Secondary capillary rarefaction in pregnancy: can it ...
Effects of Candesartan versus Amlodipine on Capillary Rarefaction, pulse wave velocity, and central blood pressure in patients with Essential Hypertension1Rajendra P Raghuraman, MSc, 2Christine Carney, RGN, 2Helen Mullahy, RGN, 2Oluwabusola Ogunseitan, RGN, 3Duolao Wang, PhD, 1,2Tarek F Antonios, MD FESC FRCP 1 Vascular Biology Research Centre, Molecular & Clinical Sciences Research Institute, St. George’s, University of London, 2 Blood Pressure Unit, St George’s University Hospitals NHS Foundation Trust, London, and 3 Biostatistics Unit, Department of Clinical Sciences, Liverpool School of Tropical Medicine, United KingdomRunning Title: ARB Effects on microcirculation (CAMIRA study)Funding: Takeda UK Correspondence: Dr Tarek F AntoniosVascular Biology Research Centre, Molecular & Clinical Sciences Research Institute, St. George’s, University of London, London SW17 0RE, UKEmail: t.antonios@sgul.ac.uk Tel: +44 208 725 5627 Fax: +44 208 725 2722Trial registration: (EudraCT: 2008-005432-32, ISRCTN 62554526)?Abstract:BACKGROUND: A reduction in the density of capillaries (rarefaction) is known to occur in many tissues in patients with essential hypertension and play a role in increasing blood pressure (BP). The aim of this trial was to assess in a randomized, double blind, design the effects of treatment of hypertension with candesartan versus amlodipine on microvascular rarefaction and other indices of vascular function. Methods: We recruited twenty-two individuals with mild-to-moderate hypertension. After a 2-week placebo run-in period, patients who remained hypertensive (≥ 140/90 mmHg) were randomized to 8-weeks treatment with candesartan tablets 8mg daily (with forced titration to 16mg) or amlodipine tablets 5mg daily (with forced titration to 10mg). The capillary microcirculation was studied using CapiScope system CAM1. Pulse wave velocity, central BP and aortic Augmentation Index were also measured. Results: We observed significant reductions in brachial BP, and central BP after 4 and 8 weeks treatment with either candesartan or amlodipine but there was no significant effect on basal (functional) or maximal (structural) capillary densities, or pulse wave velocity. Conclusions: Eight weeks treatment of hypertension with either amlodipine or candesartan significantly reduced brachial and central BP but was not sufficient to induce a regression in functional or structural microvascular abnormalities. Keywords: Capillary density, capillary rarefaction, microcirculation, hypertension, candesartan, amlodipineTrial registration: (EudraCT: 2008-005432-32, ISRCTN 62554526)?List of AbbreviationsAI = Aortic Augmentation IndexARB = Angiotensin receptor blocker ACEi = Angiotensin converting enzyme inhibitorBCD = Basal capillary densityBP = Blood pressureCCB = Calcium channel blocker CI = Confidence intervalscSBP = Central Aortic PressureECG= ElectrocardiogramMCD = Maximal capillary densityPWV = Pulse Wave Velocity SHR = Spontaneously hypertensive ratsSE = Standard error Introduction:Increasing evidence suggests a crucial role for the microcirculation in the causation of hypertension and cardiovascular disease. ADDIN EN.CITE <EndNote><Cite><Author>Gavin</Author><Year>1998</Year><RecNum>15355</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>15355</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1440515407">15355</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gavin, J. B.</author><author>Maxwell, L.</author><author>Edgar, S. G.</author></authors></contributors><auth-address>Department of Pathology, University of Auckland, New Zealand.</auth-address><titles><title>Microvascular involvement in cardiac pathology</title><secondary-title>J Mol Cell Cardiol</secondary-title></titles><periodical><full-title>J Mol Cell Cardiol</full-title></periodical><pages>2531-40</pages><volume>30</volume><number>12</number><keywords><keyword>Cardiomyopathies/pathology</keyword><keyword>Heart Defects, Congenital/pathology</keyword><keyword>Heart Diseases/etiology/*pathology</keyword><keyword>Heart Failure/pathology</keyword><keyword>Humans</keyword><keyword>Hypertension, Renovascular/pathology</keyword><keyword>Hypertrophy/pathology</keyword><keyword>Microcirculation/*pathology</keyword><keyword>Myocardial Ischemia/pathology</keyword><keyword>Myocarditis/pathology</keyword></keywords><dates><year>1998</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0022-2828 (Print)
0022-2828 (Linking)</isbn><accession-num>9990524</accession-num><urls><related-urls><url> Impaired tissue perfusion secondary to microcirculatory abnormalities is also implicated in the pathogenesis of obesity, diabetes mellitus, and insulin resistance. ADDIN EN.CITE <EndNote><Cite><Author>Levy</Author><Year>2008</Year><RecNum>12053</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>12053</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">12053</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Levy, B. I.</author><author>Schiffrin, E. L.</author><author>Mourad, J. J.</author><author>Agostini, D.</author><author>Vicaut, E.</author><author>Safar, M. E.</author><author>Struijker-Boudier, H. A.</author></authors></contributors><auth-address>Centre de Recherche Cardiovasculaire de Lariboisiere, INSERM U689, Service d'Explorations Fonctionnelles, Hopital Lariboisiere, Paris, France. levy@larib.inserm.fr</auth-address><titles><title>Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title></periodical><pages>968-976</pages><volume>118</volume><number>9</number><keywords><keyword>Diabetic Angiopathies/epidemiology/*physiopathology/therapy</keyword><keyword>Humans</keyword><keyword>Hypertension/epidemiology/*physiopathology/therapy</keyword><keyword>Microcirculation/pathology/*physiology</keyword><keyword>Obesity/epidemiology/*physiopathology/therapy</keyword><keyword>Risk Factors</keyword><keyword>Vascular Resistance/physiology</keyword></keywords><dates><year>2008</year><pub-dates><date>Aug 26</date></pub-dates></dates><accession-num>18725503</accession-num><urls><related-urls><url> A reduction in the density (rarefaction) of capillaries and arterioles is a consistent finding among the many functional and structural microcirculatory abnormalities that occur in human hypertension. ADDIN EN.CITE <EndNote><Cite><Author>Struijker Boudier</Author><Year>1992</Year><RecNum>9078</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>9078</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954400">9078</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Struijker Boudier, H. A.</author><author>le Noble, J. L.</author><author>Messing, M. W.</author><author>Huijberts, M. S.</author><author>le Noble, F. A.</author><author>van Essen, H.</author></authors></contributors><titles><title>The microcirculation and hypertension</title><secondary-title>J Hypertens Suppl</secondary-title></titles><periodical><full-title>J Hypertens Suppl</full-title></periodical><pages>S147-S156</pages><volume>10</volume><number>7</number><keywords><keyword>Animal</keyword><keyword>Arterioles/pathology/physiology</keyword><keyword>Human</keyword><keyword>Hypertension/*physiopathology</keyword><keyword>Hypertrophy</keyword><keyword>Microcirculation/*physiopathology</keyword><keyword>Vascular Resistance/physiology</keyword></keywords><dates><year>1992</year></dates><label>93180035</label><urls></urls></record></Cite></EndNote>3 We have previously shown that much of the capillary rarefaction in hypertension is due to the structural (i.e. anatomic) absence of capillaries. ADDIN EN.CITE <EndNote><Cite><Author>Antonios</Author><Year>1999</Year><RecNum>10278</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>10278</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954400">10278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Antonios, T. F. T.</author><author>Singer, D. R.</author><author>Markandu, N. D.</author><author>Mortimer, P. S.</author><author>MacGregor, G. A.</author></authors></contributors><titles><title>Structural skin capillary rarefaction in essential hypertension</title><secondary-title>Hypertension</secondary-title></titles><periodical><full-title>Hypertension</full-title></periodical><pages>998-1001</pages><volume>33</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Capillaries/pathology</keyword><keyword>Female</keyword><keyword>Human</keyword><keyword>Hypertension/etiology/*pathology/physiopathology</keyword><keyword>Male</keyword><keyword>Middle Age</keyword><keyword>Neovascularization, Physiologic</keyword><keyword>Skin/*blood supply</keyword><keyword>Vascular Resistance</keyword></keywords><dates><year>1999</year></dates><label>99221718</label><urls><related-urls><url> We have also shown significant capillary rarefaction in patients with borderline intermittent hypertension ADDIN EN.CITE <EndNote><Cite><Author>Antonios</Author><Year>1999</Year><RecNum>10863</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>10863</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954400">10863</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Antonios, T. F. T.</author><author>Singer, D. R.</author><author>Markandu, N. D.</author><author>Mortimer, P. S.</author><author>MacGregor, G. A.</author></authors></contributors><titles><title>Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality</title><secondary-title>Hypertension</secondary-title></titles><periodical><full-title>Hypertension</full-title></periodical><pages>655-658</pages><volume>34</volume><number>4 Pt 1</number><dates><year>1999</year></dates><label>99452826</label><urls><related-urls><url> as well as in normotensive offspring of hypertensive parents suggesting that capillary rarefaction may be a primary abnormality that precedes the onset of hypertension.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbnRvbmlvczwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+
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ADDIN EN.CITE.DATA 8, 9 Therefore the improvement of microvascular abnormalities represents pertinent therapeutic targets.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBDaXVjZWlzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBDaXVjZWlzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh
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ADDIN EN.CITE.DATA 10 However, few observational and open label studies have shown non-consistent results about the reversal of microvascular rarefaction with antihypertensive treatments.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbnRvbmlvczwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+
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ADDIN EN.CITE.DATA 10-13 The aim of the CAMIRA trial was to assess in a randomized, double blind, placebo controlled two-arm parallel group clinical trial the effects of treatment of hypertension with the angiotensin receptor blocker (ARB) candesartan versus the dihydropyridine calcium channel blocker (CCB) amlodipine on microvascular rarefaction and other indices of vascular function in individuals with mild-to-moderate essential hypertension.Methodology: Participants: The CAMIRA trial (EudraCT number: 2008-005432-32, ISRCTN 62554526)?was a single center, randomized, double blind, placebo-controlled, parallel-group study performed at St. George’s Healthcare NHS Trust hospital (London, UK). The London-Surrey Borders Research Ethics Committee approved the study (number 08/H0806/72). Written informed consent was obtained from all participants. We recruited Caucasian individuals with mild-to-moderate uncomplicated essential hypertension (sitting systolic BP ≥140–<180 mmHg and/or sitting diastolic BP ≥ 90 - <110 mmHg) who have never been previously treated for their high BP or have been off their antihypertensive medications for at least 8 weeks. Patients were excluded from the study if they had diabetes mellitus (fasting plasma glucose ≥7.0mmol/L, random plasma glucose ≥11.1mmol/L or HbA1c >6.5%) secondary hypertension (excluded hyperaldosteronism, renal artery stenosis, pheochromocytoma by measuring plasma renin, plasma aldosterone, 24 hour urinary metanephrines, magnetic resonance imaging of renal arteries), chronic kidney or liver disease (normal renal & liver function tests), ischemic heart disease (normal ECG), heart failure (normal echocardiogram), skin diseases, or cold hands (measuring skin temperature). After a 2-weeks single-blind placebo run-in period, patients who remained hypertensive (systolic BP 140–180 mmHg and/or diastolic BP 90 -110 mmHg) were randomized to 8-weeks treatment with either candesartan 8mg orally once daily (with forced titration to 16mg once daily after 2 weeks) or amlodipine 5mg orally once daily (with forced titration to 10mg once daily after 2 weeks). Total study duration was 10 weeks. Blood pressure measurement: At each visit, subjects were seated with their backs supported for at least 10 minutes in a temperature-controlled room. All measurements were taken throughout the study from the same arm. Three sitting and 2 standing BP measurements were obtained at 2-minute intervals using appropriate cuff size using the Omron HEM705CP (Hutchings Health Care Ltd., Sussex, UK). Intravital capillary microscopy studies (Capillaroscopy):Previously validated methods PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbnRvbmlvczwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA 4-6, 14 were used to assess capillary density in the skin of the dorsum of the fingers. The studies were performed in a temperature-controlled laboratory (21°-24° C) after the study subjects had at least 20-minute rest for acclimatization. Subjects were seated with the left arm and hand supported at heart level. Microscopic images were obtained using the CapiScope system CAM1 and the number of capillaries was counted on-line using computer software (KK Technology, Exeter, UK). Basal capillary density (BCD) represents the number of capillaries that are “open” or “functioning” at the time of measurement, and was calculated as the mean of 4 microscopic fields.Maximization of capillaries: A miniature BP cuff was wrapped around the base of the finger and was then inflated to 60mmHg and further images were recorded using one of the above four fields chosen at random. Venous congestion was maintained for 2 minutes. ADDIN EN.CITE <EndNote><Cite><Author>Antonios</Author><Year>1999</Year><RecNum>10864</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>10864</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954400">10864</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Antonios, T. F. T.</author><author>Rattray, F. E.</author><author>Singer, D. R.</author><author>Markandu, N. D.</author><author>Mortimer, P. S.</author><author>MacGregor, G. A.</author></authors></contributors><titles><title>Maximization of skin capillaries during intravital video-microscopy in essential hypertension: comparison between venous congestion, reactive hyperaemia and core heat load tests</title><secondary-title>Clin Sci</secondary-title></titles><periodical><full-title>Clinical Science</full-title><abbr-1>Clin Sci</abbr-1></periodical><pages>523-528</pages><volume>97</volume><number>4</number><dates><year>1999</year></dates><label>0</label><urls><related-urls><url> Skin and room temperatures were monitored at each visit. Capillaroscopy measurements were performed at the end of the placebo-run in visit, after 4-weeks and 8-weeks of active drug treatment. Carotid-Femoral Pulse Wave Velocity (PWV) measurements: PWV was measured non-invasively using the COMPLIOR device as previously described.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc21hcjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 15 Two different pressure wave signals were recorded simultaneously using pressure sensitive transducers placed on the skin at two sites, the right common carotid artery and the right femoral artery. All calculations over 10 – 12 cardiac cycles were automated. Aortic Augmentation Index (AI) & Central Aortic Pressure (cSBP):AI and cSBP were measured using the Omron HEM-9000AI device (Omron Healthcare, Kyoto, Japan) ADDIN EN.CITE <EndNote><Cite><Author>Kips</Author><Year>2011</Year><RecNum>15345</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>15345</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1439371150">15345</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kips, J. G.</author><author>Schutte, A. E.</author><author>Vermeersch, S. J.</author><author>Huisman, H. W.</author><author>Van Rooyen, J. M.</author><author>Glyn, M. C.</author><author>Fourie, C. M.</author><author>Malan, L.</author><author>Schutte, R.</author><author>Van Bortel, L. M.</author><author>Segers, P.</author></authors></contributors><auth-address>Heymans Institute of Pharmacology, Belgium. Jan.Kips@UGent.be</auth-address><titles><title>Comparison of central pressure estimates obtained from SphygmoCor, Omron HEM-9000AI and carotid applanation tonometry</title><secondary-title>J Hypertens</secondary-title></titles><periodical><full-title>Journal of Hypertension</full-title><abbr-1>J Hypertens</abbr-1></periodical><pages>1115-20</pages><volume>29</volume><number>6</number><keywords><keyword>Adult</keyword><keyword>African Continental Ancestry Group</keyword><keyword>Aged</keyword><keyword>*Blood Pressure</keyword><keyword>Carotid Arteries/*physiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Manometry/*methods</keyword><keyword>Middle Aged</keyword><keyword>*Sphygmomanometers</keyword></keywords><dates><year>2011</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1473-5598 (Electronic)
0263-6352 (Linking)</isbn><accession-num>21505351</accession-num><urls><related-urls><url>. Radial artery tonometry was performed on the left arm of each participant, and BP was measured. All vascular measurements were performed by a single experienced operator (R.R.) in a quiet temperature-controlled laboratory. Laboratory Tests:Blood and urine samples were obtained at entry to the study, end of placebo run-in period, and after 4 weeks and 8 weeks of active drug treatment. Variables measured were serum electrolytes, urea, creatinine, uric acid, glucose, total cholesterol, triglycerides and full blood count. 24hour urinary excretion of sodium, potassium and creatinine were measured as well. Statistical analysis: The primary outcome variable was the change in maximal (structural) skin capillary density during venous congestion after 8 weeks of active treatment. All other variables recorded were prospectively defined as secondary outcome criteria. The mean, standard deviation (SD), and range are reported for all continuous variables, which were normally distributed. For maximal capillary density during venous congestion, an analysis of covariance was performed adjusted on basal capillary density and age. Pairwise comparisons between groups and within groups were performed using this analysis of covariance model, without adjustment for multiple comparisons in this preliminary approach. All other parameters were analysed similarly. Student’s paired and unpaired t tests were used to evaluate differences between and among groups. For the other criteria, difference between groups was assessed with a two?tailed Student’s t?test for independent samples or with nonparametric test for non?normal distribution. A type error of 5% was set for all test procedures. Statistical significance was declared when the p-value was <0.05. All statistical analysis was carried out using the IBM SPSS 22, USA.Results: A total of 155 Caucasian subjects were invited to participate in the study, and subsequently 114 subjects were screened for eligibility. Of these, 42 individuals did not meet the inclusion criteria (mainly because of normalization of their BP on the follow-up visit), 38 subjects withdrew consent, 8 were found to be receiving antihypertensive medications from their general practitioner, and 4 had abnormal laboratory results. Eventually 22 subjects were recruited into the study but 1 subject withdrew consent during the run-in period. Table 1 shows the baseline characteristics of the recruited subjects. The average age of the subjects was 42.4 years (range 26-59 years) and the average BMI was 29.0 (range 20.0-43.2). At entry to the study mean±SD sitting and standing BP were 147/97±14/8mmHg and 147/96±16/8mmHg respectively. At the end of the 2 weeks single blind placebo run-in period mean sitting BP was 144/94±14/9mmHg (p=0.07 and p=0.057 respectively compared to baseline levels). In six subjects the BP dropped significantly on placebo, so much so they did not meet the inclusion criteria and were therefore excluded form the randomized phase. There were no significant changes in other clinical or laboratory parameters. Table 2 shows the baseline characteristics of the randomized subjects. In total 9 subjects were randomized to candesartan and 6 subjects were randomized to amlodipine. Table 3 shows the longitudinal changes in BMI, sitting and standing systolic and diastolic BP, pulse rate, central systolic BP, PWV, basal and maximal capillary densities, and Aortic augmentation from baseline. Blood Pressure Changes:In paired comparisons of sitting systolic BP, there was a significant decrease from the end of the placebo run-in period to 4 weeks active treatment (mean change -19.0 mmHg; 95% CI -11.1 to -26.9, p<0.0001), and to 8 weeks active treatment (mean change -26.3 mmHg; 95% CI -17.5 to -35.0, p<0.0001). (Table 3). Similarly there was a significant decrease in sitting diastolic BP at 4 weeks active treatment (mean change -13.8 mmHg; 95% CI -9.8 to -17.7, p<0.0001), and to 8 weeks active treatment (mean change -16.1 mmHg; 95% CI -13.1 to -19.0, p<0.0001). For standing systolic BP, there was also a significant decrease at 4 weeks active treatment (mean change -21.9 mmHg; 95% CI -11.1 to -32.7, p=0.001), and to 8 weeks active treatment (mean change -26.5 mmHg; 95% CI -15.8 to -37.3, p<0.0001). Standing diastolic BP decreased significantly after 4 weeks of active treatment (mean change -11.8 mmHg; 95% CI -6.4 to -17.3, p<0.0001), and to 8 weeks active treatment (mean change -16.1 mmHg; 95% CI -11.4 to -20.8, p<0.0001). There were no significant differences between the responses to amlodipine versus candesartan in all BP parameters.Central Systolic Blood Pressure and Aortic Augmentation Changes:cSBP decreased significantly after 4 weeks of treatment (mean change -18.4 mmHg; 95% CI -8.0 to -28.8, p=0.002), and after 8 weeks (mean change -22.6 mmHg; 95% CI -13.6 to -31.6, p<0.0001). AI also decreased significantly after 4 weeks of treatment (mean change -7.6 mmHg; 95% CI -2.2 to -13.0, p=0.010), and after 8 weeks (mean change -9.2 mmHg; 95% CI -4.7 to -13.6, p=0.001). There were no significant differences between the responses to amlodipine versus candesartan.Pulse Wave velocity:The changes in PWV were not significant at any point in the study. (Table 3) We could not rule out the possibility that we have not seen significant differences because of the small number of subjects. Capillary Density Changes: There were no significant changes in basal (i.e. before venous congestion) capillary density after 4 weeks (mean change -0.4 cap/field; 95% CI -3.5 to 2.6, p=0.76) or after 8 weeks of active treatment (mean change 1.2 cap/field; 95% CI -2.3 to 4.7, p=0.48). Similarly, there were no significant changes in maximal (i.e. with venous congestion) capillary density after 4 weeks (mean change 1.5 cap/field; 95% CI -2.1 to 5.2, p=0.38) or after 8 weeks of active treatment (mean change 1.8 cap/field; 95% CI -1.1 to 1.8, p=0.20). Discussion:This is the first randomized, double blind, placebo controlled, parallel-group study aimed at comparing the effects of treatment of hypertension with a CCB versus an ARB on skin capillary density in hypertensive patients using well-validated techniques. The study showed that after 4 weeks and 8 weeks treatment with either candesartan or amlodipine, there were significant reductions in both systolic and diastolic brachial BP and central systolic BP but there was no significant effect on basal (functional) or maximal (structural) capillary densities. The study also showed that both candesartan and amlodipine significantly reduced Aortic Augmentation Index but had no significant effect on pulse wave velocity. Preclinical studies have suggested that treatment with antihypertensive medications may reverse or even prevent microvascular rarefaction, although inconsistent results were obtained with different classes of drugs.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaXp6b25pPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48
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ADDIN EN.CITE.DATA 17 One study that compared the effects of different antihypertensive treatments on capillary density in spontaneously hypertensive rats (SHR) led to the conclusion that despite their similar effectiveness in decreasing BP, functional rarefaction was reversed by losartan, nifedipine, and enalapril, while structural rarefaction was normalized only by losartan and enalapril while atenolol had no noticeable effect.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWJpbm88L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 18 It was therefore suggested that dihydropyridine CCB and renin–angiotensin system blockers were effective in this regard, while data on diuretics and beta-blockers were inconclusive. These selective desirable effects on the microcirculation have been implicated in explaining the beneficial effects of these drugs in reducing micro albuminuria and preserving renal function. Very little, however, is known about the effects of treatment of human essential hypertension on capillary rarefaction which may be related to end-organ damage, as suggested by the association between hypertensive myocardial disease and reduced myocardial capillary density. ADDIN EN.CITE <EndNote><Cite><Author>Strauer</Author><Year>1990</Year><RecNum>15353</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>15353</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1440503969">15353</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Strauer, B. E.</author></authors></contributors><auth-address>Department of Medicine, University of Duesseldorf, Federal Republic of West Germany.</auth-address><titles><title>Significance of coronary circulation in hypertensive heart disease for development and prevention of heart failure</title><secondary-title>Am J Cardiol</secondary-title></titles><periodical><full-title>Am J Cardiol</full-title></periodical><pages>34G-41G</pages><volume>65</volume><number>14</number><keywords><keyword>Adult</keyword><keyword>Animals</keyword><keyword>Cardiac Output, Low/*etiology/prevention & control</keyword><keyword>Cardiomegaly/etiology/*physiopathology/prevention & control</keyword><keyword>Coronary Circulation/drug effects/*physiology</keyword><keyword>Coronary Disease/complications/*physiopathology</keyword><keyword>Coronary Vessels/physiopathology</keyword><keyword>Felodipine/therapeutic use</keyword><keyword>Humans</keyword><keyword>Hydralazine/therapeutic use</keyword><keyword>Hypertension/complications/*physiopathology/prevention & control</keyword><keyword>Metoprolol/therapeutic use</keyword><keyword>Nifedipine/therapeutic use</keyword><keyword>Rats</keyword><keyword>Rats, Inbred SHR</keyword><keyword>Rats, Inbred WKY</keyword><keyword>Vascular Resistance/drug effects/physiology</keyword></keywords><dates><year>1990</year><pub-dates><date>Apr 3</date></pub-dates></dates><isbn>0002-9149 (Print)
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ADDIN EN.CITE.DATA 10, 13, 20, 21 It was postulated that treatment of hypertension and a reduction in BP represents a necessary but not a sufficient circumstance for inducing a regression in microvascular abnormalities, because drugs with similar hemodynamic profile may have dissimilar effects on small artery morphology. ADDIN EN.CITE <EndNote><Cite><Author>Agabiti-Rosei</Author><Year>2009</Year><RecNum>15347</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>15347</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1440147142">15347</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Agabiti-Rosei, E.</author><author>Heagerty, A. M.</author><author>Rizzoni, D.</author></authors></contributors><auth-address>Clinica Medica, Department of Medical and Surgical Sciences, University of Brescia, Italy.</auth-address><titles><title>Effects of antihypertensive treatment on small artery remodelling</title><secondary-title>J Hypertens</secondary-title></titles><periodical><full-title>Journal of Hypertension</full-title><abbr-1>J Hypertens</abbr-1></periodical><pages>1107-14</pages><volume>27</volume><number>6</number><keywords><keyword>Animals</keyword><keyword>Antihypertensive Agents/*therapeutic use</keyword><keyword>Arteries/*drug effects/*pathology/physiopathology</keyword><keyword>Cardiovascular Diseases/etiology/pathology</keyword><keyword>Humans</keyword><keyword>Hypertension/complications/*drug therapy/*pathology/physiopathology</keyword><keyword>Hypertrophy</keyword><keyword>Prognosis</keyword><keyword>Risk Factors</keyword><keyword>Vascular Resistance/drug effects</keyword></keywords><dates><year>2009</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1473-5598 (Electronic)
0263-6352 (Linking)</isbn><accession-num>19293726</accession-num><urls><related-urls><url> In a previous open-label pilot study in individuals with treatment-na?ve mild-to-moderate essential hypertension, we found that 6-weeks treatment with the ARB irbesartan resulted in significant lowering of both systolic and diastolic BP and significant increase in maximal capillary density (with venous congestion). ADDIN EN.CITE <EndNote><Cite><Author>Rattray</Author><Year>2004</Year><RecNum>11801</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>11801</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">11801</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rattray, F.E.</author><author>Coltart, R.A.</author><author>Markandu, N.D.</author><author>MacGregor, G.A.</author><author>Antonios, T.F.T.</author></authors></contributors><titles><title>Effect of an angiotensin II antagonist; irbesartan on blood pressure and skin capillary density in patients with essential hypertension</title><secondary-title>Journal of Hypertens</secondary-title></titles><periodical><full-title>Journal of Hypertens</full-title></periodical><pages>S25</pages><volume>22</volume><number>S1</number><dates><year>2004</year></dates><urls></urls></record></Cite></EndNote>23 In another observational study we reported that capillary density was 25- 30% higher in treated compared with untreated hypertensive patients but was significantly lower than in age-matched normotensive controls. ADDIN EN.CITE <EndNote><Cite><Author>Antonios</Author><Year>2001</Year><RecNum>11372</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>11372</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">11372</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Antonios, T. F.</author><author>Kaski, J. C.</author><author>Hasan, K. M.</author><author>Brown, S. J.</author><author>Singer, D. R.</author></authors></contributors><auth-address>Clinical Pharmacology Unit, Department of Pharmacology & Clinical Pharmacology, St George's Hospital Medical School, Cranmer Terrace, London, U.K.</auth-address><titles><title>Rarefaction of skin capillaries in patients with anginal chest pain and normal coronary arteriograms</title><secondary-title>Eur Heart J</secondary-title></titles><periodical><full-title>Eur Heart J</full-title></periodical><pages>1144-1148.</pages><volume>22</volume><number>13</number><dates><year>2001</year></dates><accession-num>11428855</accession-num><urls><related-urls><url> Debbabi and colleagues, in an observational study, evaluated skin capillary density in hypertensive patients who were treated with different antihypertensive drugs and who had their BP well controlled below 140/90mmHg for at least 12 months. They found that basal (functional) and maximal (structural) skin capillary densities in treated hypertensive patients were significantly higher when compared to never-treated hypertensive patients or to normotensive subjects. ADDIN EN.CITE <EndNote><Cite><Author>Debbabi</Author><Year>2006</Year><RecNum>11803</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>11803</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">11803</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Debbabi, H.</author><author>Uzan, L.</author><author>Mourad, J. J.</author><author>Safar, M.</author><author>Levy, B. I.</author><author>Tibirica, E.</author></authors></contributors><auth-address>Department of Physiology and non-invasive investigations, Inserm U689, Hopital Lariboisiere, Paris, France.</auth-address><titles><title>Increased skin capillary density in treated essential hypertensive patients</title><secondary-title>Am J Hypertens</secondary-title></titles><periodical><full-title>Am J Hypertens</full-title></periodical><pages>477-83</pages><volume>19</volume><number>5</number><dates><year>2006</year><pub-dates><date>May</date></pub-dates></dates><accession-num>16647618</accession-num><urls><related-urls><url> The finding of a higher capillary density in treated hypertensive patients is very curious and rather difficult to construe. ADDIN EN.CITE <EndNote><Cite><Author>Antonios</Author><Year>2006</Year><RecNum>11804</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>11804</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">11804</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Antonios, T. F.</author></authors></contributors><auth-address>Blood Pressure Unit, Department of Cardiac and Vascular Sciences, St. George's, University of London, London, England.</auth-address><titles><title>Microvascular Rarefaction in Hypertension-Reversal or Over-Correction by Treatment?</title><secondary-title>Am J Hypertens</secondary-title></titles><periodical><full-title>Am J Hypertens</full-title></periodical><pages>484-485</pages><volume>19</volume><number>5</number><dates><year>2006</year><pub-dates><date>May</date></pub-dates></dates><accession-num>16647619</accession-num><urls><related-urls><url> In another open-label cross-sectional study the same group reported that only hypertensive patients who were treated and adequately controlled with perindopril / indapamide combination for more than 6 months had significantly higher maximal capillary density than both patients treated and controlled by other drugs, and normotensive individuals. ADDIN EN.CITE <EndNote><Cite><Author>Debbabi</Author><Year>2010</Year><RecNum>12283</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>12283</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">12283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Debbabi, H.</author><author>Bonnin, P.</author><author>Levy, B. I.</author></authors></contributors><auth-address>Department of Non-Invasive Investigations, PARCC Inserm U790, Inserm U965, Lariboisiere Hospital, AP-HP, University Paris Diderot, Paris, France.</auth-address><titles><title>Effects of Blood Pressure Control With Perindopril/Indapamide on the Microcirculation in Hypertensive Patients</title><secondary-title>Am J Hypertens</secondary-title></titles><periodical><full-title>Am J Hypertens</full-title></periodical><pages>1136-1143</pages><volume>23</volume><number>10</number><dates><year>2010</year><pub-dates><date>May 27</date></pub-dates></dates><accession-num>20508624</accession-num><urls><related-urls><url> They suggested that the normalization of the skin capillary density could be, at least partially, BP independent as equivalent BP control is not synonymous with equivalent microvascular benefits and suggest different long-term results for end-organ damage. Of interest in their study is that most of the patients in the controlled-other group (48%) were treated with an ARB. ADDIN EN.CITE <EndNote><Cite><Author>Debbabi</Author><Year>2010</Year><RecNum>12283</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>12283</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">12283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Debbabi, H.</author><author>Bonnin, P.</author><author>Levy, B. I.</author></authors></contributors><auth-address>Department of Non-Invasive Investigations, PARCC Inserm U790, Inserm U965, Lariboisiere Hospital, AP-HP, University Paris Diderot, Paris, France.</auth-address><titles><title>Effects of Blood Pressure Control With Perindopril/Indapamide on the Microcirculation in Hypertensive Patients</title><secondary-title>Am J Hypertens</secondary-title></titles><periodical><full-title>Am J Hypertens</full-title></periodical><pages>1136-1143</pages><volume>23</volume><number>10</number><dates><year>2010</year><pub-dates><date>May 27</date></pub-dates></dates><accession-num>20508624</accession-num><urls><related-urls><url> Several other studies have shown similar negative effects of ARBs on capillary rarefaction. Kaiser and colleagues in an open-label randomized design studied skin capillary density in 44 subjects with mild to moderate essential hypertension before and after six months treatment with either a beta-blocker (metoprolol) or an ARB (olmesartan). ADDIN EN.CITE <EndNote><Cite><Author>Kaiser</Author><Year>2013</Year><RecNum>14565</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>14565</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1404729702">14565</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kaiser, S. E.</author><author>Sanjuliani, A. F.</author><author>Estato, V.</author><author>Gomes, M. B.</author><author>Tibirica, E.</author></authors></contributors><auth-address>Clinical and Experimental Pathophysiology Unit, State University of Rio de Janeiro, Rio de Janeiro, Brazil.</auth-address><titles><title>Antihypertensive treatment improves microvascular rarefaction and reactivity in low-risk hypertensive individuals</title><secondary-title>Microcirculation</secondary-title><alt-title>Microcirculation</alt-title></titles><periodical><full-title>Microcirculation</full-title></periodical><alt-periodical><full-title>Microcirculation</full-title></alt-periodical><pages>703-16</pages><volume>20</volume><number>8</number><dates><year>2013</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1549-8719 (Electronic)
1073-9688 (Linking)</isbn><accession-num>23692260</accession-num><urls><related-urls><url> Interestingly, they found that only treatment with metoprolol resulted in a significant reversal of rarefaction and an increase in capillary density whilst treatment with olmesartan had no significant effect on capillary density. Treatment with valsartan showed conflicting results as one study showing significant increase in capillary density after only 4 weeks ADDIN EN.CITE <EndNote><Cite><Author>Jumar</Author><Year>2016</Year><RecNum>16291</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>16291</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1468493365">16291</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jumar, A.</author><author>Harazny, J. M.</author><author>Ott, C.</author><author>Kistner, I.</author><author>Friedrich, S.</author><author>Schmieder, R. E.</author></authors></contributors><auth-address>Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Erlangen, Germany.
Department of Pathophysiology, University of Warmia and Mazury Olsztyn, Olsztyn, Poland.</auth-address><titles><title>Improvement in Retinal Capillary Rarefaction After Valsartan Treatment in Hypertensive Patients</title><secondary-title>J Clin Hypertens (Greenwich)</secondary-title></titles><periodical><full-title>J Clin Hypertens (Greenwich)</full-title></periodical><dates><year>2016</year><pub-dates><date>Jun 16</date></pub-dates></dates><isbn>1751-7176 (Electronic)
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ADDIN EN.CITE.DATA 27 On the other hand, several other studies have shown no effect of hypertension treatment on capillary rarefaction. Penna et al evaluated functional and structural capillary density in treated and well-controlled patients with essential hypertension. ADDIN EN.CITE <EndNote><Cite><Author>Penna</Author><Year>2008</Year><RecNum>12151</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>12151</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">12151</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Penna, G. L.</author><author>Garbero Rde, F.</author><author>Neves, M. F.</author><author>Oigman, W.</author><author>Bottino, D. A.</author><author>Bouskela, E.</author></authors></contributors><auth-address>Department of Clinical Medicine, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.</auth-address><titles><title>Treatment of essential hypertension does not normalize capillary rarefaction</title><secondary-title>Clinics (Sao Paulo)</secondary-title></titles><periodical><full-title>Clinics (Sao Paulo)</full-title></periodical><pages>613-8</pages><volume>63</volume><number>5</number><dates><year>2008</year><pub-dates><date>Oct</date></pub-dates></dates><accession-num>18925320</accession-num><urls><related-urls><url> They found that treated hypertensive patients had lower mean functional capillary density at baseline, during post-occlusive reactive hyperemia, and during venous congestion suggesting that treatment and control of BP, regardless of the type of therapy used, does not necessarily results in reversing capillary rarefaction. De Ciuceis and colleagues, in an open-label design, studied the effects of treatment of hypertension on structural alterations of retinal arterioles, skin capillary density, arterial distensibility, and oxidative stress with a CCB alone and the combination of a CCB with either an ACE inhibitor or a diuretic in patients with mild to moderate essential hypertension.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBDaXVjZWlzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh
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ADDIN EN.CITE.DATA 10 All their patients were treated with lercanidipine for 4 weeks and then either enalapril (n=10) or hydrochlorothiazide (n=10) was added for 6 months. They found no change in basal capillary density at any point in the study. After 4 weeks of treatment with lercanidipine alone, maximal capillary density was slightly but not significantly increased. After 6 months of treatment with the combination of lercanidipine and enalapril, the increase in maximal capillary density was statistically significant. The change in maximal capillary density with the combination of lercanidipine and hydrochlorothiazide was not statistically significant. Similar to our study, the authors found no change in PWV between groups or between any time points despite the fact that central SBP was significantly reduced. More recently, the same group, in another randomized open-label design, studied the effects of one-year treatment of hypertension with either ramipril or aliskiren and found no significant effects on capillary rarefaction.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZSBDaXVjZWlzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh
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ADDIN EN.CITE.DATA 28 The results from our present study and the aforementioned studies suggest that the reduction and normalization of BP values may not be sufficient for obtaining a regression of microvascular rarefaction in essential hypertension even after one year.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hpZmZyaW48L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFy
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ADDIN EN.CITE.DATA 29 These findings also suggest that the improvement of capillary rarefaction and other microcirculatory abnormalities with selective ARBs or ACEi drugs may not represent a class effect but rather drug-specific additional properties of these particular drugs on the microcirculation. ADDIN EN.CITE <EndNote><Cite><Author>Debbabi</Author><Year>2010</Year><RecNum>12283</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>12283</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1382954401">12283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Debbabi, H.</author><author>Bonnin, P.</author><author>Levy, B. I.</author></authors></contributors><auth-address>Department of Non-Invasive Investigations, PARCC Inserm U790, Inserm U965, Lariboisiere Hospital, AP-HP, University Paris Diderot, Paris, France.</auth-address><titles><title>Effects of Blood Pressure Control With Perindopril/Indapamide on the Microcirculation in Hypertensive Patients</title><secondary-title>Am J Hypertens</secondary-title></titles><periodical><full-title>Am J Hypertens</full-title></periodical><pages>1136-1143</pages><volume>23</volume><number>10</number><dates><year>2010</year><pub-dates><date>May 27</date></pub-dates></dates><accession-num>20508624</accession-num><urls><related-urls><url> Our finding of no significant change in PWV in treated hypertensive patients is not novel, as other groups have found similar results.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYWp6ZXI8L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 10, 30-32 We acknowledge that our study has several limitations. Our inability to find a significant effect of both candesartan and amlodipine treatment on capillary rarefaction can be feasibly explained by the small number of subjects who completed the study (type 2 error) or the shorter duration of active treatment with these 2 drugs. Additionally we could not rule out any persisting effects of previous antihypertensive medications our subjects received before enrolling in this study. It is also conceivable that amlodipine and candesartan may genuinely lack substantial microvascular effects as other studies have shown that treatment with amlodipine did not improve coronary flow reserve in hypertensive patientsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYXlhPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 33, 34 Similarly in the spontaneously hypertensive rat amlodipine and candesartan did not show any significant reverse arteriolar remodeling compared to placebo. ADDIN EN.CITE <EndNote><Cite><Author>Mancini</Author><Year>2016</Year><RecNum>16300</RecNum><DisplayText><style face="superscript">35</style></DisplayText><record><rec-number>16300</rec-number><foreign-keys><key app="EN" db-id="ztzasxe5cs00v4efwrpvftrwtafzwe22xezt" timestamp="1472033064">16300</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mancini, M.</author><author>Scavone, A.</author><author>Sartorio, C. L.</author><author>Baccaro, R.</author><author>Kleinert, C.</author><author>Pernazza, A.</author><author>Buia, V.</author><author>Leopizzi, M.</author><author>D'Amati, G.</author><author>Camici, P. G.</author></authors></contributors><auth-address>Istituto "Marco Pasquali" ICOT GIOMI, Latina, Italy.
Vita Salute University and Scientific Institute San Raffaele, Milan, Italy.
Department of Radiology, Oncology and Pathology, "Sapienza" University, Rome, Italy.</auth-address><titles><title>Effect of different drug classes on reverse remodeling of intramural coronary arterioles in the spontaneously hypertensive rat</title><secondary-title>Microcirculation</secondary-title></titles><periodical><full-title>Microcirculation</full-title></periodical><keywords><keyword>Shr</keyword><keyword>Antihypertensive drugs</keyword><keyword>Coronary blood flow</keyword><keyword>Coronary microcirculation</keyword><keyword>Hypertension</keyword><keyword>Vascular remodeling</keyword></keywords><dates><year>2016</year><pub-dates><date>Jul 21</date></pub-dates></dates><isbn>1549-8719 (Electronic)
1073-9688 (Linking)</isbn><accession-num>27441420</accession-num><urls><related-urls><url> In conclusion, this study has shown that 4 weeks and 8 weeks treatment with candesartan or amlodipine resulted in significant reductions of both systolic and diastolic brachial BP and central systolic BP but had no significant effect on basal (functional) or maximal (structural) capillary densities. These results indicate that normalization of BP with amlodipine or candesartan treatment does not necessarily results in reversal of capillary rarefaction in essential hypertension. The study also showed that both candesartan and amlodipine significantly reduced Aortic Augmentation Index but had no significant effect on pulse wave velocity.Conflicts of Interest and Source of Funding: Takeda, UK funded the study. The authors declare no conflict of interest.Details of ethics approval:The London-Surrey Borders Research Ethics committee approved this study. (REC: 08/H0806/72)Trial registration: (EudraCT: 2008-005432-32, ISRCTN 62554526)?References: ADDIN EN.REFLIST 1.Gavin JB, Maxwell L, Edgar SG. Microvascular involvement in cardiac pathology. J Mol Cell Cardiol. 1998;30:2531-2540.2.Levy BI, Schiffrin EL, Mourad JJ, Agostini D, Vicaut E, Safar ME, Struijker-Boudier HA. Impaired tissue perfusion: A pathology common to hypertension, obesity, and diabetes mellitus. Circulation. 2008;118:968-976.3.Struijker Boudier HA, le Noble JL, Messing MW, Huijberts MS, le Noble FA, van Essen H. The microcirculation and hypertension. J Hypertens Suppl. 1992;10:S147-S156.4.Antonios TFT, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Structural skin capillary rarefaction in essential hypertension. Hypertension. 1999;33:998-1001.5.Antonios TFT, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. 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Cardiology. 2012;122:230-236.35.Mancini M, Scavone A, Sartorio CL, Baccaro R, Kleinert C, Pernazza A, Buia V, Leopizzi M, D'Amati G, Camici PG. Effect of different drug classes on reverse remodeling of intramural coronary arterioles in the spontaneously hypertensive rat. Microcirculation. 2016.Table 3. Changes in Variables from End of Placebo run-in period to 4 and 8 weeks Visit in randomised subjectsVariableAllCandesartanAmlodipineBetween Groupst testp-valuet-test Overallp-valueMean (SE) changeMean (SE) changeMean (SE) changeSitting Systolic BP (mmHg)4 weeks treatment-19.0(3.7)-19.4(5.6)-18.5(4.8)0.25<0.00018 weeks treatment-26.3(4.0)-29.4(5.6)-21.8(5.4)0.94<0.0001Sitting Diastolic BP (mmHg)4 weeks treatment-13.8(1.8)-11.8(2.5)-16.5(2.5)0.93<0.00018 weeks treatment-16.1(1.3)-15.9(1.8)-16.4(2.3)0.49<0.0001Sitting Mean BP (mmHg)4 weeks treatment-15.0(2.4)-14.5(3.3)-15.8(3.8)0.80<0.00018 weeks treatment-18.7(2.4)-20.6(2.7)-16.1(4.5)0.39<0.0001Standing Systolic BP (mmHg)4 weeks treatment-21.9(5.0)-24.8(5.3)-17.4(10.2)0.63<0.00018 weeks treatment-26.5(4.8)-30.1(4.0)-20.3(11.6)0.88<0.0001Standing Diastolic BP (mmHg)4 weeks treatment-11.8(2.5)-11.0(3.2)-13.2(4.4)0.99<0.00018 weeks treatment-16.1(2.1)-16.4(1.8)-15.5(5.4)0.24<0.0001Basal Capillary Density (capillaries per field)4 weeks treatment-0.4(1.4)0(1.5)-1.0(2.8)0.730.768 weeks treatment1.2(1.6)2.2(2.1)-0.2(2.7)0.480.48Maximal Capillary Density (capillaries per field)4 weeks treatment1.5(1.7)0.4(2.0)3.0(3.0)0.480.388 weeks treatment1.8(1.3)0.6(1.6)3.5(2.3)0.300.2Pulse Wave Velocity (meters per second)4 weeks treatment-0.1(0.3)-0.3(0.5)0.04(0.4)0.800.678 weeks treatment0.1(0.4)0.5(0.5)-0.5(0.7)0.250.79Central Systolic BP (mmHg)4 weeks treatment-18.4(4.8)-18.5(7.3)-18.2(5.3)0.980.0028 weeks treatment-22.6(4.0)-24.9(6.0)-18.8(4.2)0.50<0.0001Augmentation Index (%)4 weeks treatment-7.6(2.5-4.3(3.2)-13.0(2.7)0.090.018 weeks treatment-9.2(2.0)-8.4(3.1)-10.5(1.7)0.640.001 ................
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