Download PDF
Int J Angiol 2021; 30(02): 122-131
DOI: 10.1055/s-0041-1723948
Original Article

l-Arginine Can Enhance the Beneficial Effect of Losartan in Patients with Chronic Aortic Regurgitation and Isolated Systolic Hypertension

Shoa-Lin Lin‡   *
1   Division of Cardiology, Yuan's General Hospital, Kaohsiung City, Taiwan
,
Mike Lin‡   *
2   Department of Medicine, Gou-Zen Hospital, Pingtong City, Taiwan
,
Kuei-Liang Wang
3   An-Fa Institution of Preventive Medicine, Taipei, Taiwan
,
Hsien-Wen Kuo
4   Institute of Occupation and Environment Health Science, National Yang-Ming University, Taipei, Taiwan
,
Tahir Tak
5   Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
› Author Affiliations Funding An-Fa Institution of Preventive Medicine
AFSR 2010-2
Yuan's General Hospital, Kaohsiung City, Taiwan
YGH17 - 010
› Further Information
    Permissions and Reprints

Abstract

Information about the effects of angiotensin II receptor blocker (ARB) therapy on the hemodynamic and cardiac structure in patients with chronic aortic regurgitation (CAR) and isolated systolic hypertension (ISH) is limited.

This study planned to test the hypothesis that l-arginine could further enhance the beneficial effect of an ARB, losartan, and provide a favorable effect on the natural history of CAR and ISH.

Sixty patients with CAR and ISH were enrolled in a randomized, double-blind trial comparing hemodynamic and ultrasonic change in two treatment arms: losartan + l-arginine and losartan-only treated groups. Serial echocardiographic and hemodynamic studies were evaluated before and after treatment.

Both groups had a significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP), left ventricular end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), LV mass index (LVMI), and LV mean wall stress after 6- and 12-month treatment (p <0.01 in all comparisons). Both groups had a significant increase in LV ejection fraction and exercise duration after 6- and 12-month treatment (p < 0.01 in all comparisons). Using multivariate linear regression analysis, only losartan + l-arginine therapy achieved a significantly lower LVESVI (38.89 ± 0.23 mL/m2), LVEDVI (102.3 ± 0.3 mL/m2), LVMI (107.6 ± 0.3 g/m2), SBP (123.5 ± 1.0 mm Hg), and greater exercise duration (7.38 ± 0.02 minutes) than those of the losartan-only treated groups (p <0.01 in all comparisons).

These findings suggest that early co-administrative strategy provides a beneficial approach to favorably influence the natural history of CAR.

Keywords

aortic regurgitation - isolated systolic hypertension - left ventricular mass - echocardiography - l-arginine

Disclosures

All authors have no conflicts of interest to disclose.


* Contributed equally to this work.




Publication History

Article published online:
11 May 2021

© 2021. International College of Angiology. This article is published by Thieme.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Mahajerin A, Gurm HS, Tsai TT, Chan PS, Nallamothu BK. Vasodilator therapy in patients with aortic insufficiency: a systematic review. Am Heart J 2007; 153 (04) 454-461
    CrossrefPubMedGoogle Scholar
  • 2 Bonow RO, Rosing DR, McIntosh CL. et al. The natural history of asymptomatic patients with aortic regurgitation and normal left ventricular function. Circulation 1983; 68 (03) 509-517
    CrossrefPubMedGoogle Scholar
  • 3 Lin M, Chiang HT, Lin SL. et al. Vasodilator therapy in chronic asymptomatic aortic regurgitation: enalapril versus hydralazine therapy. J Am Coll Cardiol 1994; 24 (04) 1046-1053
    CrossrefPubMedGoogle Scholar
  • 4 Scognamiglio R, Fasoli G, Ponchia A, Dalla-Volta S. Long-term nifedipine unloading therapy in asymptomatic patients with chronic severe aortic regurgitation. J Am Coll Cardiol 1990; 16 (02) 424-429
    CrossrefPubMedGoogle Scholar
  • 5 Greenberg B, Massie B, Bristow JD. et al. Long-term vasodilator therapy of chronic aortic insufficiency. A randomized double-blinded, placebo-controlled clinical trial. Circulation 1988; 78 (01) 92-103
    CrossrefPubMedGoogle Scholar
  • 6 Scognamiglio R, Rahimtoola SH, Fasoli G, Nistri S, Dalla Volta S. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med 1994; 331 (11) 689-694
    CrossrefPubMedGoogle Scholar
  • 7 Willenheimer R, Dahlöf B, Rydberg E, Erhardt L. AT1-receptor blockers in hypertension and heart failure: clinical experience and future directions. Eur Heart J 1999; 20 (14) 997-1008
    CrossrefPubMedGoogle Scholar
  • 8 Chobanian AV, Bakris GL, Black HR. et al. The Seventh Report of the Joint National Committee Blood Pressure: the JNC 7 report. JAMA 2003; 289 (19) 2560-2572
    CrossrefPubMedGoogle Scholar
  • 9 Plante E, Lachance D, Beaudoin J. et al. Comparative study of vasodilators in an animal model of chronic volume overload caused by severe aortic regurgitation. Circ Heart Fail 2009; 2 (01) 25-32
    CrossrefPubMedGoogle Scholar
  • 10 Roberts PA, Lin ACW, Cowan BR, Young AA, Stewart R. Comparison of effects of losartan and metoprolol on left ventricular and aortic function at rest and during exercise in chronic aortic regurgitation. Int J Cardiovasc Imaging 2018; 34 (04) 615-624
    CrossrefPubMedGoogle Scholar
  • 11 Koifman B, Topilski I, Megidish R. et al. Effects of losartan + L-arginine on nitric oxide production, endothelial cell function, and hemodynamic variables in patients with heart failure secondary to coronary heart disease. Am J Cardiol 2006; 98 (02) 172-177
    CrossrefPubMedGoogle Scholar
  • 12 Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329 (27) 2002-2012
    CrossrefPubMedGoogle Scholar
  • 13 Siani A, Pagano E, Iacone R, Iacoviello L, Scopacasa F, Strazzullo P. Blood pressure and metabolic changes during dietary L-arginine supplementation in humans. Am J Hypertens 2000; 13 (5 Pt 1): 547-551
    CrossrefPubMedGoogle Scholar
  • 14 Böger RH, Bode-Böger SM. The clinical pharmacology of L-arginine. Annu Rev Pharmacol Toxicol 2001; 41: 79-99
    CrossrefPubMedGoogle Scholar
  • 15 Böger RH, Bode-Böger SM, Frölich JC. The L-arginine-nitric oxide pathway: role in atherosclerosis and therapeutic implications. Atherosclerosis 1996; 127 (01) 1-11
    CrossrefPubMedGoogle Scholar
  • 16 Zoghbi WA, Enriquez-Sarano M, Foster E. et al; American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003; 16 (07) 777-802
    CrossrefPubMedGoogle Scholar
  • 17 Lang RM, Badano LP, Mor-Avi V. et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015; 28 (01) 1-39.e14
    CrossrefPubMedGoogle Scholar
  • 18 Quinones MA, Mokotoff DM, Nouri S, Winters Jr WL, Miller RR. Noninvasive quantification of left ventricular wall stress. Validation of method and application to assessment of chronic pressure overload. Am J Cardiol 1980; 45 (04) 782-790
    CrossrefPubMedGoogle Scholar
  • 19 Lang RM, Bierig M, Devereux RB. et al; Chamber Quantification Writing Group, American Society of Echocardiography's Guidelines and Standards Committee, European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography's guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18 (12) 1440-1463
    CrossrefPubMedGoogle Scholar
  • 20 Chirinos JA, Segers P, De Buyzere ML. et al. Left ventricular mass: allometric scaling, normative values, effect of obesity, and prognostic performance. Hypertension 2010; 56 (01) 91-98
    CrossrefPubMedGoogle Scholar
  • 21 Yano Y, Stamler J, Garside DB. et al. Isolated systolic hypertension in young and middle-aged adults and 31-year risk for cardiovascular mortality: the Chicago Heart Association Detection Project in Industry study. J Am Coll Cardiol 2015; 65 (04) 327-335
    CrossrefPubMedGoogle Scholar
  • 22 Bavishi C, Goel S, Messerli FH. Isolated systolic hypertension: an update after SPRINT. Am J Med 2016; 129 (12) 1251-1258
    CrossrefPubMedGoogle Scholar
  • 23 Mancia G, Fagard R, Narkiewicz K. et al. 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). Eur Heart J 2013; 34 (28) 2159-2219
    CrossrefPubMedGoogle Scholar
  • 24 Whelton PK, Carey RM, Aronow WS. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018; 138 (17) e484-e594
    PubMedGoogle Scholar
  • 25 Perry GJ, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol 1987; 9 (04) 952-959
    CrossrefPubMedGoogle Scholar
  • 26 Scognamiglio R, Negut C, Palisi M, Fasoli G, Dalla-Volta S. Long-term survival and functional results after aortic valve replacement in asymptomatic patients with chronic severe aortic regurgitation and left ventricular dysfunction. J Am Coll Cardiol 2005; 45 (07) 1025-1030
    CrossrefPubMedGoogle Scholar
  • 27 Acar J, Michel PL, Luxereau P. et al. How to manage patients with severe left ventricular dysfunction and valvular regurgitation. J Heart Valve Dis 1996; 5 (04) 421-429
    PubMedGoogle Scholar
  • 28 Klodas E, Enriquez-Sarano M, Tajik AJ, Mullany CJ, Bailey KR, Seward JB. Optimizing timing of surgical correction in patients with severe aortic regurgitation: role of symptoms. J Am Coll Cardiol 1997; 30 (03) 746-752
    CrossrefPubMedGoogle Scholar
  • 29 Dujardin KS, Enriquez-Sarano M, Schaff HV, Bailey KR, Seward JB, Tajik AJ. Mortality and morbidity of aortic regurgitation in clinical practice. A long-term follow-up study. Circulation 1999; 99 (14) 1851-1857
    CrossrefPubMedGoogle Scholar
  • 30 Henry WL, Bonow RO, Rosing DR, Epstein SE. Observations on the optimum time for operative intervention for aortic regurgitation. II. Serial echocardiographic evaluation of asymptomatic patients. Circulation 1980; 61 (03) 484-492
    CrossrefPubMedGoogle Scholar
  • 31 Scognamiglio R, Fasoli G, Dalla Volta S. Progression of myocardial dysfunction in asymptomatic patients with severe aortic insufficiency. Clin Cardiol 1986; 9 (04) 151-156
    CrossrefPubMedGoogle Scholar
  • 32 Henry WL, Bonow RO, Borer JS. et al. Observations on the optimum time for operative intervention for aortic regurgitation. I. Evaluation of the results of aortic valve replacement in symptomatic patients. Circulation 1980; 61 (03) 471-483
    CrossrefPubMedGoogle Scholar
  • 33 Nishimura RA, Otto CM, Bonow RO. et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63 (22) 2438-2488
    CrossrefPubMedGoogle Scholar
  • 34 Iung B, Gohlke-Bärwolf C, Tornos P. et al; Working Group on Valvular Heart Disease. Recommendations on the management of the asymptomatic patient with valvular heart disease. Eur Heart J 2002; 23 (16) 1253-1266
    CrossrefPubMedGoogle Scholar
  • 35 Tsioufis C, Stougiannos P, Kakkavas A. et al. Relation of left ventricular concentric remodeling to levels of C-reactive protein and serum amyloid A in patients with essential hypertension. Am J Cardiol 2005; 96 (02) 252-256
    CrossrefPubMedGoogle Scholar
  • 36 Schillaci G, Verdecchia P, Porcellati C, Cuccurullo O, Cosco C, Perticone F. Continuous relation between left ventricular mass and cardiovascular risk in essential hypertension. Hypertension 2000; 35 (02) 580-586
    CrossrefPubMedGoogle Scholar
  • 37 Lin M. Reappraisal of L-arginine in the field of cardiovascular medicine for clinical applications and pharmacology: an update. J Intern Med Taiwan 2007; 18: 225-235
    PubMedGoogle Scholar
  • 38 Morris Jr SM. Enzymes of arginine metabolism. J Nutr 2004; 134 (10, Suppl) 2743S-2747S, discussion 2765S–2767S
    CrossrefPubMedGoogle Scholar
  • 39 Jabecka A, Ast J, Bogdaski P. et al. Oral L-arginine supplementation in patients with mild arterial hypertension and its effect on plasma level of asymmetric dimethylarginine, L-citruline, L-arginine and antioxidant status. Eur Rev Med Pharmacol Sci 2012; 16 (12) 1665-1674
    PubMedGoogle Scholar
  • 40 Ast J, Jabłecka A, Bogdański P, Smolarek I, Krauss H, Chmara E. Evaluation of the antihypertensive effect of L-arginine supplementation in patients with mild hypertension assessed with ambulatory blood pressure monitoring. Med Sci Monit 2010; 16 (05) CR266-CR271
    PubMedGoogle Scholar
  • 41 Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 1991; 338 (8782-8783): 1546-1550
    CrossrefPubMedGoogle Scholar
  • 42 Hambrecht R, Hilbrich L, Erbs S. et al. Correction of endothelial dysfunction in CHF: additional effect of exercise training and oral L-arginine supplementation. J Am Coll Cardiol 2000; 35 (03) 706-713
    CrossrefPubMedGoogle Scholar
  • 43 Reske SN, Heck I, Kropp J. et al. Captopril mediated decrease of aortic regurgitation. Br Heart J 1985; 54 (04) 415-419
    CrossrefPubMedGoogle Scholar
  • 44 Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 2003; 24 (03) 261-271
    CrossrefPubMedGoogle Scholar
  • 45 Grinstead WC, Young JB. The myocardial renin-angiotensin system: existence, importance, and clinical implications. Am Heart J 1992; 123 (4 Pt 1): 1039-1045
    CrossrefPubMedGoogle Scholar
  • 46 Katz AM. Angiotensin II: hemodynamic regulator or growth factor?. J Mol Cell Cardiol 1990; 22 (07) 739-747
    CrossrefPubMedGoogle Scholar
  • 47 Hoi Y, Zhou YQ, Zhang X, Henkelman RM, Steinman DA. Correlation between local hemodynamics and lesion distribution in a novel aortic regurgitation murine model of atherosclerosis. Ann Biomed Eng 2011; 39 (05) 1414-1422
    CrossrefPubMedGoogle Scholar
  • 48 Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep 2010; 12 (06) 448-455
    CrossrefPubMedGoogle Scholar
  • 49 Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation 2000; 101 (14) 1653-1659
    CrossrefPubMedGoogle Scholar
  • 50 Vacher E, Richer C, Giudicelli J-F. Effects of losartan on cerebral arteries in stroke-prone spontaneously hypertensive rats. J Hypertens 1996; 14 (11) 1341-1348
    CrossrefPubMedGoogle Scholar
  • 51 Lerman A, Burnett Jr JC, Higano ST, McKinley LJ, Holmes Jr DR. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998; 97 (21) 2123-2128
    CrossrefPubMedGoogle Scholar
  • 52 Chen PY, Sanders PW. L-arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats. J Clin Invest 1991; 88 (05) 1559-1567
    CrossrefPubMedGoogle Scholar
  • 53 Patel A, Layne S, Watts D, Kirchner KA. L-arginine administration normalizes pressure natriuresis in hypertensive Dahl rats. Hypertension 1993; 22 (06) 863-869
    CrossrefPubMedGoogle Scholar