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Comparison of lercanidipine plus hydrochlorothiazide vs. lercanidipine plus enalapril on micro and macrocirculation in patients with mild essential hypertension

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Abstract

Dihydropyridine calcium channel blockers may possess antioxidant properties, and might improve micro and macrovascular structure and function. Combination treatment with an ACE inhibitor may have additional advantages, compared with a thiazide diuretic. The aim of the present study is to investigate the effects of a short-term treatment with lercanidipine, and to compare two combination treatments: lercanidipine + enalapril vs. lercanidipine + hydrochlorothiazide on structural alterations in retinal arterioles, on skin capillary density and on large artery distensibility. Thirty essential hypertension patients are included in the study, and treated for 4 weeks with lercanidipine 20 mg per day orally. Then, they were treated for 6 months with lercanidipine + enalapril (n = 15) or lercanidipine + hydrochlorothiazide (n = 15) combinations. Investigations were performed on basal condition, after appropriate wash out of previous treatments, after 4 weeks of lercanidipine monotherapy treatment, and at the end of the combination treatment. Non-invasive measurements of wall-to-lumen ratio (WLR) and other morphological parameters of retinal arterioles were performed using either scanning laser Doppler flowmetry or adaptive optics. Capillary density was evaluated by capillaroscopy, while pulse wave velocity was measured, and central blood pressures were assessed by pressure waveform analysis. A significant improvement of WLR and other indices of retinal artery structure is observed with both technical approaches after treatment with lercanidipine alone, with a further improvement after treatment with lercanidipine + enalapril, while after treatment with lercanidipine + hydrochlorothiazide, the improvement is partially blunted. Central systolic and diastolic blood pressures are similarly reduced by both therapeutic strategies. Capillary density is increased only after treatment with lercanidipine + enalapril. In conclusion, lercanidipine both in monotherapy and in combination with enalapril but not with hydrochlorothiazide is able to improve microvascular structure; on the other hand, a decrease in central blood pressure is observed with both therapeutic combinations.

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References

  1. Mulvany MJ, Aalkjaer C (1990) Structure and function of small arteries. Physiol Rev 70:921–971

    CAS  PubMed  Google Scholar 

  2. Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Muiesan P, Giulini SM, Agabiti Rosei E (1996) Vascular hypertrophy and remodeling in secondary hypertension. Hypertension 28:785–790

    Article  CAS  PubMed  Google Scholar 

  3. Schiffrin EL (2004) Remodeling of resistance arteries in essential hypertension and effects of antihypertensive treatment. Am J Hypertens 17:1192–1200

    Article  CAS  PubMed  Google Scholar 

  4. Struijker Boudier HAJ (1999) Microcirculation in hypertension. Eur Heart J 1(Suppl. L):L32–L37

    Google Scholar 

  5. Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HAJ (2001) Microcirculation in hypertension. A new target for treatment? Circulation 104:735–740

    Article  CAS  PubMed  Google Scholar 

  6. Tsioufis C, Dimitriadis K, Katsiki N, Tousoulis D (2015) Microcirculation in hypertension: an update on clinical significance and therapy. Curr Vasc Pharmacol 13:413–417

    Article  CAS  PubMed  Google Scholar 

  7. Paiardi S, Rodella LF, De Ciuceis C, Porteri E, Boari GE, Rezzani R, Rizzardi N, Platto C, Tiberio GA, Giulini SM, Rizzoni D, Agabiti-Rosei E (2009) Immunohistochemical evaluation of microvascular rarefaction in hypertensive humans and in spontaneously hypertensive rats. Clin Hemorheol Microcirc 42:259–268

    CAS  PubMed  Google Scholar 

  8. Safar ME, O’Rourke ME (2006) Handbook of hypertension, vol 23, Arterial Stiffness in Hypertension. Elsevier, Amsterdam, p 598

    Google Scholar 

  9. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H, European Network for Non-invasive Investigation of Large Arteries (2006) Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 27:2588–2605

    Article  PubMed  Google Scholar 

  10. Muiesan ML, Salvetti M, Rizzoni D, Paini A, Agabiti-Rosei C, Aggiusti C, Bertacchini F, Stassaldi D, Gavazzi A, Porteri E, De Ciuceis C, Agabiti-Rosei E (2013) Pulsatile hemodynamics and microcirculation: evidence for a close relationship in hypertensive patients. Hypertension 61:130–136

    Article  CAS  PubMed  Google Scholar 

  11. Laurent S, Agabiti-Rosei E. The cross-talk between the macro- and the microcirculation. In: Nilsson P, Olsen MH & Laurent S Eds Early Vascular Aging (EVA): new directions in cardiovascular protection. Elsevier Inc, London, UK, pp 105–118

  12. Rizzoni D, Porteri E, Boari GE, De Ciuceis C, Sleiman I, Muiesan ML, Castellano M, Miclini M, Agabiti-Rosei E (2003) Prognostic significance of small-artery structure in hypertension. Circulation 108:2230–2235

    Article  PubMed  Google Scholar 

  13. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A (2001) Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37:1236–1241

    Article  CAS  PubMed  Google Scholar 

  14. Laurent S, Rizzoni D. Targeting central blood pressure through the micro-and macrocirculation cross-talk. In: Nilsson P, Olsen MH, Laurent S (eds) Early vascular aging (EVA): new directions in cardiovascular protection. Elsevier Inc, London, UK, pp 297–306

  15. Agabiti-Rosei E, Heagerty AM, Rizzoni D (2009) Effects of antihypertensive treatment on small artery remodelling. J Hypertens 27:1107–1114

    Article  CAS  PubMed  Google Scholar 

  16. Rizzoni D, De Ciuceis C, Salvetti M, Paini A, Rossini C, Agabiti-Rosei C, Muiesan ML (2015) Interactions between macro- and micro-circulation: are they relevant? High Blood Press Cardiovasc Prev 22:119–128

    Article  CAS  PubMed  Google Scholar 

  17. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O’Rourke M, CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee (2006) Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 113:1213–1225

    Article  CAS  PubMed  Google Scholar 

  18. Taddei S, Virdis A, Ghiadoni L, Magagna A, Favilla S, Pompella A, Salvetti A (2001) Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. Hypertension 37(3):943–948

    Article  CAS  PubMed  Google Scholar 

  19. Savoia C, Schiffrin EL (2007) Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci (Lond) 112:375–384

    Article  CAS  Google Scholar 

  20. De Ciuceis C, Salvetti M, Rossini C, Muiesan ML, Paini A, Duse S, La Boria E, Semeraro F, Cancarini A, Agabiti Rosei C, Sarkar A, Ruggeri G, Caimi L, Ricotta D, Rizzoni D, Agabiti Rosei E (2014) Effect of antihypertensive treatment on microvascular structure, central blood pressure and oxidative stress in patients with mild essential hypertension. J Hypertens 32:565–574

    Article  PubMed  Google Scholar 

  21. Virdis A, Savoia C, Grassi G, Lembo G, Vecchione C, Seravalle G, Taddei S, Volpe M, Agabiti Rosei E, Rizzoni D (2014) Evaluation of microvascular structure in humans: a ‘state-of-the-art’ document of the Working Group on Macrovascular and Microvascular Alterations of the Italian Society of Arterial Hypertension. J Hypertens 32:2120–2129

    Article  CAS  PubMed  Google Scholar 

  22. Rizzoni D, Porteri E, Duse S, De Ciuceis C, Rosei CA, La Boria E, Semeraro F, Costagliola C, Sebastiani A, Danzi P, Tiberio GA, Giulini SM, Docchio F, Sansoni G, Sarkar A, Agabiti Rosei E (2012) Relationship between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles evaluated noninvasively by scanning laser Doppler flowmetry. J Hypertens 30:1169–1175

    Article  CAS  PubMed  Google Scholar 

  23. Bang LM, Chapman TM, Goa KL (2003) Lercanidipine: a review of its efficacy in the management of hypertension. Drugs 63:2449–2472

    Article  CAS  PubMed  Google Scholar 

  24. Taddei S, Virdis A, Ghiadoni L, Versari D, Salvetti G, Magagna A, Salvetti A (2003) Calcium antagonist treatment by lercanidipine prevents hyperpolarization in essential hypertension. Hypertension 41:950–955

    Article  CAS  PubMed  Google Scholar 

  25. De Ciuceis C, Rossini C, Tincani A, Airò P, Scarsi M, Agabiti-Rosei C, Ruggeri G, Caimi L, Ricotta D, Agabiti-Rosei E, Rizzoni D (2016) Effect of antihypertensive treatment with lercanidipine on endothelial progenitor cells and inflammation in patients with mild to moderate essential hypertension. Blood Press 25:337–343

    Article  PubMed  Google Scholar 

  26. Borghi C, Cicero AF (2010) Rationale for the use of a fixed-dose combination in the management of hypertension: efficacy and tolerability of lercanidipine/enalapril. Clin Drug Investig 30:843–854

    Article  CAS  PubMed  Google Scholar 

  27. Tocci G, Palano F, Pagannone E, Chin D, Ferrucci A, Volpe M (2009) Fixed-combination therapies in hypertension management: focus on enalapril/lercanidipine. Expert Rev Cardiovasc Ther 7:115–123

    Article  CAS  PubMed  Google Scholar 

  28. Koch E, Rosenbaum D, Brolly A, Sahel JA, Chaumet-Riffaud P, Girerd X, Rossant F, Paques M (2014) Morphometric analysis of small arteries in the human retina using adaptive optics imaging: relationship with blood pressure and focal vascular changes. J Hypertens 32:890–898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rizzoni D, Docchio F (2016) Assessment of retinal arteriolar morphology by noninvasive methods: the philosopher’s stone? J Hypertens 34:1044–1046

    Article  CAS  PubMed  Google Scholar 

  30. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Task Force Members (2013) ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013(31):1281–1357

    Article  Google Scholar 

  31. Rizzoni D, Muiesan ML, Montani G, Zulli R, Calebich S, Agabiti-Rosei E (1992) Relationship between initial cardiovascular structural changes and daytime and nighttime blood pressure monitoring. Am J Hypertens 5:180–186

    Article  CAS  PubMed  Google Scholar 

  32. Salvetti M, Agabiti Rosei C, Paini A, Aggiusti C, Cancarini A, Duse S, Semeraro F, Rizzoni D, Agabiti Rosei E, Muiesan ML (2014) Relationship of wall-to-lumen ratio of retinal arterioles with clinic and 24-hour blood pressure. Hypertension 63:1110–1115

    Article  CAS  PubMed  Google Scholar 

  33. Harazny JM, Ritt M, Baleanu D, Ott C, Heckmann J, Schlaich MP, Michelson G, Schmieder RE (2007) Increased wall:lumen ratio of retinal arterioles in male patients with a history of a cerebrovascular event. Hypertension 50:623–829

    Article  CAS  PubMed  Google Scholar 

  34. Ritt M, Harazny JM, Ott C, Schlaich MP, Schneider MP, Michelson G, Schmieder RE (2008) Analysis of retinal arteriolar structure in never-treated patients with essential hypertension. J Hypertens 26:1427–1434

    Article  CAS  PubMed  Google Scholar 

  35. Rosenbaum D, Mattina A, Koch E, Rossant F, Gallo A, Kachenoura N, Paques M, Redheuil A, Girerd X (2016) Effects of age, blood pressure and antihypertensive treatments on retinal arterioles remodeling assessed by adaptive optics. J Hypertens 34:1115–1122

    Article  CAS  PubMed  Google Scholar 

  36. Antonios TF, Singer DR, Markandu ND, Mortimer PS, MacGregor GA (1999) Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. Hypertension 34(4 Pt 1):655–658

    Article  CAS  PubMed  Google Scholar 

  37. Antonios TF, Singer DR, Markandu ND, Mortimer PS, MacGregor GA (1999) Structural skin capillary rarefaction in essential hypertension. Hypertension 33:998–1001

    Article  CAS  PubMed  Google Scholar 

  38. De Ciuceis C, Rossini C, Porteri E, La Boria E, Corbellini C, Mittempergher F, Di Betta E, Sarkar A, Agabiti Rosei C, Casella C, Nascimbeni R, Rezzani R, Rodella LF, Borsani E, Enrico Agabiti Rosei E, Rizzoni D (2013) Circulating endothelial progenitor cells, microvascular density and fibrosis in obesity before and after bariatric surgery. Blood Press 22:165–172

    Article  PubMed  Google Scholar 

  39. Muiesan ML, Salvetti M, Monteduro C, Bonzi B, Paini A, Viola S, Poisa P, Rizzoni D, Castellano M, Agabiti-Rosei E (2004) Left ventricular concentric geometry during treatment adversely affects cardiovascular prognosis in hypertensive patients. Hypertension 43:731–738

    Article  CAS  PubMed  Google Scholar 

  40. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St John Sutton M, Stewart W, American Society of Echocardiography’s Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of Cardiology (2006) Recommendations for chamber quantification. Eur J Echocardiogr 7:79–108

    Article  PubMed  Google Scholar 

  41. De Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, Alderman MH (1992) Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 20:1251–1260

    Article  PubMed  Google Scholar 

  42. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, Csiba L, Desvarieux M, Ebrahim S, Hernandez R, Jaff M, Kownator S, Naqvi T, Prati P, Rundek T, Sitzer M, Schminke U, Tardif JC, Taylor A, Vicaut E, Woo KS (2012) Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis 34:290–296

    Article  PubMed  PubMed Central  Google Scholar 

  43. Muiesan ML, Salvetti M, Paini A, Monteduro C, Agabiti Rosei C, Aggiusti C, Belotti E, Bertacchini F, Galbassini G, Stassaldi D, Castellano M, Agabiti Rosei E (2010) Pulse wave velocity and cardiovascular risk stratification in a general population: the Vobarno study. J Hypertens 28:1935–1943

    Article  CAS  PubMed  Google Scholar 

  44. Heagerty AM (2007) Predicting hypertension complications from small artery structure. J Hypertens 25:939–940

    Article  CAS  PubMed  Google Scholar 

  45. Schiffrin EL, Deng LY (1996) Structure and function of resistance arteries of hypertensive patients treated with a beta blocker or a calcium channel antagonist. J Hypertens 14:1237–1244

    Article  Google Scholar 

  46. Debbabi H, Uzan L, Mourad JJ, Safar M, Levy BI, Tibiriçà E (2006) Increased skin capillary density in treated essential hypertensive patients. Am J Hypertens 19:477–483

    Article  PubMed  Google Scholar 

  47. Debbabi H, Bonnin P, Levy BI (2010) Effects of blood pressure control with perindopril/indapamide on the microcirculation in hypertensive patients. Am J Hypertens 23:1136–1143

    Article  CAS  PubMed  Google Scholar 

  48. Zhou MS, Schulman IH, Jaimes EA, Raij L (2008) Thiazide diuretics, endothelial function, and vascular oxidative stress. J Hypertens 26:494–500

    Article  CAS  PubMed  Google Scholar 

  49. Neutel JM (1996) Metabolic manifestations of low-dose diuretics. Am J Med 101:71S–82S

    Article  CAS  PubMed  Google Scholar 

  50. Feig DI (2012) The role of uric acid in the pathogenesis of hypertension in the young. J Clin Hypertens (Greenwich) 14:346–352

    Article  CAS  Google Scholar 

  51. De Ciuceis C, Rossini C, Airò P, Scarsi M, Tincani A, Tiberio GA, Piantoni S, Porteri E, Solaini L, Duse S, Semeraro F, Petroboni B, Mori L, Castellano M, Gavazzi A, Agabiti Rosei C, Agabiti Rosei E, Rizzoni D (2017) Relationship between different subpopulations of circulating CD4+ T-lymphocytes and microvascular structural alterations in humans. Am J Hypertens 30:51–60

    Article  PubMed  Google Scholar 

  52. De Ciuceis C, Agabiti-Rosei C, Rossini C, Airò P, Scarsi M, Tincani A, Tiberio GA, Piantoni S, Porteri E, Solaini L, Duse S, Semeraro F, Petroboni B, Mori L, Castellano M, Gavazzi A, Agabiti-Rosei E, Rizzoni D (2017) Relationship between different subpopulations of circulating CD4+ T lymphocytes and microvascular or systemic oxidative stress in humans. Blood Press 26:237–245

    Article  PubMed  Google Scholar 

  53. Bruno RM, Duranti E, Ippolito C, Segnani C, Bernardini N, Di Candio G, Chiarugi M, Taddei S, Virdis A (2017) Different impact of essential hypertension on structural and functional age-related vascular changes. Hypertension 69:71–78

    Article  CAS  PubMed  Google Scholar 

  54. Safar ME, Rizzoni D, Blacher J, Muiesan ML, Agabiti-Rosei E (2008) Macro and microvasculature in hypertension: therapeutic aspects. J Hum Hypertens 22:590–595

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, c/o 2ª Medicina, Spedali Civili, 25100, Brescia, Italy

    Carolina De Ciuceis, Massimo Salvetti, Anna Paini, Claudia Rossini, Maria Lorenza Muiesan, Stefano Caletti, Maria Antonietta Coschignano, Valentina Trapletti, Fabio Bertacchini, Valeria Brami, Alina Petelca, Enrico Agabiti Rosei, Damiano Rizzoni & Claudia Agabiti Rosei

  2. Chair of Ophthalmology, University of Brescia, Brescia, Italy

    Sarah Duse & Francesco Semeraro

  3. Division of Medicine, Istituto Clinico Città di Brescia, Brescia, Italy

    Damiano Rizzoni

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  1. Carolina De Ciuceis
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Correspondence to Damiano Rizzoni.

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The protocol of the study was approved by the Ethics Committee of our institution (Medical School, University of Brescia). The procedures followed were in accordance with institutional guidelines.

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De Ciuceis, C., Salvetti, M., Paini, A. et al. Comparison of lercanidipine plus hydrochlorothiazide vs. lercanidipine plus enalapril on micro and macrocirculation in patients with mild essential hypertension. Intern Emerg Med 12, 963–974 (2017). https://doi.org/10.1007/s11739-017-1696-7

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