**4. Medical therapy in chronic mitral regurgitation**

In chronic MR the persistent volume overload results in activation of compensatory mechanisms which include activation of sympathetic nervous system-renin angiotensin aldosterone system, the Frank-Starling mechanism and eccentric hypertrophy [3, 13]. Over the long-term, these compensatory mechanisms are deleterious and culminate in myocardial dysfunction and failure. These pathways have provided the rationale for benefit of medical therapy in MR. The following agents have been studied in chronic MR:


#### **4.1 Vasodilators in chronic mitral regurgitation**

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce the severity of MR and hence HF symptoms by decreasing the afterload and potentially reversing the remodelling process. The decrease in predominantly peripheral vascular resistance results primarily in decrease in the size of the LV and thus size of the mitral annulus and that of the regurgitant orifice [14–16].

ACEIs have been used in the treatment of systolic HF with significant reductions in morbidity and mortality [17]. In the context of MR, benazepril was used in dogs with moderate to severe MR and showed improved survival [18]. Wisenbaugh et al. studied the effects of captopril in 32 patients with severe isolated MR over a 6-month period, and found no difference in LV diameters or ejection fraction when compared to placebo [19]. In a trial on humans assessing a combined population of patients with moderate to severe aortic regurgitation and MR, a significant reduction in regurgitant fraction, LV end-systolic and end diastolic volumes and LV mass, was noted when quinapril was used [20]. One study looked at the use of lisinopril in patients with chronic moderate MR with preserved LV ejection fraction and without symptoms. Twenty-three patients were randomised to receive lisinopril or placebo for a period of 12 months. A decrease in regurgitant fraction was noted in the group on lisinopril compared to the placebo arm without a change in left atrial or LV size [21].

In a paediatric case-control study of patients with moderate to severe MR the effect of ACEI on LV size and function was small after a follow-up period of 1 month to 1 year [22].

ARBs seem to produce a similar beneficial effect. In a, small study on the use of losartan for the treatment of MR, a modest but variable improvement in the severity of MR was noted. Specifically, the regurgitant volume and the effective regurgitant orifice decreased and the effect was durable for 1 month [15]. Another trial assessing moderate degenerative and rheumatic MR also found a beneficial effect with losartan over a 6-week period with regards to MR severity, LA size, and LV function [23].

Irbesartan was tested in an animal study. In this study irbesartan was administered to animals with new onset MR for a duration of 3 months. It reduced peripheral vascular resistance in the study group compared to group that received no therapy. However, no effect on LV dimensions was noted [24].

Hydralazine and lisinopril in combination with isosorbide dinitrate have been studied in patients with HF complicated by secondary MR [25, 26]. Hydralazine was tested in a small study of 15 patients with HF and MR, it should a variable response with half the patients showing no or minimal improvement over a follow-up period of 13 months. A second study looked at the benefit of lisinopril and isosorbide dinitrate in patients with HF and MR. This study showed an overall improvement in symptoms, hospitalisations due to HF and in peak oxygen consumption. In terms of reduction in MR severity and LV size, the response was variable.

It is important to note the aetiology of MR when using drugs that venodilate. Venodilators tend to worsen MR in patients with a fixed orifice such as rheumatic heart disease. In these patients venodilation results in a decrease in pulmonary venous pressure and hence a decrease in left atrial pressure, which results in tendency of the blood to follow the path of least resistance, that is, from LV into the left atrium. A reduction in just the systemic vascular resistance as in patients with rheumatic MR and co-morbidity of hypertension results in decrease in MR severity [26].

#### **4.2 Beta blockers in chronic mitral regurgitation**

The adrenergic system becomes activated at an early stage in patients with mitral regurgitation [27]. It acts as a support mechanism to maintain the contractility and cardiac output in MR. However, catecholamines are deleterious overlong term. Increased catecholamines induce myocyte apoptosis [28]. Hence, beta blockers are beneficial by preventing cardiac myocyte death due to excessive sympathetic activity.

Beta-blockade has demonstrated efficacy in reducing mortality in patients with cardiac failure due to non-valvular causes [17]. In canine models with chronic experimental MR chronic beta-blocker therapy improves LV function [13]. A pilot study involving patients with moderate to severe MR on beta-blocker therapy (metoprolol) was conducted over a 2-week period. Cardiac magnetic resonance imaging was used

**71**

*Role of Medical Therapy in Chronic Mitral Regurgitation*

end-diastolic volume or LV end-systolic volume was noted [30].

**4.3 Aldosterone receptor antagonist in chronic mitral regurgitation**

Aldosterone play an important role in HF progression [31]. In HF there is a decline in cardiac output which results in the activation of neurohormonal system and the renin angiotensin aldosterone pathway. The increased level of aldosterone stimulates inflammation and cardiac fibrosis. This results in pathologic cardiac

Spironolactone has been evaluated in the context of systolic HF resulting in favourable LV remodelling and a decline in morbidity and mortality through aldosterone antagonism [17, 32]. The mortality reduction in HF was attributed to a decrease in sudden death and progression of HF. No human trials with spironolactone in MR have been noted in the literature. In dogs however, a study investigating spironolactone in moderate to severe MR resulted in a significant reduction (55%) in a composite end-point of cardiac-related death, euthanasia, or severe worsening

**4.4 Combination anti-remodelling therapy in chronic mitral regurgitation**

therapy in systolic HF as a result of ischaemia and cardiomyopathies [17, 34, 35]. Guidelines on valvular heart disease recommend medical therapy for HF (EF < 50%)

in chronic MR (class IIa, level of evidence B) [36]. However, there are no randomised controlled studies on effects of combination therapy in HF secondary to MR. Recently, in a small observational study Meel et al. showed that combination anti-remodelling therapy may be beneficial for HF secondary to chronic rheumatic MR with no HF related admissions or deaths, and no deterioration in echocardio-

graphic parameters of ventricular size and function [37].

There is proven mortality and morbidity benefit of combination anti-remodelling

Most of above-mentioned trials were small studies involving vasodilators such as ACEIs and beta-blockers in degenerative MR and have been inconclusive. There is limited data pertaining to role of medical therapy in rheumatic MR. In general, LV dysfunction secondary to primary MR tends to respond poorly compared to LV dysfunction complicated by secondary MR. Currently there is no role of medical therapy in asymptomatic patients with chronic MR and preserved LV systolic function. Larger studies are needed to confirm benefit of medical therapy in

to follow-up this cohort. No reduction in regurgitant volume was demonstrated, however, LV work was reduced by beta-blocker therapy [29]. A larger study was therefore proposed to assess the effect of beta-blockers on LV function and symptoms due to MR. A subsequent trial was published, involving patients with moderate to severe, degenerative MR on beta-blocker therapy, (metoprolol) over a 2-year follow-up. LV function was assessed using cardiac magnetic resonance imaging. Improvements were found in LV ejection fraction and LV early diastolic filling rate. No change in LV

*DOI: http://dx.doi.org/10.5772/intechopen.89027*

remodelling.

of MR [33].

**5. Conclusion**

chronic MR.

**Conflicts of interest**

The author has no conflicts of interest.

*Role of Medical Therapy in Chronic Mitral Regurgitation DOI: http://dx.doi.org/10.5772/intechopen.89027*

*The Current Perspectives on Coronary Artery Bypass Grafting*

1 month to 1 year [22].

LV function [23].

severity [26].

period, and found no difference in LV diameters or ejection fraction when compared to placebo [19]. In a trial on humans assessing a combined population of patients with moderate to severe aortic regurgitation and MR, a significant reduction in regurgitant fraction, LV end-systolic and end diastolic volumes and LV mass, was noted when quinapril was used [20]. One study looked at the use of lisinopril in patients with chronic moderate MR with preserved LV ejection fraction and without symptoms. Twenty-three patients were randomised to receive lisinopril or placebo for a period of 12 months. A decrease in regurgitant fraction was noted in the group on lisinopril

compared to the placebo arm without a change in left atrial or LV size [21].

In a paediatric case-control study of patients with moderate to severe MR the effect of ACEI on LV size and function was small after a follow-up period of

ARBs seem to produce a similar beneficial effect. In a, small study on the use of losartan for the treatment of MR, a modest but variable improvement in the severity of MR was noted. Specifically, the regurgitant volume and the effective regurgitant orifice decreased and the effect was durable for 1 month [15]. Another trial assessing moderate degenerative and rheumatic MR also found a beneficial effect with losartan over a 6-week period with regards to MR severity, LA size, and

Irbesartan was tested in an animal study. In this study irbesartan was administered to animals with new onset MR for a duration of 3 months. It reduced peripheral vascular resistance in the study group compared to group that received no

Hydralazine and lisinopril in combination with isosorbide dinitrate have been studied in patients with HF complicated by secondary MR [25, 26]. Hydralazine was tested in a small study of 15 patients with HF and MR, it should a variable response with half the patients showing no or minimal improvement over a follow-up period of 13 months. A second study looked at the benefit of lisinopril and isosorbide dinitrate in patients with HF and MR. This study showed an overall improvement in symptoms, hospitalisations due to HF and in peak oxygen consumption. In terms of

It is important to note the aetiology of MR when using drugs that venodilate. Venodilators tend to worsen MR in patients with a fixed orifice such as rheumatic heart disease. In these patients venodilation results in a decrease in pulmonary venous pressure and hence a decrease in left atrial pressure, which results in tendency of the blood to follow the path of least resistance, that is, from LV into the left atrium. A reduction in just the systemic vascular resistance as in patients with rheumatic MR and co-morbidity of hypertension results in decrease in MR

The adrenergic system becomes activated at an early stage in patients with mitral regurgitation [27]. It acts as a support mechanism to maintain the contractility and cardiac output in MR. However, catecholamines are deleterious overlong term. Increased catecholamines induce myocyte apoptosis [28]. Hence, beta blockers are beneficial by preventing cardiac myocyte death due to excessive sympathetic

Beta-blockade has demonstrated efficacy in reducing mortality in patients with cardiac failure due to non-valvular causes [17]. In canine models with chronic experimental MR chronic beta-blocker therapy improves LV function [13]. A pilot study involving patients with moderate to severe MR on beta-blocker therapy (metoprolol) was conducted over a 2-week period. Cardiac magnetic resonance imaging was used

therapy. However, no effect on LV dimensions was noted [24].

reduction in MR severity and LV size, the response was variable.

**4.2 Beta blockers in chronic mitral regurgitation**

**70**

activity.

to follow-up this cohort. No reduction in regurgitant volume was demonstrated, however, LV work was reduced by beta-blocker therapy [29]. A larger study was therefore proposed to assess the effect of beta-blockers on LV function and symptoms due to MR. A subsequent trial was published, involving patients with moderate to severe, degenerative MR on beta-blocker therapy, (metoprolol) over a 2-year follow-up. LV function was assessed using cardiac magnetic resonance imaging. Improvements were found in LV ejection fraction and LV early diastolic filling rate. No change in LV end-diastolic volume or LV end-systolic volume was noted [30].

#### **4.3 Aldosterone receptor antagonist in chronic mitral regurgitation**

Aldosterone play an important role in HF progression [31]. In HF there is a decline in cardiac output which results in the activation of neurohormonal system and the renin angiotensin aldosterone pathway. The increased level of aldosterone stimulates inflammation and cardiac fibrosis. This results in pathologic cardiac remodelling.

Spironolactone has been evaluated in the context of systolic HF resulting in favourable LV remodelling and a decline in morbidity and mortality through aldosterone antagonism [17, 32]. The mortality reduction in HF was attributed to a decrease in sudden death and progression of HF. No human trials with spironolactone in MR have been noted in the literature. In dogs however, a study investigating spironolactone in moderate to severe MR resulted in a significant reduction (55%) in a composite end-point of cardiac-related death, euthanasia, or severe worsening of MR [33].

#### **4.4 Combination anti-remodelling therapy in chronic mitral regurgitation**

There is proven mortality and morbidity benefit of combination anti-remodelling therapy in systolic HF as a result of ischaemia and cardiomyopathies [17, 34, 35]. Guidelines on valvular heart disease recommend medical therapy for HF (EF < 50%) in chronic MR (class IIa, level of evidence B) [36]. However, there are no randomised controlled studies on effects of combination therapy in HF secondary to MR. Recently, in a small observational study Meel et al. showed that combination anti-remodelling therapy may be beneficial for HF secondary to chronic rheumatic MR with no HF related admissions or deaths, and no deterioration in echocardiographic parameters of ventricular size and function [37].

### **5. Conclusion**

Most of above-mentioned trials were small studies involving vasodilators such as ACEIs and beta-blockers in degenerative MR and have been inconclusive. There is limited data pertaining to role of medical therapy in rheumatic MR. In general, LV dysfunction secondary to primary MR tends to respond poorly compared to LV dysfunction complicated by secondary MR. Currently there is no role of medical therapy in asymptomatic patients with chronic MR and preserved LV systolic function. Larger studies are needed to confirm benefit of medical therapy in chronic MR.

#### **Conflicts of interest**

The author has no conflicts of interest.
