1

Restoring Sinus Rhythm: A Novel Antihypertensive Therapy?ANTONIO RAVIELE, M.D., F.E.S.C., F.H.R.S.

From ALFA-Alliance to Fight Atrial fibrillation, Venice, Italy

Editorial Comment

Hypertension and atrial fibrillation (AF) are 2 commonclinical disorders that often coexist. According to epidemio-logical studies, a significant proportion of hypertensive pa-tients (approximately 10%) have AF.1 Likewise, hyperten-sion is very frequent in AF patients, being found in up to65% of cases.2 Moreover, patients with concomitant hyper-tension and AF have an increased risk (2–3 times higher)of cardiovascular events, in particular of all-cause mortality,cardiovascular mortality, stroke, and congestive heart fail-ure.3,4 Because of this potentially dangerous relationship,it is essential in clinical practice to implement preventivemeasures to avoid AF in hypertensive patients and to loweradequately blood pressure in AF patients.

Hypertension as a Risk Factor for AF

It is common knowledge that hypertension is an impor-tant and well-established predictor of AF5: the higher theblood pressure, the greater the rate of occurrence of AF.6 Inthe Framingham study, after adjustment for other associatedconditions, people with hypertension had a 70–80% higherrisk of AF.7 The development of left ventricular hypertrophyin hypertensive patients further increases this risk.8,9 Sys-tolic blood pressure is a better predictor of AF than diastolicblood pressure.6 Interestingly, even systolic blood pressurevalues as low as 130 mmHg (below the current thresholdfor the diagnosis of hypertension) are independently associ-ated with AF.6 Moreover, high pulse pressure amplitude mayalso increase the risk of AF.10 This implies that preclinicalhypertension may commonly underlie AF, and suggests thattighter blood pressure control may be prudent in an attemptto prevent AF.11

The pathophysiological link between hypertension andAF can be explained by the structural and electrophysiologi-cal changes that elevated blood pressure induces in the heart,which are known as atrial remodeling. The most relevantof these changes are left atrial hypertrophy and dilatation(secondary to increased left atrial pressure), myolysis andcellular apoptosis, increased collagen content with patchyfibrosis (due in part to activation of the renin-angiotensin-aldosterone system), widespread conduction abnormalities,and increased refractoriness.12-14 All these changes act as a

J Cardiovasc Electrophysiol, Vol. pp. 1-2

Dr. Raviele reports serving as a consultant and/or on the medical advisoryboard of sanofi-aventis; he received honoraria relevant to this topic from thecompany.

Address for correspondence: Dr. Antonio Raviele, M.D., F.E.S.C., F.H.R.S.,via Torino 151/c, 30171 Mestre-Venice, Italy. Fax: +39 041 5329484;E-mail: araviele@tin.it

doi: 10.1111/j.1540-8167.2012.02330.x

substrate for the occurrence of AF. Once AF develops, itspresence hinders blood pressure control.15

To reduce the risk of new onset or recurrent AF and itsadverse consequences in hypertensive patients, the first andmost important step is to lower blood pressure to recom-mended levels. According to the literature data, all the vari-ous classes of medications to lower blood pressure are ableto do this.16,17 However, in patients with left ventricular hy-pertrophy, renin-angiotensin-aldosterone system inhibitors(angiotensin-converting enzyme inhibitors and angiotensinreceptor blockers) seem to confer better protection than theother antihypertensive agents.18,19

AF as a Possible Cause of Hypertension

AF may not only be the effect of hypertension; it mayalso contribute to its development and maintenance. This isa relatively new notion that has emerged from the originalresearch on the relationship between hypertension and AFthat Hamdan et al. have systematically conducted in recentyears.20-22

In this issue of the Journal of Cardiovascular Electro-physiology, the Salt Lake City group adds new informationto this topic.23 In a case-control study, these authors exam-ined the effects of sinus rhythm restoration in 18 patients withpersistent AF and hypertension. Three 24-hour blood pres-sure measurements were taken: before (within 1 week), onday 1 and on day 30 after successful electrical cardioversion.A significant decrease in diastolic and mean blood pressurewas observed in patients who remained in sinus rhythm onday 30. By contrast, in a control group of 22 patients withpersistent AF and hypertension who did not undergo car-dioversion, no significant changes in blood pressure valueswere found on using the same protocol. These results suggestthat AF may increase blood pressure and that this effect isreversed when sinus rhythm is restored.23

The most likely explanation for the AF-associated rise inblood pressure is an increase in sympathetic activity, whichis further accentuated by the irregular ventricular responseduring AF. Indeed, according to previous papers by the samegroup, sympathetic nerve activity is higher during inducedAF than during normal sinus rhythm, and is significantlyhigher during irregular atrial pacing than during regular atrialpacing.20,21 Other possible factors that may contribute tothe AF-induced increase in blood pressure are the activa-tion of the renin-angiotensin-aldosterone system12,24 and theendothelial dysfunction reported in patients with AF.25

However, regardless of the mechanism responsible for theAF-induced increase in blood pressure, the results reportedin the paper by Sanders et al. constitute another argument infavor of a rhythm control strategy in hypertensive patients.Indeed, if the restoration of sinus rhythm really determines areduction in blood pressure in such patients, ideally it shouldbe pursued in an attempt to reduce the risk of hypertension-associated complications. In any case, it remains to be

2 Journal of Cardiovascular Electrophysiology Vol. No.

established which therapeutic tools (drugs or ablation) shouldbe used after successful cardioversion in order not to lose thebenefits conferred by the restoration of sinus rhythm.

It should, however, be pointed out that the study carriedout by Sanders et al. has 2 important limitations: its nonran-domized design and the relatively small number of patientsenrolled. The results must therefore be regarded as prelimi-nary and need to be confirmed by rigorously conducted ran-domized trials involving a sufficiently large population ofpatients.

Meanwhile, Sanders et al. should be congratulated fortheir efforts to clarify the relationship between hyperten-sion and AF and for their original hypothesis that AF maybe not only the consequence but also a possible cause ofhypertension.

References

1. Morillas P, Pallares V, Llisterri JL, Sanchis C, Sanchez T, Facila L,Perez-Alonso M, Castillo J, Redon J, Bertomeu V; FAPRES RegistryResearchers: Prevalence of atrial fibrillation and use of antithromboticsin hypertensive patients aged > or = 65 years. The FAPRES trial. RevEsp Cardiol 2010;63:943-950.

2. Nieuwlaat R, Capucci A, Camm AJ, Olsson SB, Andresen D, DaviesDW, Cobbe S, Breithardt G, Le Heuzey JY, Prins MH, Levy S, CrijnsHJ; European Heart Survey Investigators: Atrial fibrillation manage-ment: A prospective survey in ESC member countries: The Euro heartsurvey on atrial fibrillation. Eur Heart J 2005;26:2422-2434.

3. Schneider MP, Hua TA, Bohm M, Wachtell K, Kjeldsen SE, SchmiederRE: Prevention of atrial fibrillation by renin–angiotensin system inhi-bition a meta-analysis. J Am Coll Cardiol 2010;55:2299-2307.

4. Wachtell K, Hornestam B, Lehto M, Slotwiner DJ, Gerdts E, OlsenMH, Aurup P, Dahlof B, Ibsen H, Julius S, Kjeldsen SE, Lindholm LH,Nieminen MS, Rokkedal J, Devereux RB: Cardiovascular morbidityand mortality in hypertensive patients with a history of atrial fibrilla-tion: The Losartan intervention for end point reduction in hypertension(LIFE) study. J Am Coll Cardiol 2005;45:705-711.

5. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, WolfPA: Independent risk factors for atrial fibrillation in a population-basedcohort. The Framingham heart study. JAMA 1994;271:840-844.

6. Conen D, Tedrow UB, Koplan BA, Glynn RJ, Buring JE, Albert CM:Influence of systolic and diastolic blood pressure on the risk of incidentatrial fibrillation in women. Circulation 2009;119:2146-2152.

7. Kannel WB, Wolf PA, Benjamin EJ, Levy D: Prevalence, inci-dence, prognosis, and predisposing conditions for atrial fibrillation:Population-based estimates. Am J Cardiol 1998;82:2N-9N.

8. Verdecchia P, Reboldi R, Gattobigio R, Bentivoglio M, Borgioni C,Angeli F, Carluccio E, Sardone MG, Porcellati C: Atrial fibrillationin hypertension: Predictors and outcome. Hypertension 2003;41:218-223.

9. Wachtell K, Lehto M, Gerdts E, Olsen MH, Hornestam B, Dahlof B,Ibsen H, Julius S, Kjeldsen SE, Lindholm LH, Nieminen MS, Dev-ereux RB: Angiotensin II receptor blockade reduces new-onset atrialfibrillation and subsequent stroke compared to atenolol: The Losartanintervention for end point reduction in hypertension (LIFE) study. JAm Coll Cardiol 2005;45:712-719.

10. Mitchell GF, Vasan RS, Keyes MJ, Parise H, Wang TJ, Larson MG,D’Agostino RB Sr, Kannel WB, Levy D, Benjamin EJ: Pulse pressureand risk of new-onset atrial fibrillation. JAMA 2007;297:709-715.

11. Kirchhof P, Lip GY, Van Gelder IC, Bax J, Hylek E, Kaab S, Schot-ten U, Wegscheider K, Boriani G, Brandes A, Ezekowitz M, DienerH, Haegeli L, Heidbuchel H, Lane D, Mont L, Willems S, Dorian

P, Aunes-Jansson M, Blomstrom-Lundqvist C, Borentain M, Breiten-stein S, Brueckmann M, Cater N, Clemens A, Dobrev D, Dubner S,Edvardsson NG, Friberg L, Goette A, Gulizia M, Hatala R, Horwood J,Szumowski L, Kappenberger L, Kautzner J, Leute A, Lobban T, MeyerR, Millerhagen J, Morgan J, Muenzel F, Nabauer M, Baertels C, OeffM, Paar D, Polifka J, Ravens U, Rosin L, Stegink W, Steinbeck G,Vardas P, Vincent A, Walter M, Breithardt G, Camm AJ: Comprehen-sive risk reduction in patients with atrial fibrillation: Emerging diag-nostic and therapeutic options—A report from the 3rd atrial fibrillationcompetence NETwork/European heart rhythm association consensusconference. Europace 2012;14:8-27.

12. Kistler PM, Sanders P, Dodic M, Spence SJ, Samuel CS, Zhao C,Charles JA, Edwards GA, Kalman JM: Atrial electrical and structuralabnormalities in an ovine model of chronic blood pressure elevationafter prenatal corticosteroid exposure: Implications for development ofatrial fibrillation. Eur Heart J 2006;27:3045-3056

13. Lau DH, Mackenzie L, Kelly DJ, Psaltis PJ, Worthington M, RajendramA, Kelly DR, Nelson AJ, Zhang Y, Kuklik P, Brooks AG, Worthley SG,Faull RJ, Rao M, Edwards J, Saint DA, Sanders P: Short-term hyperten-sion is associated with the development of atrial fibrillation substrate: Astudy in an ovine hypertensive model. Heart Rhythm 2010;7:396-404.

14. Medi C, Kalman JM, Spence SJ, Teh AW, Lee G, Bader I, KayeDM, Kistler PM: Atrial electrical and structural changes associatedwith longstanding hypertension in humans: Implications for the sub-strate for atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:1317-1334.

15. Barrios V, Escobar C, Echarri R: Atrial fibrillation and coronary arterydisease: Fatal attraction. J Atrial Fibrill 2009;1:262-269.

16. Schaer BA, Schneider C, Jick SS, Conen D, Osswald S, Meier CR: Riskfor incident atrial fibrillation in patients who receive antihypertensivedrugs: A nested case-control study. Ann Intern Med 2010;152:78-84.

17. Barrios V, Escobar C: Risk alteration for atrial fibrillation with differentantihypertensive drugs. J Atrial Fibrill 2011;2:1-13.

18. Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, YusufS, Connolly SJ: Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Ameta-analysis. J Am Coll Cardiol 2005;45:1832-1839.

19. Okin PM, Wachtell K, Devereux RB, Harris KE, Jern S, Kjeldsen SE,Julius S, Lindholm LH, Nieminen MS, Edelman JM, Hille DA, DahlofB: Regression of electrocardiographic left ventricular hypertrophy anddecreased incidence of new-onset atrial fibrillation in patients withhypertension. JAMA 2006;296:1242-1248.

20. Wasmund SL, Li JM, Page RL, Joglar JA, Kowal RC, Smith ML,Hamdan MH: Effect of atrial fibrillation and an irregular ventricularresponse on sympathetic nerve activity in human subjects. Circulation2003;107:2011-2015.

21. Segerson NM, Sharma N, Smith ML, Wasmund SL, Kowal RC, AbedinM, Macgregor JF, Pai RK, Freedman RA, Klein RC, Wall TS, StoddardG, Hamdan MH: The effects of rate and irregularity on sympatheticnerve activity in human subjects. Heart Rhythm 2007;4:20-26.

22. Masood SO, Wasmund SL, Akoum NW, Egger MJ, Hsiai T, HamdanMH: The effects of rate and rhythm control on blood pressure andantihypertensive drug usage in patients with atrial fibrillation and hy-pertension enrolled in the AFFIRM trial. J Cardiovasc Electrophysiol2010;21:1094-1098.

23. Sanders NA, Bertolone C, Jetter TL, Wasmund SL, Croci F, Solano A,Brignole M, Hamdan WH: Restoring sinus rhythm results in blood pres-sure reduction in patients with persistent atrial fibrillation and a historyof hypertension. J Cardiovasc Electrophysiol; DOI:10.1111/j.1540–8167.2012.02280.x

24. Dixen U, Ravn L, Soeby-Rasmussen C, Paulsen AW, Parner J, FrandsenE, Jensen GB: Raised plasma aldosterone and natriuretic peptides inatrial fibrillation. Cardiology 2007;108:35-39.

25. Raviele A, Ronco F: Endothelial dysfunction and atrial fibrillation:What is the relationship? J Cardiovasc Electrophysiol 2011;22:383-384.