Effect of ACE-inhibition on coronary microvascular function and symptoms in normotensive women with microvascular angina: A randomized placebo-controlled trial

Marie Mide Michelsen, Anna Bay Rask, Elena Suhrs, Kristoffer Flintholm Raft, Nis Høst, Eva Prescott, Marie Mide Michelsen, Anna Bay Rask, Elena Suhrs, Kristoffer Flintholm Raft, Nis Høst, Eva Prescott

Abstract

Objective: Studies have suggested a beneficial effect of angiotensin-converting enzyme (ACE) inhibition. To explore whether the ACE inhibitor ramipril has a direct effect on the microvasculature beyond the blood pressure (BP) lowering effect, we investigated whether ramipril improved coronary microvascular function in normotensive women with coronary microvascular dysfunction (CMD).

Methods: We included 63 normotensive women with angina, no epicardial stenosis>50% and CMD defined as a coronary flow velocity reserve (CFVR)<2.2 assessed by adenosine stress-echocardiography in a randomized double-blinded, superiority trial with 1:1 allocation to placebo or ramipril (maximum dose 10 mg depending on blood pressure) for 24±6 weeks. Primary outcome was CFVR. Secondary outcomes were left ventricular systolic and diastolic function and symptoms evaluated by Seattle Angina Questionnaire (clinicaltrials.gov, NCT02525081).

Results: Follow-up was available on 55 patients. BP remained unchanged during treatment in both groups. CFVR improved in both the ramipril (p = 0.004) and placebo group (p = 0.026) with no difference between groups (p = 0.63). Symptoms improved in both groups with no significant between-group differences. No changes were detected in parameters of systolic and diastolic function. No serious adverse reactions were reported.

Conclusions: In normotensive women with angina and CMD, treatment with ramipril had no significant effect on CFVR or symptoms compared with placebo. The effect of ACE inhibition previously reported may be mediated by blood pressure reduction.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Up titration of project medication.
Fig 1. Up titration of project medication.
Blood pressure (BP) will be controlled after each visit. If possible treatment dose (per day) is increased. If patients have adverse reactions, project medication dose will be reduced. The least acceptable dose for staying in the study is 2.5 mg per day.
Fig 2. General study outline.
Fig 2. General study outline.
CFVR: Coronary flow reserve velocity, LV: Left ventricular, SAQ: Seattle Angina Questionnaire, eGFR: Estimated glomerular filtration rate, BP: blood pressure.
Fig 3. Participant flow-chart.
Fig 3. Participant flow-chart.
3 CAD: Coronary artery disease. CFVR: Coronary flow velocity reserve, ACE: Angiotensin-converting enzyme, GFR: Glomerular filtration rate.

References

    1. Camici PG, Crea F. Coronary Microvascular Dysfunction. N Engl J Med. 2007. February;356(8):830–40. doi:
    1. Reis SE, Holubkov R, Conrad Smith AJ, Kelsey SF, Sharaf BL, Reichek N, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001. May;141(5):735–41.
    1. Sicari R, Rigo F, Cortigiani L, Gherardi S, Galderisi M, Picano E. Additive prognostic value of coronary flow reserve in patients with chest pain syndrome and normal or near-normal coronary arteries. Am J Cardiol. 2009. March;103(5):626–31. doi:
    1. Mygind ND, Michelsen MM, Pena A, Frestad D, Dose N, Aziz A, et al. Coronary Microvascular Function and Cardiovascular Risk Factors in Women With Angina Pectoris and No Obstructive Coronary Artery Disease: The iPOWER Study. J Am Heart Assoc. 2016;5(3).
    1. Marinescu MA, Löffler AI, Ouellette M, Smith L, Kramer CM, Bourque JM. Coronary microvascular dysfunction, microvascular angina, and treatment strategies. JACC Cardiovasc Imaging. 2015. February;8(2):210–20. doi:
    1. Duncker DJ, Koller A, Merkus D, Canty JM. Regulation of Coronary Blood Flow in Health and Ischemic Heart Disease. Prog Cardiovasc Dis. 2015. March;57(5):409–22. doi:
    1. Heeneman S, Sluimer JC, Daemen MJAP. Angiotensin-converting enzyme and vascular remodeling. Circ Res. 2007. August;101(5):441–54. doi:
    1. Manolis AJ, Iraklianou S, Pittaras A, Zaris M, Tsioufis K, Psaltiras G, et al. Arterial compliance changes in diabetic normotensive patients after angiotensin-converting enzyme inhibition therapy. Am J Hypertens. 2005. January;18(1):18–22. doi:
    1. Benetos A, Albaladejo P, Levy BI, Safar ME. Acute and long-term effects of angiotensin converting enzyme inhibition on larger arteries and cardiac hypertrophy: mechanical and structural parameters. J Int Soc Hypertens. 1994. July;12(4):S21–29.
    1. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J. Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet (London, England). 2001. December;358(9299):2130–1.
    1. Suhrs HE, Michelsen MM, Prescott E. Treatment strategies in coronary microvascular dysfunction: a systematic review of interventional studies. Microcirculation. 2017. November 11.
    1. Task Force Members, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013. October;34(38):2949–3003. doi:
    1. Chen J-W, Hsu N-W, Wu T-C, Lin S-J, Chang M-S. Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol. 2002. November;90(9):974–82.
    1. Pauly DF, Johnson BD, Anderson RD, Handberg EM, Smith KM, Cooper-DeHoff RM, et al. In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: A double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE). Am Heart J. 2011. October;162(4):678–84. doi:
    1. Akinboboye OO, Chou R-L, Bergmann SR. Augmentation of myocardial blood flow in hypertensive heart disease by angiotensin antagonists: a comparison of lisinopril and losartan. J Am Coll Cardiol. 2002. August;40(4):703–9.
    1. Buus NH, Bøttcher M, Jørgensen CG, Christensen KL, Thygesen K, Nielsen TT, et al. Myocardial perfusion during long-term angiotensin-converting enzyme inhibition or beta-blockade in patients with essential hypertension. Hypertens (Dallas, Tex 1979). 2004. October;44(4):465–70.
    1. Kawata T, Daimon M, Hasegawa R, Teramoto K, Toyoda T, Sekine T, et al. Effect on coronary flow velocity reserve in patients with type 2 diabetes mellitus: comparison between angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor antagonist. Am Heart J. 2006. April;151(4):798.e9–15.
    1. Parodi O, Neglia D, Palombo C, Sambuceti G, Giorgetti A, Marabotti C, et al. Comparative effects of enalapril and verapamil on myocardial blood flow in systemic hypertension. Circulation. 1997. August;96(3):864–73.
    1. Masuda D, Nohara R, Tamaki N, Hosokawa R, Inada H, Hikai T, et al. Evaluation of coronary blood flow reserve by 13N-NH3 positron emission computed tomography (PET) with dipyridamole in the treatment of hypertension with the ACE inhibitor (Cilazapril). Ann Nucl Med. 2000. October;14(5):353–60.
    1. Stamatelopoulos K, Bramos D, Manios E, Alexaki E, Kaladaridou A, Georgiopoulos G, et al. Pleiotropic effects of the acute and chronic inhibition of the renin-angiotensin system in hypertensives. J Hum Hypertens. 2014. June;28(6):378–83. doi:
    1. Schlaifer JD, Wargovich TJ, O’Neill B, Mancini GB, Haber HE, Pitt B, et al. Effects of quinapril on coronary blood flow in coronary artery disease patients with endothelial dysfunction. TREND Investigators. Trial on Reversing Endothelial Dysfunction. Am J Cardiol. 1997. December;80(12):1594–7.
    1. Schwartzkopff B, Brehm M, Mundhenke M, Strauer BE. Repair of coronary arterioles after treatment with perindopril in hypertensive heart disease. Hypertension. 2000. August;36(2):220–5.
    1. Motz W, Strauer BE. Improvement of coronary flow reserve after long-term therapy with enalapril. Hypertension. 1996. May;27(5):1031–8.
    1. Neglia D, Fommei E, Varela-Carver A, Mancini M, Ghione S, Lombardi M, et al. Perindopril and indapamide reverse coronary microvascular remodelling and improve flow in arterial hypertension. J Hypertens. 2011. February;29(2):364–72. doi:
    1. Engholm M, Mulvany MJ, Eftekhari A, Mathiassen ON, Buus NH, Christensen KL. Positive effects of aggressive vasodilator treatment of well-treated essential hypertensive patients. J Hum Hypertens. 2016. November;30(11):690–6. doi:
    1. Kawata T, Daimon M, Hasegawa R, Teramoto K, Toyoda T, Sekine T, et al. Effect of angiotensin-converting enzyme inhibitor on serum asymmetric dimethylarginine and coronary circulation in patients with type 2 diabetes mellitus. Int J Cardiol. 2009. February;132(2):286–8. doi:
    1. Bakris GL, Slataper R, Vicknair N, Sadler R. ACE inhibitor mediated reductions in renal size and microalbuminuria in normotensive, diabetic subjects. J Diabetes Complications. 1994. March;8(1):2–6.
    1. Marre M, Chatellier G, Leblanc H, Guyene TT, Menard J, Passa P. Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ. 1988. October;297(6656):1092–5.
    1. Parving HH, Hommel E, Damkjaer Nielsen M, Giese J. Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ. 1989. August;299(6698):533–6.
    1. Elliott HL, Macdonald NJ, Meredith PA, Reid JL. Dose responses and pharmacokinetics for the angiotensin converting enzyme inhibitor quinapril. Clin Pharmacol Ther. 1992. March;51(3):260–5.
    1. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med. 1998. June;128(12 Pt 1):982–8.
    1. Mehlsen J, Jeppesen P, Erlandsen M, Poulsen PL, Bek T. Lack of effect of short-term treatment with amlodipine and lisinopril on retinal autoregulation in normotensive patients with type 1 diabetes and mild diabetic retinopathy. Acta Ophthalmol. 2011. December;89(8):764–8. doi:
    1. Kvetny J, Gregersen G, Pedersen RS. Randomized placebo-controlled trial of perindopril in normotensive, normoalbuminuric patients with type 1 diabetes mellitus. QJM Mon J Assoc Physicians. 2001. February;94(2):89–94.
    1. Naqvi SAJ, Ahsan S, Fawwad A, Basit A, Shera AS. Effect of angiotensin converting enzyme inhibitor on glomerular hyperfiltration in patients with type 1 diabetes. Pakistan J Med Sci. 2016. June;32(3):559–64.
    1. Krysiak R, Okopień B. Different effects of perindopril and enalapril on monocyte cytokine release in coronary artery disease patients with normal blood pressure. Pharmacol reports PR. 2012;64(6):1466–75.
    1. Mathiesen ER, Hommel E, Giese J, Parving HH. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ. 1991. July;303(6794):81–7.
    1. Sano T, Kawamura T, Matsumae H, Sasaki H, Nakayama M, Hara T, et al. Effects of long-term enalapril treatment on persistent micro-albuminuria in well-controlled hypertensive and normotensive NIDDM patients. Diabetes Care. 1994. May;17(5):420–4.
    1. Ravid M, Savin H, Jutrin I, Bental T, Lang R, Lishner M. Long-term effect of ACE inhibition on development of nephropathy in diabetes mellitus type II. Kidney Int Suppl. 1994. February;45:S161–164.
    1. Prescott E, Abildstrøm SZ, Aziz A, Merz NB, Gustafsson I, Halcox J, et al. Improving diagnosis and treatment of women with angina pectoris and microvascular disease: the iPOWER study design and rationale. Am Heart J. 2014. April;167(4):452–8. doi:
    1. Michelsen MM, Pena A, Mygind ND, Frestad D, Gustafsson I, Hansen HS, et al. Coronary Flow Velocity Reserve Assessed by Transthoracic Doppler: The iPOWER Study: Factors Influencing Feasibility and Quality. J Am Soc Echocardiogr. 2016. July; 29(7):709–16. doi:
    1. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, et al. Clinical Practice Guidelines for the Management of Hypertension in the Community: A Statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens. 2014. January;16(1):14–26.
    1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2013. October;62(16):e147–239. doi:
    1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000. January;342(3):145–53. doi:
    1. Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, et al. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol. 1995. February;25(2):333–41.
    1. Voigt J-U, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R, et al. Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J Cardiovasc Imaging. 2015. January;16(1):1–11. doi:
    1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification. Eur J Echocardiogr J Work Gr Echocardiogr Eur Soc Cardiol. 2006. March;7(2):79–108.
    1. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr J Work Gr Echocardiogr Eur Soc Cardiol. 2009. March;10(2):165–93.
    1. Michelsen MM, Mygind ND, Pena A, Olsen RH, Christensen TE, Ghotbi AA, et al. Transthoracic Doppler echocardiography compared with positron emission tomography for assessment of coronary microvascular dysfunction: The iPOWER study. Int J Cardiol. 2017. February;228:435–43. doi:
    1. Faber R, Zander M, Pena A, Michelsen MM, Mygind ND, Prescott E. Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes—a randomized, single-blinded, cross-over pilot study. Cardiovasc Diabetol. 2015;14:41 doi:
    1. Fitzmaurice Garrett M., Laird Nan M., Ware James H. Applied Longitudinal Analysis, 2nd Edition.
    1. Pizzi C, Manfrini O, Fontana F, Bugiardini R. Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in cardiac Syndrome X: role of superoxide dismutase activity. Circulation. 2004. January;109(1):53–8. doi:
    1. Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med. 2003. July;115(1):41–6.
    1. Yu W-C, Lin Y-P, Lin I-F, Chuang S-Y, Chen C-H. Effect of Ramipril on Left Ventricular Mass in Normotensive Hemodialysis Patients. Am J Kidney Dis. 2006. March;47(3):478–84. doi:

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