45%. Twenty-two patients had permanent ST depression, and they had also greater LVM and more frequent ventricular arrhythmias than those without permanent ST depression. The area under the ST trend curve of all significant ST depressions was correlated to the LVM (r = 0.42, p &lt; 0.001). Patients with arrhythmias had significantly greater area under the ST trend curve of all significant ST depressions than patients without arrhythmias (p &lt; 0.05). In patients with LVH and permanent ST depression, the media:lumen ratio of the peripheral vessels was greater than that of patients with LVH but without permanent ST depression (11.6 +/- 2.9 vs. 9.8 +/- 2.0, p &lt; 0.01). This suggests that hypertensive structural changes similar to those observed in peripheral vessels might occur in the walls of myocardial resistance arteries.
The aim of this study was to describe the renal function (renal hemodynamics, water and sodium ha... more The aim of this study was to describe the renal function (renal hemodynamics, water and sodium handling) and its relation to cardiovascular structural changes in a population of essential hypertensive patients before and after antihypertensive treatment. Glomerular filtration rate and renal plasma flow were measured by a constant infusion technique. The reference substances used were [131I]iodohippurate (Hippuran) and [125I]iothalamate. The lithium clearance method was used for measuring renal water and sodium handling. Microalbuminuria was measured. A subcutaneous gluteal biopsy was taken and the media thickness to lumen diameter ratio of small resistance vessels was determined. Left ventricular mass index was determined by echocardiography. Thirty-seven patients with newly diagnosed or poorly controlled essential hypertension were randomized to treatment with regimens based upon either isradipine, perindopril or hydrochlorothiazide-amiloride. Atenolol and hydralazine were added as secondary and tertiary drugs, respectively, when needed for normalization of diastolic blood pressure. Investigations were performed before and after 9 months of normalization of blood pressure. Renal function in untreated hypertensive patients was characterized by increased renal vascular resistance, decreased renal blood flow, normal glomerular filtration fraction and normal serum creatinine. No association was found between peripheral resistance vessel structure in subcutaneous vessels and renal hemodynamic parameters. Patients with severe left ventricular hypertrophy (left ventricular mass &gt;360 g) had lower glomerular filtration fraction, greater renal vascular resistance, lower renal blood flow and increased microalbuminuria in comparison with patients with less pronounced cardiac changes. After 1 year of treatment, which had a profound effect on heart and vessel structure, renal hemodynamics were unchanged in patients receiving antihypertensive treatment regimens based on the ACE inhibitor perindopril or the Ca-antagonist isradipine, whereas renal plasma flow was reduced, glomerular filtration rate preserved and filtration fraction significantly increased in those treated with a regimen based on diuretics. The serum creatinine concentration was decreased in the former group, whereas it was unchanged in the latter two. Significantly detrimental effect on uric acid homeostasis was only found in patients treated with a regimen based on diuretics.
Immunoreactive endothelin (ir-ET) was measured in peripheral venous plasma in 12 patients with re... more Immunoreactive endothelin (ir-ET) was measured in peripheral venous plasma in 12 patients with renovascular hypertension (RVH) due to unilateral renal arterial stenosis, in 12 patients with essential hypertension (EH), and in 12 control subjects (C). In the patients with RVH, ir-ET was also measured in the aorta and in both renal veins before and 1 h after 25 mg of captopril was given orally. In peripheral venous plasma, ir-ET was the same in RVH (median 1.02 pmol/l (range 0.53-1.65)) as in EH (0.96 pmol/l (0.76-1.32)) and in C (1.00 pmol/l (0.77-1.16)). In RVH, the concentrations of ir-ET decrease from the aorta to the renal vein of both the affected (0.88 pmol/l (0.54-1.28) vs 0.68 (0.51-1.24), p &amp;amp;lt; 0.01) and in the unaffected kidney (0.85 pmol/l (0.62-1.38) vs 0.78 pmol/l (0.36-1.25), p &amp;amp;lt; 0.01). Renal extraction of ir-ET was the same on the affected side (15.1% (-3.7-33.2)) and on the unaffected side (11.2% (0.5-46.4)). In the aorta, ir-ET was significantly lower than in peripheral venous plasma (p &amp;amp;lt; 0.05). The renal handling of ir-ET did not change in response to captopril in either the affected or unaffected kidney. It is concluded that circulating levels of ir-ET are normal in renovascular hypertension associated with unilateral renal artery stenosis and in essential hypertension. There is significant renal extraction of ir-ET which is unaffected by renal artery stenosis and captopril.
In a double-blind parallel-group randomized study, 28 patients with essential hypertension (World... more In a double-blind parallel-group randomized study, 28 patients with essential hypertension (World Health Organization class I/II) were allocated in equal numbers to one of two groups for treatment with either isradipine 5 to 20 mg twice daily or atenolol 50 to 100 mg once daily. At the end of the study, 12 patients were evaluable in the isradipine group and nine in the atenolol group. Assessments at baseline and after 20 weeks of treatment included arterial and venous compliance, mean peripheral perfusion pressure, heart rate, and digital vascular resistance using photoplethysmography. Isradipine had a direct relaxing effect on the arterioles, revealed by a significant increase in arterial compliance and a concomitant normalization of the digital vascular resistance. Atenolol had no significant effect on these parameters but, as expected, it lowered the heart rate, which was not affected by isradipine in the long term. The venous compliance remained low in both groups and, since isradipine--unlike atenolol--is known to have venodilating properties in vitro, its lack of effect in vivo is most likely due to reflex activation of sympathetically mediated venous tone. Because of the preference of isradipine for the arterial side of the peripheral vascular tree, the mean peripheral perfusion pressure remained higher in this group than in the atenolol group, although central systemic blood pressure was lowered equally and satisfactorily in both groups.
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