Ole Lederballe

Small artery structure is an independent predictor of cardiovascular events in essential hypertension.

Objective 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. Methods 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. Results Thirty patients suffered a documented predefined cardiovascular event during follow-up. Increased relative risk (RR) was associated with M: L ≥ 0.083 (mean level of the hypertensive cohort), RR = 2.34 [95% confidence interval (CI) 1.11–4.95], and with M: L ≥ 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). Conclusion Abnormal resistance artery structure independently predicts cardiovascular events in essential hypertensive patients at moderate risk.

Normalization of Structural Cardiovascular Changes During Antihypertensive Treatment with a Regimen Based on the ACE-inhibitor Perindopril

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 > 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 < 0.05), while left ventricular mass decreased from 299 (75) g to 199 (53) g (p < 0.001). Correlation was found between changes in left ventricular mass index and media:lumen ratio (r = 0.62, p < 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.

The relation between peripheral vascular structure, left ventricular hypertrophy, and ambulatory blood pressure in essential hypertension

The relations between left ventricular mass (LVM), peripheral resistance artery structure, and ambulatory BP were studied in 83 patients with previously untreated or poorly regulated essential hypertension and 20 healthy controls of similar age and sex. LVM was assessed by echocardiography. Signs of left ventricular hypertrophy (LVH) were present in 67 (81%) of the patients and in none of the controls. Peripheral resistance arteries were isolated from surgical gluteal skin biopsies and mounted in a Mulvany-Halpern isometric small vessel myograph, and their media:lumen ratio, media thickness, and media cross-sectional area were determined under standardized conditions. Mean (+/- SD) ambulatory BP was 122 +/- 9 mm Hg among patients and 96 +/- 8 mm Hg among controls (P < .001). LVM was 327 +/- 99 g among patients and 197 +/- 37 g among controls (P < .001). Media thickness of resistance arteries was 21.0 +/- 4.2 microns among hypertensives and 16.2 +/- 2.6 microns among controls (P < .001). The media:lumen ratio of arteries from patients was 10.2 +/- 2.6% v 7.9 +/- 2.0% in arteries of similar internal diameter from controls (P < .01). Both LVM index (LVMI) and media/lumen ratio correlated significantly with BP. There was significant correlation between media:lumen ratio and LVMI among hypertensive patients (r = 0.45, P < .001), but if patients were subdivided according to the presence of LVH this correlation was found only among patients with LVH (r = 0.60 P< .001) and not among patient without LVH nor controls. Multiple regression analyses of age, body surface area, media/lumen ratio, and BP on LVM or LVMI revealed independent contributions of media/lumen ratio and BP. Age had no influence in the models. Similar results were obtained when casual BP was replaced with ambulatory BP in these analyses. No correlation was found between LVMI and media cross-sectional area. A minor subset of patients with complete absence of nocturnal BP drop had particularly great LVM and media:lumen ratio. The study suggests that cardiac and arteriolar tissue undergo parallel structural remodeling in essential hypertension.

Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial

Background: Renal denervation (RDN), treating resistant hypertension, has, in open trial design, been shown to lower blood pressure (BP) dramatically, but this was primarily with respect to office BP. Method: We conducted a SHAM-controlled, double-blind, randomized, single-center trial to establish efficacy data based on 24-h ambulatory BP measurements (ABPM). Inclusion criteria were daytime systolic ABPM at least 145 mmHg following 1 month of stable medication and 2 weeks of compliance registration. All RDN procedures were carried out by an experienced operator using the unipolar Medtronic Flex catheter (Medtronic, Santa Rosa, California, USA). Results: We randomized 69 patients with treatment-resistant hypertension to RDN (n = 36) or SHAM (n = 33). Groups were well balanced at baseline. Mean baseline daytime systolic ABPM was 159 ± 12 mmHg (RDN) and 159 ± 14 mmHg (SHAM). Groups had similar reductions in daytime systolic ABPM compared with baseline at 3 months [−6.2 ± 18.8 mmHg (RDN) vs. −6.0 ± 13.5 mmHg (SHAM)] and at 6 months [−6.1 ± 18.9 mmHg (RDN) vs. −4.3 ± 15.1 mmHg (SHAM)]. Mean usage of antihypertensive medication (daily defined doses) at 3 months was equal [6.8 ± 2.7 (RDN) vs. 7.0 ± 2.5 (SHAM)]. RDN performed at a single center and by a high-volume operator reduced ABPM to the same level as SHAM treatment and thus confirms the result of the HTN3 trial. Conclusion: Further, clinical use of RDN for treatment of resistant hypertension should await positive results from double-blinded, SHAM-controlled trials with multipolar ablation catheters or novel denervation techniques.

Effect of antihypertensive treatment on cardiac and subcutaneous artery structure: a comparison between calcium channel blocker and thiazide-based regimens.

The effects of two antihypertensive regimens (isradipine and hydrochlorothiazide-amiloride) on the ratio between media thickness and lumen diameter of subcutaneous arteries and on left ventricular mass in essential hypertension were compared. Fifty patients, aged 46.3+/-8 (mean+/-SD) years, with newly diagnosed or poorly controlled essential hypertension were randomized to treatment with either isradipine or hydrochlorothiazide-amiloride. Atenolol and hydralazine were added in both groups as secondary and tertiary drugs, respectively, when needed for normalization of diastolic blood pressure. A subcutaneous gluteal biopsy was taken surgically before medication and again after 9 months of successful antihypertensive treatment. Two small resistance arteries were isolated from each biopsy and mounted in a Mulvany-Halpem isometric small vessel myograph. The media thickness-to-lumen diameter ratio (percentage) of the vessels was measured under standardized conditions and meaned. Left ventricular mass (LVM) index was determined by echocardiography according to the Penn convention. Ten patients were treated with isradipine as monotherapy, whereas only one patient was well controlled on diuretics as monotherapy. Mean blood pressure was reduced equally with the two regimens, from 131+/-9 mm Hg to 101+/-10 mm Hg with the isradipine and from 128+/-9 mm Hg to 99+/-7 mm Hg with the thiazide/atenolol regimen. LVM decreased significantly in both groups by 130+/-75 g with the isradipine-based regimen and by 70+/-53 g with the hydrochlorothiazide/atenolol-based regimen. The reduction of LVM was significantly greater on the isradipine-based regimen than on the thiazide-based regimen (P < .01). There was a significant reduction of media thickness-to-lumen diameter ratio during treatment with the isradipine-based regimen from 10.9% to 8.8% (P < .01). The reduction in the thiazide regimen was from 9.7% to 8.5%, which was not significant (P = .07). The study demonstrated significant reduction of hypertensive changes in peripheral resistance artery structure during antihypertensive treatment with an isradipine-based regimen. The thiazide/betablocker-based regimen did not have a significant effect on the vessels. Significant reduction of LVM was achieved with both isradipine-based and thiazide/atenolol-based regimens. The reduction of LVM obtained with the isradipine-based regimen was significantly greater than that of the thiazide/atenolol-based regimen.

Influence of Humoral and Neurohormonal Factors on Cardiovascular Hypertrophy in Intreated Essential Hypertensives

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 = 54) who had never received antihypertensive treatment (R = 0.42/0.32, respectively). A weak, though statistically significant, correlation was found between the catecholamine excretion and systolic BP (R = 0.26, P = .03). A statistically negative correlation existed between catecholamines and end-diastolic left ventricular internal diameter index (R = -0.36, P = .001). No significant relationship was found between hormonal levels and the tunica media structure of the resistance arteries. In conclusion, P-Ang II was in this study significantly correlated to IVSDd, but not to resistance artery structure. In essential hypertension a complex relationship exists between humoral and hemodynamic factors and cardiovascular remodeling.

Regression of media-to-lumen ratio of human subcutaneous arteries and left ventricular hypertrophy during treatment with an angiotensin-converting enzyme inhibitor-based regimen in hypertensive patients

A total of 25 patients with newly diagnosed or poorly controlled essential hypertension were randomly selected from a larger group referred to hospital. Treatment was initiated with perindopril (4-8 mg orally). If normotension was not achieved, isradipine (5-10 mg orally) was added and, if necessary, hydralazine was added. Before treatment and at the end of a 9-month period of normotension (diastolic blood pressure < or = 90 mm Hg), 24-hour blood pressure and echocardiographic measurements were performed and resistance artery structure was determined. A total of 20 age- and sex-matched normotensives were used as controls. During antihypertensive treatment, mean blood pressure was reduced from 128 +/- 11 to 103 +/- 6 mm Hg. Left ventricular mass was reduced from 300 +/- 76 to 198 +/- 54 g. The media:lumen ratio of the resistance arteries decreased from 9.8 +/- 2.6% to 7.8 +/- 1.9%; control subjects exhibited a media:lumen ratio of the same magnitude (7.9 +/- 2.0%). Results indicate that a perindopril-based regimen is extremely efficient in normalizing resistance artery and cardiac ventricular structures within one year of treatment. The impact of these findings on the excess cardiovascular morbidity and mortality in arterial hypertension still remains to be demonstrated.

Long-term renal and cardiovascular effects of antihypertensive treatment regimens based upon isradipine, perindopril and thiazide

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 >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.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 >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.

Myocardial ischemia and ventricular arrhythmias in relation to left ventricular mass and resistance artery structure

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 < 0.001). Patients with arrhythmias had significantly greater area under the ST trend curve of all significant ST depressions than patients without arrhythmias (p < 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 < 0.01). This suggests that hypertensive structural changes similar to those observed in peripheral vessels might occur in the walls of myocardial resistance arteries.