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Atrial Fibrillation and Co-Morbidity

Dalmo A. R. Moreira M.D, PhD

Dante Pazzanese Institute of Cardiology
São Paulo, Brazil

Atrial fibrillation is an arrhythmia caused by multiple factors, which makes its treatment
sometimes complex, involving different classes of drugs whose effects are additive. This
observation underscores the importance of heterogeneity of mechanisms involved in the
genesis of atrial fibrillation, with obvious implications in various modes of treatment,
indicating that the same form of address should not show the same result for all the
different causes of this arrhythmia. Atrial fibrillation is often associated with other medical
conditions for which identification and pharmacological approach, become necessary when
one wants to also correct the rhythm disturbance. Such conditions not only facilitate atrial
fibrillation emergence, as aggravate its evolution making it something more serious than it
would if it was presented alone. This presentation will discuss the main co-morbidities
associated with atrial fibrillation and how the treatment of these conditions affect the results
of treatment of arrhythmia specifically.

Cardiac and non-cardiac causes of Atrial Fibrillation

Hypertension and heart failure are the most frequently causes associated with the onset of
atrial fibrillation and, among the noncardiac causes, distinguished by its frequency, is the
metabolic syndrome. Although some patients can develop hyperthyroidism with atrial
fibrillation, this is not a frequent cause in the clinic. In general, for clinical matters, it is very
unlikely to maintain a normal heart rhythm if these co-morbidities are not identified and

Heart Failure

There is frequent association of heart failure (50% of cases) with atrial fibrillation, the point
of not knowing at the clinic, which was manifested first1. Moreover, the therapeutic success
of a condition surely brings impact on treatment outcomes in another. In other words, for
the compensation of a heart failure state, it is crucial that the heart rate in atrial fibrillation is
controlled or sinus rhythm restored. The same must be said with regard to atrial fibrillation,
that is, normal heart rhythm can hardly be restored if the patient is not with their standard
hemodynamic conditions.

Patients with heart failure have elevated ventricular diastolic pressure, increased intra-atrial
pressure and increased pulmonary pressure. These factors enhance the appearance of
atrial ectopic beats, particularly in the left atrium near the territory of the pulmonary veins.
These ectopic foci may act as a mechanism for accelerating the atrial emptying, thus
permitting the reduction of pressure in the pulmonary veins. The consequence of this is that
the rapid and irregular atrial activation favors to atrial electrical histological remodeling that
facilitates the emergence and maintenance of atrial fibrillation. Furthermore, it has been
demonstrated experimentally that in animals with heart failure caused by rapid ventricular
pacing for more than two consecutive weeks, there is a higher potential emergence of
areas of fibrosis in the atria, another factor that favors the slow conduction and
unidirectional block in the spread of atrial activation wavefront. These effects are crucial for
triggering atrial reentry.

In clinical practice, treatment of patients with atrial fibrillation includes the use of an
antiarrhythmic drug. According to the international guidelines2 the only drug with proven
success in maintaining sinus rhythm in patients with heart failure is amiodarone. This agent
is safe because it has low risk for proarrhythmic effects, besides being effective in
preventing recurrences. In many cases sinus rhythm maintenance is achieved with low
doses, 100 to 200 mg daily. Moreover, it is essential that these patients are treated with a
regimen that involves diuretics, angiotensin converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs) and spironolactone. Diuretics reduce blood volume
and intra-atrial pressure, that may facilitate the reduction of the frequency of atrial ectopic
activity. ACEI or ARB reduces the degree of atrial fibrosis and relieve the intra-atrial
pressure. Beta-blockers such as carvedilol or metoprolol are beneficial in this population
because studies have show a significant reduction in recurrences of atrial fibrillation, as
well as in total and cardiovascular mortality. An anti-apoptosis and anti-oxidant effects and
also reduction of peripheral resistance (systemic vasodilation) would be the main
mechanisms of action of this class of drugs in patients with atrial fibrillation associated with
failure cardíaca3.
In cases of arrhythmia recurrence, it should be noted that the causes involved should be
investigated. Among them the incorrect use of medication stands out. Moreover, excessive
consumption of salt, infectious processes, excessive physical activity, or cardiovascular
stress factors, such as arterial hypertension or valvular disease, must be identified and
corrected. When it comes to excessive consumption of salt in many cases only increasing
the dose of diuretics can restore normal heart rhythm.


Hypertension, which evolves with left ventricular hypertrophy and left atrial enlargement, is
another risk factor that increases the likelihood of atrial fibrillation. It is one of the most
frequent comorbidity in patients with this arrhythmia. Increased left ventricular end diastolic
pressure which affects the left atrium, faciltates the appearance of ectopic atrial
arrhythmias. These ectopic beats may facilitate the appearance of electrical remodeling
and atrial myocyte histologic changes and predispose patients to atrial tachycardia and
atrial fibrillation at last. Another aggravating factor in this clinical condition is increased left
ventricular mass, crucial in the perpetuation of the increase in final diastolic pressure4.

Drugs that reduce left ventricular hypertrophy, as well as the degree of myocardial fibrosis,
decrease the possibility of recurrence of atrial fibrillation. Inhibitors of angiotensin
converting enzyme and valsartan and ramipril, reduced the incidence of atrial fibrillation in
hypertensive patients5, 6. There is a remarkable decrease of atrial fibrillation frequency when
arterial hypertension is controlled effectively. This finding is associated with reduced atrial
and left ventricular hypertrophy, a common finding in hypertensive disease.

Metabolic Syndrome

Both diabetes and hypertension, identified as independent predictors of cardiovascular risk

may be associated with obesity, sleep apnea and dyslipidemia, thus forming another group
of co-morbidities known as metabolic syndrome. The metabolic syndrome is recognized
today as an independent risk factor for onset of atrial fibrillation7. Specifically the production
of cytokines that cause cardiac inflammation (interleukin 6, tumor necrosis factor,
ultrasensitive C-reactive protein and others) is associated with the onset of atrial fibrillation,
particularly in individuals with normal hearts. One can prove the importance of inflammation
in metabolic syndrome by reducing the incidence of atrial fibrillation when patients are
treated with anti-inflammatory agents or even with statins. In general, however, treatment of
each of these factors, objectively, may reduce the risk of atrial fibrillation and improve
outcome of patients at risk.

In conclusion, these previous paragraphs indicates that the treatment of atrial fibrillation
should not be restricted only to antiarrhythmic drug, reinforcing the idea that atrial fibrillation
is an arrhythmia caused by multiple factors. The adjuvant medication plays an important
role and it is possible that treatment failures are not related to use of these agents.
Furthermore, systemic influences, mainly noncardiac, which facilitate the occurrence of
atrial fibrillation, can be addressed with this specific therapy, who together with
antiarrhythmics, should give greater stability to the electrical atrial tissue and reduce


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