Journal of Hypertension:
Hypertension, inflammation and atrial fibrillation
Angeli, Fabioa; Reboldi, Gianpaolob; Verdecchia, Paoloc
aDivision of Cardiology and Cardiovascular Pathophysiology, Teaching Hospital ‘S.M. della Misericordia’, Perugia
bDepartment of Internal Medicine, University of Perugia, Perugia
cDepartment of Internal Medicine, Hospital of Assisi, Assisi, Italy
Correspondence to Fabio Angeli, MD, Division of Cardiology and Cardiovascular Pathophysiology, Teaching Hospital ‘S.M. della Misericordia’, 06100 Perugia, Italy. Tel: +39-075-5782394; fax: +39-075-5271509; e-mail: email@example.com
Atrial fibrillation is the most common cardiac arrhythmia in clinical practice and is a major risk factor for stroke and mortality . It affects approximately 1–2% of the general population, being a disease of aging [2,3]. Its incidence doubles with each decade after 50 years, and its prevalence increases from 0.1% for those below 50 years of age to between 7.3 and 13.7% for those above 80 years of age . Atrial fibrillation is responsible for 15% of strokes overall and 25% of strokes in individuals above 80 years of age [4,5]. Atrial fibrillation is also associated with an increase in the relative risk (RR) of mortality (ranging from 1.3 to 2.4, independent of other risk factors), and adversely affects quality of life [6,7]. Notably, patients who present with stroke in atrial fibrillation have a considerably worse outcome, defined by a higher mortality and morbidity and longer hospital stays, compared with patients who have a stroke in the absence of atrial fibrillation [8,9].
Several clinical conditions such as valvular heart disease, hypertension, diabetes, coronary artery disease (CAD), congestive heart failure (CHF), and obesity are well established risk factors for the development of atrial fibrillation. Nevertheless, hypertension is the most prevalent, independent, and potentially modifiable risk factor for atrial fibrillation . Although the RR of developing atrial fibrillation in patients with hypertension is modest when compared with other conditions (i.e. CHF and valvular disease), because almost 25–30% of people in the developed countries have high blood pressure (BP) [10–12], hypertension accounts for more cases of atrial fibrillation than any other risk factor [13–16]. Cohort studies showed that hypertension was present in up to 53% of patients with atrial fibrillation and was causative in 15% [2,17]. Similarly, hypertension was highly present in individuals enrolled in major atrial fibrillation clinical trials [18–21]. In general population studies, hypertension was an independent risk factor for atrial fibrillation. The risk of atrial fibrillation in hypertensive individuals compared with normotensive individuals was increased by 1.9 times in the Framingham Heart Study  and 1.4 times in the Manitoba Follow-up Study . In addition to its role as a risk factor for the development of atrial fibrillation, the presence of hypertension significantly increases the risk of stroke in patients with atrial fibrillation: patients with atrial fibrillation show a three-fold to six-fold increase in stroke risk compared with the general population , and the coexistence of hypertension worsens the stroke rate by an additional two-fold to three-fold [23,24].
The pathophysiological mechanisms underlying the link between hypertension and atrial fibrillation are complex and incompletely understood. However, it is now recognized that hypertension, especially if untreated or suboptimally treated, leads to the development of structural changes of the left ventricle and the left atrium that are associated with atrial fibrillation. They include left ventricular (LV) hypertrophy and left atrial enlargement, with subsequent altered mechanical and electrical functions [5,25]. With the development of LV hypertrophy (Fig. 1), there is an enhanced connective tissue deposition and fibrosis, LV compliance is reduced, LV filling pressure and wall stress increase, coronary flow reserve is decreased, and there is the activation of the renin–angiotensin–aldosterone system (RAAS) [25,26]. Similarly, electrical and structural remodeling of the left atrium is a key step in the progression from hypertension to atrial fibrillation. In particular, two distinct abnormalities in atrial electrical properties occur early in hypertensive heart disease and are associated with the development and maintenance of atrial fibrillation: the prolongation of atrial conduction velocity as assessed by the signal-averaged P-wave duration and the decrease in atrial refractoriness [27,28]. There is also accumulation of calcium within atrial myocytes, leading to a reduction of the inward L-type Ca2+ current, which in turn contributes to the shortening of the atrial effective refractory period and the promotion and maintenance of multiple wavelet-re-entry circuits  (Fig. 2). In addition, structural remodeling of the atria occurs in parallel with the changes of electrical remodeling. These structural changes include dilatation and increasing atrial fibrosis . Key to this fibrotic process is the deposition of increased amounts of connective tissue between individual cells and with the deposition of large amounts of collagen and fibronectin . This leads to separation of myocites from one another and subsequent impairment of atrial conduction at the microscopic level. These changes culminate in alterations in the biophysical properties of atrial tissue, allowing the initiation and perpetuation of atrial fibrillation  (Fig. 2).
From an epidemiological standpoint, some clinical studies confirmed the role of LV hypertrophy and left atrial enlargement as predictors of atrial fibrillation. For example, in a study by Ciaroni et al., 97 consecutive patients with hypertension who attended a cardiology outpatients clinic were followed for a mean of 25 months, and 19 patients subsequently developed atrial fibrillation. In the multivariable analysis, age, daytime SBP, echocardiographic LV mass, and left atrial dimension were independent predictors for the onset of atrial fibrillation. More recently, a report from the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale study showed that in a large cohort of hypertensive patients, left atrial enlargement and LV mass were independent predictors of atrial fibrillation .
Interestingly, inflammation acts as a catalyst to the remodeling processes of left ventricle and left atrium and is a stimulus for increased RAAS activity and production of angiotensin II .
Some studies showed that chronic inflammation, estimated by high C reactive protein (CRP) levels, is associated with LV hypertrophy occurrence independent of several other important factors, such as adipose tissue distribution, hemodynamic factors, presence of diabetes and CAD, serum lipids, renal function, age, and sex [35,36].
Moreover, results of atrial biopsies taken from patients in atrial fibrillation compared with controls have demonstrated evidence of inflammatory infiltrates and oxidative damage within the atrial tissue [37,38]. In particular, one of these studies documented abnormal atrial histology in 12 patients with lone atrial fibrillation, compared with normal histology in all of the controls, with 66% of the atrial fibrillation group showing evidence of occult myocarditis .
Finally, there is histological evidence to support a potential link between inflammation, the RAAS, and atrial fibrillation. Both inflammation and atrial fibrillation have been shown to upregulate angiotensin receptors [39,40], and an experimental canine model linked increased atrial expression of angiotensin II receptors with increased atrial cell death and leukocyte infiltration .
At this regard, the new posthoc analysis of the Losartan Intervention For Endpoint reduction in hypertension study , published in this issue of the Journal, adds further evidence linking atrial fibrillation with inflammatory conditions in hypertension.
Historically, the clinical association between atrial fibrillation and inflammation is supported by the frequent association of atrial fibrillation with inflammatory diseases of the heart, such as myocarditis and pericarditis [43,44] and by the evidence that the peak incidence of atrial fibrillation occurs on the second and third postoperative days, which coincide with the peak elevation of CRP levels . With their analysis, Bang et al.  extended these evidence among hypertensive patients noting that atrial fibrillation is linked with systemic inflammatory disease such as psoriasis. Specifically, they observed that psoriasis was associated with an increased risk of new-onset atrial fibrillation (hazard ratio: 1.74; 95% confidence interval: 1.06–2.86, P = 0.029). Such association was independent of other risk factors for the development of atrial fibrillation, including age, sex, diabetes, BP, incident CHF, left atrial size, and LV hypertrophy . Although intriguing, this analysis is limited by its posthoc nature and by the modest number of atrial fibrillation cases observed during follow-up. In particular, only 17 (11%) patients in the psoriasis group (n = 154) developed new-onset atrial fibrillation. We should also consider other aspects. The study by Bang et al. did not address the value of psoriasis over and behind inflammatory markers, whether assessed by serum or plasma indices. Consequently, the results do not inform us on whether the link between psoriasis and atrial fibrillation is merely association or causal in the complex pathophysiology of this arrhythmia.
Finally, emerging data supporting the association between inflammation and atrial fibrillation created exciting potential opportunities to target inflammatory processes for the prevention of atrial fibrillation. In particular, there is evidence supporting the use of some drug therapies, such as RAAS-blockers and statins, to prevent atrial fibrillation by modulating inflammatory pathways [15,46]. Although Bang et al.  did not find any interaction between randomized treatment (losartan vs. atenolol) and psoriasis in predicting new-onset atrial fibrillation, the number of patients with psoriasis at baseline is not large enough to show what contribution individual antihypertensive agents may have had on the risk of atrial fibrillation.
This study was funded in part by the Fondazione Umbra Cuore e Ipertensione – ONLUS, Perugia, Italy.
Conflicts of interest
None of the authors of this study has financial or other reasons that could lead to a conflict of interest.
1. Wilhelmsen L, Rosengren A, Lappas G. Hospitalizations for atrial fibrillation in the general male population: morbidity and risk factors. J Intern Med
2. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol
3. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention – The anticoagulation and risk factors in atrial fibrillation (atria) study. JAMA
4. Wolf PA, Dawber TR, Thomas HE Jr, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The framingham study. Neurology
5. Hart RG, Coull BM, Hart D. Early recurrent embolism associated with nonvalvular atrial fibrillation: a retrospective study. Stroke
6. Lehto M, Snapinn S, Dickstein K, Swedberg K, Nieminen MS. Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the optimal experience. Eur Heart J
7. Gronefeld GC, Lilienthal J, Kuck KH, Hohnloser SH. Impact of rate versus rhythm control on quality of life in patients with persistent atrial fibrillation. Results from a prospective randomized study. Eur Heart J
8. Steger C, Pratter A, Martinek-Bregel M, Avanzini M, Valentin A, Slany J, Stollberger C. Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke Registry. Eur Heart J
9. Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the international stroke trial. Stroke
10. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res
11. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, 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). J Hypertens
12. Verdecchia P, Angeli F. The Seventh Report Of The Joint National Committee On The Prevention, Detection, Evaluation And Treatment Of High Blood Pressure: the weapons are ready. Rev Esp Cardiol
13. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med
14. Wong ND, Lopez VA, L’Italien G, Chen R, Kline SE, Franklin SS. Inadequate control of hypertension in US adults with cardiovascular disease comorbidities in 2003-2004. Arch Intern Med
15. Manolis AJ, Rosei EA, Coca A, Cifkova R, Erdine SE, Kjeldsen S, et al. Hypertension and atrial fibrillation: diagnostic approach, prevention and treatment. Position paper of the working group ’hypertension arrhythmias and thrombosis’ of the European Society Of Hypertension. J Hypertens
16. Verdecchia P, Angeli F. Natural history of hypertension subtypes. Circulation
17. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: The Framingham Study. N Engl J Med
18. Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: The Strategies Of Treatment Of Atrial Fibrillation (STAF) Study. J Am Coll Cardiol
19. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med
20. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med
21. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med
22. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke
23. Tohgi H, Tajima T, Konno T, Towada S, Kamata A, Yamazaki M. The risk of cerebral infarction in nonvalvular atrial fibrillation: effects of age, hypertension and antihypertensive treatment. Eur Neurol
24. Vaziri S, Bikkina M, Levy D. Predictors of thromboembolism in atrial fibrillation. Ann Intern Med
25. Verdecchia P, Angeli F, Achilli P, Castellani C, Broccatelli A, Gattobigio R, Cavallini C. Echocardiographic left ventricular hypertrophy in hypertension: marker for future events or mediator of events? Curr Opin Cardiol
26. Angeli F, Reboldi G, Verdecchia P. Microcirculation and left-ventricular hypertrophy. J Hypertens
27. Guidera SA, Steinberg JS. The signal-averaged P wave duration: a rapid and noninvasive marker of risk of atrial fibrillation. J Am Coll Cardiol
28. Satoh T, Zipes DP. Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation. J Cardiovasc Electrophysiol
29. Nattel S. New ideas about atrial fibrillation 50 years on. Nature
30. Boldt A, Wetzel U, Lauschke J, Weigl J, Gummert J, Hindricks G, et al. Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart
31. Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res
32. Ciaroni S, Cuenoud L, Bloch A. Clinical study to investigate the predictive parameters for the onset of atrial fibrillation in patients with essential hypertension. Am Heart J
33. Verdecchia P, Reboldi G, Gattobigio R, Bentivoglio M, Borgioni C, Angeli F, et al. Atrial fibrillation in hypertension: predictors and outcome. Hypertension
34. Maksimowicz-McKinnon K, Bhatt DL, Calabrese LH. Recent advances in vascular inflammation: C-reactive protein and other inflammatory biomarkers. Curr Opin Rheumatol
35. Salles GF, Fiszman R, Cardoso CR, Muxfeldt ES. Relation of left ventricular hypertrophy with systemic inflammation and endothelial damage in resistant hypertension. Hypertension
36. Pedrinelli R, Dell’Omo G, Di Bello V, Pellegrini G, Pucci L, Del Prato S, Penno G. Low-grade inflammation and microalbuminuria in hypertension. Arterioscler Thromb Vasc Biol
37. Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, Bauer JA. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation
38. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation
39. Kranzhofer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kubler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol
40. Boldt A, Wetzel U, Weigl J, Garbade J, Lauschke J, Hindricks G, et al. Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease. J Am Coll Cardiol
41. Cardin S, Li D, Thorin-Trescases N, Leung TK, Thorin E, Nattel S. Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways. Cardiovasc Res
42. Bang CN, Okin PM, Koøber L, Wachtell K, Gottlieb AB, Devereux RB. Psoriasis is associated with subsequent atrial fibrillation in hypertensive patients with left ventricular hypertrophy: the Losartan Intervention For Endpoint study. J Hypertens
43. Spodick DH. Arrhythmias during acute pericarditis. A prospective study of 100 consecutive cases. JAMA
44. Morgera T, Di Lenarda A, Dreas L, Pinamonti B, Humar F, Bussani R, et al. Electrocardiography of myocarditis revisited: clinical and prognostic significance of electrocardiographic changes. Am Heart J
45. Bruins P, te Velthuis H, Yazdanbakhsh AP, Jansen PG, van Hardevelt FW, de Beaumont EM, et al. Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia. Circulation
46. Reboldi G, Gentile G, Angeli F, Verdecchia P. Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trials. Vasc Health Risk Manag
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