Heart Disease and Atrial Fibrillation: DISCUSSION

In: Disease

24 Apr 2010

Atrial FibrillationDo Selective Beta, Blockers Affect Chronic Heart Failure Related to Rheumatic Fever?

The evidence supports a profound protective effect of beta blockers in their ability to inhibit activation of the neuro-endocrine system in regard to chronic HF: (1) the early activation of the sympathetic nervous system in chronic HF; (2) the beneficial effect of beta blockers on sudden death, especially important in early stages of chronic HF; and (3) the dual inhibitory effect of beta blockers on renin and the sympathetic nervous system.

ACE-inhibitors have been shown to decrease mortality by approximately 25% in patients with chronic HF. Some large outcome studies and several meta-analyses have documented a reduction in mortality of approximately 35% with the addition of a beta blocker. The escape of angiotensin II from ACE-inhibitors is attenuated in the patients who take beta blockers.

RHD is still an important cause of chronic HF in developing countries, including China. The predominant pathological change associated with RHD is rheumatic mitral stenosis. Numerous studies have reported increased sympathetic activity in patients with mitral stenosis, because low cardiac output mediated by mitral stenosis activates the sympathetic nervous system.
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As shown by Razzolini et al., sympathetic activity decreased after mitral balloon valvuloplasty was significantly correlated with the increase in the cardiac index. ACE-inhibitors or nonselective beta blockers with alpha-adrenergic activity have an obvious vasodilatory effect, which can worsen a low cardiac output, whereas a selective beta1 adrenoceptor antagonist (e.g., bisoprolol with a half-life of 10 to 12 hours) does not have any partial agonist or vasodilatory effect. On the basis of these assumptions, the selective beta1 blocker bisoprolol was used to treat chronic HF patients with RHD in this study.

We assessed 67 patients: 16 treated patients (48.5%) and 17 control patients (50.0%) had significant mitral stenosis. Thus, approximately 50% of patients with RHD had pure and non-pure mitral stenosis; for these patients, the use of vasodilators might be not appropriate. In our study, only 13 treated patients (39.4%) and 16 controls (47.1%) used an ACE-inhibitor/ARB.

The average maximum bisoprolol dose was 6.52 ± 2.7 mg/day. In the treatment group, 54.5% of patients tolerated at least 5 mg of bisoprolol once daily during the maintenance phase. Five patients (11.3%) withdrew from the study because of suspected ADEs from bisoprolol. No severe hypotension or bradycardia occurred. Bisoprolol decreased the length of hospitalstay, reduced the incidence of cardiac events, and improved exercise capacity over six to 12 months of treatment.

Our results were similar to the findings of the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Prospective Randomized Cumulative Survival Study (COPERNICUS), and the MERIT-HF trial. In our study, the average maximum bisoprolol dose was lower, but the tolerance of at least 5 mg of once daily was not significantly different from that of the CIBI-II trial (54.5% versus 67%), probably because the cause of chronic HF in our study differed from that in other studies.

Chronic HF caused by RHD is associated with a lower cardiac output, which can bring about deterioration in the increased sympathetic nervous system. However, our results and those of other studies showed that the benefits derived from bisoprolol, when used to treat patients with chronic HF, clearly outweighed the risk of ADEs.

In clinical practice, these patients cannot usually tolerate optimum doses of both an ACE-inhibitor and a beta blocker. This lack of tolerance is especially common among the elderly. The CIBIS-III findings indicated that chronic HF therapy should be not started with both an ACE-inhibitor and a beta blocker simultaneously, especially in elderly patients or in those with special circumstances. Therefore, we concluded that a selective beta1 blocker might be a reasonable choice of therapy for chronic HF patients with RHD.

Do Selective Beta, Blockers Affect Chronic Heart Failure Related to Atrial Fibrillation?

In patients with RHD, AF is the most common sustained arrhythmia and it is the most common cause of chronic HF resulting from a loss of atrial contraction and an associated rapid ventricular rate. One study showed that decreased sympathetic activity after balloon mitral valvuloplasty occurred only in patients with mitral stenosis and sinus rhythm but not in patients with AF. The results indicated that patients with mitral stenosis and AF experienced a more adverse neuro-hormonal change. However, the effects of selective beta1 block-ers on chronic HF accompanying AF remain to be explored.

In patients without HF, beta blockers improved ventricular rate control in AF when they were added to or when they were used alone. Among patients with AF and HF, only a few trials have suggested that beta blockers reduce ventricular rate, improve ventricular function, and are well tolerated. However, these studies used agents with high intrinsic sym-pathomimetic activity, and these agents are now generally thought to be contraindicated for patients with HF.

In our study, all patients in the treated group received biso-prolol. Thirty patients (90.9%) in the treated group and 32 patients (94.1%) in the control group used digoxin. Compared with the control patients, the treated patients showed a shorter length of hospital stay (-2.4 ± 3.8 days) and better exercise tolerance at discharge.

During six to 12 months of follow-up, the combined endpoint of chronic HF-related and thromboembolism-associated hospitalization or death decreased significantly, from 32.4% in the controls to 12.1% in the treated patients. The 24-hour average ventricular rate did not change significantly in the control group, but the rate did decrease in the treated patients (see Table 1). The difference in the absolute change between the two groups was statistically significant (P < .001).

We found that bisoprolol benefited patients with chronic HF related to RHD and AF. A study by Fung et al. supported the idea that the benefits of the beta blocker in patients with HF extend to patients with HF complicated by AF. The beta blocker had an incremental benefit when added to digoxin for the management of AF in patients with HF.

Are Selective Beta, Blockers More Useful in Chronic Heart Failure Accompanying Normal or Near-Normal Systolic Function?

LV diastolic dysfunction usually precedes systolic dysfunction, but it can also be present for a longer period of time, even years. Impairment of diastolic function appears to be age-related. Although fewer than 10% of patients with heart failure younger than 50 years of age tend to have diastolic dysfunction, the number rises to 70% in patients older than 80 years of age. However, the prognosis of chronic HF patients with preserved systolic function (or diastolic HF) is similar to that for those with systolic dysfunction.
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Although there is currently no worldwide accepted definition of diastolic HF, the American College of Cardiology/American Heart Association Guidelines have proposed that if patients have symptoms of HF but normal systolic function, they should be classified as having HF with preserved systolic function; thus, it is no longer mandatory for diastolic function to be assessed objectively in these patients.

Diastolic HF may originate because of conditions that alter the myocardial structure (i.e., AF and valvular heart dis-ease). A certain pattern of LV diastolic filling always results from a complex interaction of various factors such as heart rate and rhythm, preload, aortic or mitral valve disease, right ventricular (RV) competence, ventricle-septum interaction, active LV relaxation, LV elasticity properties, and LA contraction. Aging, disease progression, and changes in loading conditions may lead to diastolic dysfunction. It is known that atrial contraction is very important for the filling of the heart, especially in elderly patients. Thus, abbreviated filling, in terms of sudden onset of AF, may exacerbate diastolic dysfunction and may even cause dramatic symptoms and signs (pulmonary congestion). We found the incidence of AF to be higher in subjects with diastolic HF, that is, in a quarter to a third of patients.

In the Italian Network on Congestive Heart Failure (IN-CHF) registry,16°% of patients with a low LVEF had AF, compared with 25% of patients with an LVEF above 45%.

In a multivariate analysis, AF was an independent predictor of a higher risk of diastolic HF in patients hospitalized with chronic HF. According to pathophysiological changes, patients with RHD may be classified into two groups: (1) those with predominant mitral stenosis and (2) those with predominant mitral valve regurgitation and/or aortic lesions. Predominant mitral stenosis may result in dilation of the LA and a hyper-trophic right ventricle. The latter condition may cause an increased left-sided heart preload or afterload. Eventually, patients with either condition exhibit an elevated pulmonary artery pressure.

Various factors may lead to diastolic dysfunction by complex interactions because of a hemodynamic coupling of RV and LV functions. Patients with a cardiothoracic ratio below 65% and without severe hepatic or renal dysfunction were included in our study. There was no significant age difference between the controls and the treated patients (see Table 1). For all patients at discharge, the LVEF was higher than 40%. Only three patients had an LVEF below 45% (two treated patients and one control).

At the end of the study, we observed a significant change in LVEF: it measured below 45% in four patients (in one treated patient and in three control patients). All of the patients with an LVEF below 45% had combined mitral and aortic valve disease. Our findings supported the phenomenon that chronic HF related to AF and valvular heart disease without an advanced course had a normal or near-normal LV function.

How to best treat diastolic HF remains to be determined. The IMPROVEMENT-HF study and the IN-CHF registry showed that beta blocker use was higher in patients with diastolic HF, and patients with diastolic HF tolerated beta blockers well. Beta blockers were associated with decreased resting and peak exercise heart rates and blood pressure and an increased early and late (atrial) phase (E/A ratio). Many patients with impaired RV function or pulmonary hypertension have also benefited from beta blockers.

Some studies showed that a six-month course of carvedilol therapy did not reduce the LV diameter at end-diastole and at end-systole, but it did restore physiological early diastolic filling by complex interactions between relaxation and chamber stiffness. Our study also indicated the same phenomenon; the beneficial effect of bisoprolol was not significantly related to the changes in LV volume and systolic function.

It is known that baseline heart rates and changes in heart rates are related to the prognosis in patients with chronic HF. Perhaps resting heart rate, as a simple clinical surrogate for sympathetic nervous system activity, might prove to be a simple and clinically useful predictor of benefit from beta-blocker therapy. A short diastolic period is always detrimental if myocardial function is compromised. Beta blockers prolong the diastolic period more than they prolong the systolic period, which promotes diastolic filling, improves myocardial per-fusion and metabolism, and might offer direct protective action on the myocytes against catecholamine excess.

Bergstrom et al. noted that patients with higher heart rates benefited more from canadian carvedilol than patients with lower heart rates. Patients with a heart rate above 71 beats/minute who took carvedilol showed an improved E:A ratio and E-wave velocity, whereas there was less effect on the A-wave velocity, compared with the placebo group.

These findings indicate that patients with diastolic dysfunction and higher heart rates experience improved diastolic filling through a shift of diastolic volumes from late to early diastole. It appears that this redistribution of filling volumes toward a more normal pattern is brought about by an improvement in early filling in particular, thereby inducing a more normal filling pattern.

However, it is difficult to differentiate the effects on heart rate per se from other beta-blocker effects. There is evidence that the mode of action of beta blockade is not solely through the reduction of the heart rate. Other drugs with heart rate-reducing effects (e.g., calcium-channel blockers and digitalis) do not share the positive effects of beta blockers in HF treatment. The exact mechanism of their effect is not entirely clear, but the data suggest that the primary mechanism of action of beta blockers in chronic HF is to prevent and reverse adrenergically mediated intrinsic myocardial dysfunction and remodeling.

Our study included patients with a resting ventricular rate of at least 70 beats/minute. The 24-hour average ventricular rate decreased significantly in the treatment group, in contrast to the control patients. The significantly decreased LA diameter and reduced systolic were observed only in the treated patients. This difference in ventricular rates might be attributable to the fact that a selective beta1 blocker can allow longer diastolic filling by decreasing resting and exercise ventricular rates and may produce a higher cardiac output, thereby leading to a decreased atrial diameter.

Thus, we concluded that a selective beta1 blocker might be feasible for chronic HF accompanying normal or near-normal systolic function; we were less concerned about the negative inotropic effect of the beta blocker in patients with diastolic HF than we were about systolic HF. In our study, patients were somewhat younger, had higher basic ventricular rates, and did not have end-stage disease. This was also an important reason why bisoprolol exerted beneficial effects in this subgroup.

Study Limitations

We focused on patients with RHD and AF who had no complications associated with chronic HF, such as myocardial dysfunction and liver or renal dysfunction. It was necessary to include this highly selective population as a first step to identifying the feasibility and effectiveness of bisoprolol tablet without confounding variables. Further studies are needed to address the effect of bisoprolol in patients with advanced RHD.

Another element of potential bias was the use of an unblinded treatment, which might affect hospital patient discharges and subsequent admissions.


We suggest that a selective beta1 blocker, such as bisopro-lol, can improve NYHA class and exercise tolerance for patients with chronic HF related to RHD and AF. The advantage of these effects provided by this agent might be mediated by a reduction in ventricular rate and LA volume.

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