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Ann Thorac Surg 2010;90:1899-1903. doi:10.1016/j.athoracsur.2010.08.023
© 2010 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Dual Renin-Angiotensin System Blockade for Patients With Prosthesis-Patient Mismatch

Umberto Benedetto, MD, PhD*, Giovanni Melina, MD, PhD, Simone Refice, MD, Roberta di Bartolomeo, MD, Antonino Roscitano, MD, Emiliano Angeloni, MD, Riccardo Sinatra, MD

Department of Cardiac Surgery, II School of Medicine, University of Rome "La Sapienza," Policlinico S. Andrea, Rome, Italy

Accepted for publication August 13, 2010.

Abbreviations and Acronyms ACEi = angiotensin-converting enzyme inhibitors; ARB = angiotensin II receptor blocker; AVR = aortic valve replacement; BP = blood pressure; EOA = effective orifice area; LV = left ventricular; LVID = left ventricular internal diameter; LVMI = left ventricular mass index; PPM = prosthesis-patient mismatch; PWT = posterior wall thickness; RAS = renin–angiotensin system; SWT = septal wall thickness

* Address correspondence to Dr Benedetto, Department of Cardiac Surgery, II School of Medicine, University of Rome "La Sapienza," Via di Grottarossa 1039, Rome, 00181, Italy (Email: u2benedetto{at}libero.it).

Presented at the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 25–27, 2010.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
Background: Patients with prosthesis-patient mismatch (PPM) continue to show some degrees of left ventricular hypertrophy after aortic valve replacement for aortic stenosis. The renin-angiotensin system plays a major role in promoting and sustaining hypertrophy. In a controlled, randomized study, we tested the hypothesis that the combination of angiotensin-converting enzyme inhibitors (ACEi) plus angiotensin II receptor blocker (ARB) can be more effective in decreasing hypertrophy than a largely employed association such as ACEi plus ß-blockers in PPM patients.

Methods: We enrolled a total of 72 patients with aortic valve replacement and evidence of PPM (effective orifice area <0.85 cm2/m2) at postoperative echocardiography. At discharge, they were randomly assigned to ramipril plus candesartan (n = 36) or ramipril plus metoprolol (n = 36).

Results: At baseline, age, 24-hour blood pressure, left ventricular measurements, and transprosthetic gradients were similar between the two groups. After 12 months, the extent of 24-hour systolic and diastolic blood pressure decrease was similar between the two groups (–13.3% and 16.3% versus –12.3% and 15.8%, respectively; p = 0.7 and 0.8, respectively). Left ventricular mass index significantly decreased in both groups (ACEi plus ARB 165 ± 19 g/m2 to 117 ± 17 g/m2; p < 0.0001; ACEi plus β-blockers 161 ± 15 g/m2 to 128 ± 20 g/m2; p < 0.0001). However, patients receiving ACEi plus ARB had a higher decrease of left ventricular mass (–46 ± 15 g/m2 versus –35 ± 12 g/m2; p = 0.001) and a lower rate of residual left ventricular hypertrophy (22% versus 47%; p = 0.04).

Conclusions: This study shows that in patients with PPM, the association ACEi and ARB has a greater antiremodeling effect compared with ACEi and β-blockers, and is independent of blood pressure.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Discussion
 References
 
Residual left ventricular (LV) hypertrophy remains a major concern after aortic valve replacement (AVR) for aortic stenosis because it is associated with an increased rate of adverse events such as myocardial infarction, sudden death, and congestive heart failure [1]. Prosthesis-patients mismatch (PPM), which occurs when a small-sized prosthesis is implanted, has been advocated as one of the most important determinant of incomplete LV mass regression [2].

The renin-angiotensin system (RAS) has been shown to have a major role in promoting the development of LV hypertrophy in chronic pressure overload conditions such as hypertension [3, 4] and aortic stenosis [5]. Angiotensin-converting enzyme inhibitors (ACEi), modulating the RAS, may be an attractive strategy to enhance LV reverse remodeling in these settings [6, 7]; and these effects appear to be, at least partly, independent of ACEi ability to lower blood pressure (BP) [8].

However, there is evidence that chronic ACEi treatment results in incomplete suppression of angiotensin II levels, which may reduce the drug's effectiveness on BP and LV remodeling [9, 10]. Angiotensin AT1 receptors blockers (ARB) interfere with RAS activity in a different way, blocking AT1 receptors. It has been suggested that a combination treatment with ACEi plus ARB, providing a more complete RAS blockade, may increase the effectiveness of therapy in reducing LV hypertrophy and fibrosis [11].

Therefore, we tested the hypothesis that dual RAS blockade (ACEi plus ARB) can be more effective in promoting LV hypertrophy regression in patients with PPM after AVR for aortic stenosis than a largely employed association such as ACEi plus β-blockers.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Discussion
 References
 
Our Local Ethics Committee approved this study and waived the need for patient consent.

Among consecutive patients undergoing isolated AVR for aortic stenosis between May 2005 and January 2009, we enrolled those who presented at postoperative echocardiographic examination (within 7 days from surgery) with the following criteria: (1) LV hypertrophy defined as a LV mass index (LVMI) greater than 115 g/m2 (men) or greater than 95 g/m2 (women) [12]; and (2) PPM defined as an individual effective orifice area (EOA) indexed for body surface area of 0.85 cm2/m2 or less [13]. Patients with the following characteristics were excluded: (1) serum creatinine 2 mg/dL or greater at discharge; (2) chronic obstructive pulmonary disease requiring β2-agonist and LV ejection fraction less than 0.50 at discharge; (3) heart rate at discharge less 60 beats per minute; and (4) patients who died within 30 days from surgery.

All patients received oral ramipril 2.5 mg per day and hydroclorotiazide 12.5 mg per day postoperatively. Before discharge, the patients had noninvasive 24-hour ambulatory BP monitoring and then were randomly assigned to treatment: the ACEi plus ARB group, candesartan 8 mg per day; and the ACEi plus β-blocker group, metoprolol 50 mg per day.

After discharge, the patients underwent follow-up examinations at 1, 3, and 6 months. During these outpatient clinic visits, BP was measured by sphygmomanometer three times, at 5-minute intervals in the sitting position after a 20-minute rest. At the first visit (1 month), if BP was still 140 mm Hg and 90 mm Hg or greater, ramipril was uptitrated to 5 mg per day in both groups. At the second visit (3 months), if BP was still 140 mm Hg and 90 mm Hg or greater, ramipril was uptitrated to 10 mg per day in both groups. At 6 months, if clinic blood pressure was still greater than 140 mm Hg and 90 mm Hg, hydroclorotiazide was uptitrated to 25 mg per day.

At 12 months from surgery, all the patients underwent noninvasive 24-hour ambulatory blood pressure monitoring and echocardiographic examination, and serum creatinine and potassium levels were determined using standard methods.

Echocardiographic Examination
The echocardiographic examination was performed using a Sonos 5500 with a 2.0/2.5 MHz transducer (Hewlett-Packard, Andover, MA). Left ventricular M-mode echocardiograms were recorded under two-dimensional control, at a paper speed of 100 mm/s, with a simultaneous electrocardiogram. A single operator, not aware of drug treatment, performed all the examinations.

From the short-axis view just basal to the papillary muscles, M-mode measurement for the septal wall thickness (SWT), posterior wall thickness (PWT), and LV internal diameter (LVID) were obtained. These were used in the cube-function formula for American Society of Echocardiography guidelines [14] to calculate LV mass according to following formula:


Formula 0005

(0005)

The LV mass was normalized for body surface area. Relative wall thickness (RWT) was calculated as 2 PWT divided by LVID. Left ventricular ejection fraction was assessed by the Simpson rule.

The prosthesis valve EOA was derived from the continuity equation:


Formula 0010

(0010)
where LVOT is the diameter of the LV outflow tract and TVI1 and TVI2 are the time-velocity integrals at the LV outflow tract and across the aortic valve, respectively. The peak and mean gradient was measured by use of continuous-wave Doppler echocardiography and the simplified Bernoulli equation.

Statistical Analysis
A sample size of approximately 36 patients per treatment arm was estimated on the basis of a standard deviation of 15 g/m2 for the primary outcome, change in LVMI from baseline to 12 months, a 10 g/m2 clinically meaningful difference between groups, and 80% power at a 0.05 significance level to reject the null hypothesis of equal means for ACEi plus ARB versus ACEi plus β-blockers with a two-sided test. A computer-generated random list (GraphPad Software, San Diego, CA) was used to allocate patients in each group.

The statistical evaluation of the results was carried out by means of two-by-two analysis of variance (between two treatment groups; repeated measures with two levels: basal and second evaluation) to (1) compare basal values between the two groups, (2) evaluate longitudinal changes within each group, and (3) compare the effects of treatments (ACEi plus ARB versus ACEi plus β-blockers) on BP and LV. Data were reported as mean ± SD. A probability value less than 0.05 was considered statistically significant. Statistical analysis was performed using the Statistical Package for the Social Sciences, version 11 (SPSS Inc, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Discussion
 References
 
A total of 161 patients undergoing AVR for aortic stenosis with biological (Carpentier-Edwards Perimount Magna; Edwards Lifesciences, Irvine, CA) or mechanical prosthesis (CarboMedics; Sulzer CarboMedics, Austin, TX) were screened during the study period. Reasons for exclusion were no PPM (n = 71) at postoperative echocardiography; creatinine clearance of 30 mL/min or less at discharge (n = 12); and death within 30 days from surgery (n = 6). Finally, a total of 72 patients was enrolled in the study. At discharge, 36 patients were randomly assigned to ramipril plus candesartan and 36 patients to ramipril plus metoprolol. All patients enrolled completed a 12-month follow-up.

Basal Evaluation
After randomization, the two groups were similar with regard to demographic characteristics and operative data (Table 1). All patients received a 19-mm or 21-mm size prosthesis, and no 23-mm or larger prosthesis was implanted. Mean prosthesis effective orifice area was greater than 1 cm2 for all patients and mean indexed EOA was 0.75 ± 0.08 cm2/m2. At discharge, 24-hour BP, heart rate, serum creatinine, and potassium were similar between the two groups as were LV morphofunctional variables at basal echocardiographic examination (Table 2).


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  		Table 1 Baseline Characteristics
 

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  		Table 2 Mean Values (± SD) of 24-Hour Systolic and Diastolic Blood Pressure, 24-Hour Heart Rate, Left Ventricular Morphofunctional Variables, Serum Creatinine, and Potassium Levels at Basal Evaluation and After 12-Month Treatment
 
Twelve-Month Follow-Up Results
At follow-up, the drugs doses were as follows: in the ACEis plus ARBs group, 30 of 36 patients received hydroclorotiazide 12.5 mg per day, and 6 of 36 received 25 mg; ramipril was administered at 5 mg per day to 24 of 36 patients and at 10 mg to 12 of 36 patients; candesartan was administered at 8 mg per day to 36 of 36 patients. In the ACEis plus β-blocker group, 25 of 36 patients received hydroclorotiazide 12.5 mg per day, and 11 received 25 mg per day; ramipril was administered at a dose of 5 mg per day to 28 of 36 patients and at 10 mg to 8 of 36 patients; methoprolol was administered at 50 mg per day to 36 of 36 patients.

After 12 months of treatment, BP values throughout 24 hours were significantly lower from basal in both groups, without significant treatment effect. This effect was evident for both systolic and diastolic values (Table 2, Fig 1). Uncontrolled hypertension after 12 months of treatment was present in 6 of 36 patients (16%) in the ACEi plus ARB group versus 5 of 36 patients (14%) in the ACEi plus β-blockers group (p = 0.04). This group received an average dose of ramipril similar to that of patients who had BP values within normal range (6.6 ± 2.5 mg versus 6.1 ± 2.3 mg; p = 0.38). Heart rate was lower for patients receiving ACEis plus β-blockers. Serum creatinine and potassium levels were unchanged in both groups.


Figure 1
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  		Fig 1. Mean percent changes between basal and 12-month evaluation in septal wall thickness (SWT), posterior wall thickness (PWT), left ventricular internal diameter (LVID), left ventricular mass index (LVMi), 24-hour blood pressure (BP), and heart rate (HR) in angiotensin-converting enzyme inhibitor (ACEi) plus angiotensin II receptor blocker (ARB) group (dark gray bars) and ACEi plus β-blocker (βB) group (light gray bars). *p < 0.05.

 
The LVMI significantly decreased in both groups (ACEi plus ARB, 165 ± 19 g/m2 to 117 ± 17 g/m2, p < 0.0001; ACEi plus β-blockers, 161 ± 15 g/m2 to 128 ± 20 g/m2, p < 0.0001), and the reduction in LV mass was related to a decrease in septal and posterior wall thickness without changes in LV internal diameter. Patients who received ACEi plus ARB had a higher decrease of LVMI (–46 ± 15 g/m2 versus –35 ± 12 g/m2, p = 0.001; Table 2, Fig 1), and residual LV hypertrophy persisted in 8 of 36 patients (22%) versus 17 of 36 patients (47%) in the ACEi plus ARB group and ACEi plus β-blockers group, respectively (p = 0.04).

Patients showing uncontrolled hypertension after 12 months of treatment had a less evident decrease in LV mass when compared with patients whose BP values were in a normal range (–28 ± 15 g/m2 versus –49 ± 12 g/m2, p < 0.001).

The advantage of dual RAS blockade over ACEi plus β-blockers on the extent of LV mass regression persisted when the analysis was restricted to patients with controlled BP at last follow-up (–48 ± 9 g/m2 versus –39 ± 11 g/m2, p = 0.0009), diabetic patients (–49 ± 12 g/m2 versus –36 ± 13 g/m2, p = 0.04), and patients receiving a full dose of ramipril (10 mg) at last follow-up (–45 ± 10 g/m2 versus –38 ± 11 g/m2, p = 0.02).


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Discussion
 References
 
This study showed that dual RAS blockade (ACEi plus ARB) is more effective in promoting LV hypertrophy regression than a largely employed association such as ACEi plus β-blockers in patients with evidence of PPM after AVR for aortic stenosis. This effect was BP independent since both strategies achieved a similar BP control. Incomplete LV hypertrophy regression after AVR for aortic stenosis patients may be a cause of long-term complications such as sudden death and congestive heart failure [1].

Previous studies have shown that PPM has a detrimental effect on postoperative reduction of LV mass, and PPM was reported as an independent predictor of cardiac events and mortality after AVR [2]. Despite this evidence, the reported prevalence of PPM after AVR was relevant, varying between 20% and 70% [13]. Indeed, to implant a larger prosthesis, it is usually necessary to adopt surgical strategies such as aortic root enlargement, which can be technically demanding and may increase the operative risk [13]. In addition, the use of stentless xenografts has been shown to obtain a marked, but only transient, success on LV mass regression at the expense of complicated procedure, and future degeneration is probably inevitable. When the drawbacks of using these techniques are believed to overcome the benefits of avoiding PPM, many surgeons decide to implant a "small" prosthesis.

Alternative strategies are needed to promote LV mass regression in patients undergoing AVR who have evidence of PPM postoperatively. Blood pressure control has been shown to be particularly important in LV hypertrophy regression after AVR. However, despite satisfying BP control, approximately 50% of patients continue to show some degree of LV hypertrophy [15]. Therefore, research should be broaden for potential causes affecting LV mass regression beyond chronic pressure overload.

The RAS has been shown to play a major role in promoting and substaining LV hypertrophy in hypertension [6, 7]. In this setting, chronic treatment with ACEi has been shown to have a BP-independent effect on LV mass regression [6, 7]. In addition, as ACEi treatment results in incomplete suppression of angiotensin II levels, the combination treatment with ACEi plus ARB, provides a more complete RAS blockade, thus increasing the effectiveness of therapy on LV mass regression [11].

As occurs in hypertensive patients, in aortic stenosis, the RAS regulates myocardial remodeling, promoting fibroblast proliferation, fibrosis, and directly affecting the extracellular matrix [5]. This process is modulated by an increase in ACE and AT1-receptor gene expression. In a model of compensated LV hypertrophy, it has been shown that myocardial remodeling as well as RAS gene expression are reversible after corrective surgical therapy [5]. The change in RAS gene expression can be considered part of the adaptive process of the left ventricle. These findings have suggested that after corrective surgical therapy for aortic stenosis, medical therapy modulating the RAS may be an additional strategy to enhance ventricular reverse remodeling. This therapeutic effect may be particularly useful for patients with PPM after surgery. In this setting, a chronic pressure overload persists, thus preventing the normalization of LV mass regardless of surgical correction.

In this study, we demonstrated the superiority of dual RAS blockade over ACEi plus β-blockers to promote LV mass regression in PPM patients. This medical strategy achieved a 25% absolute reduction in the incidence of residual LV hypertrophy. This result did not account for differences in BP changes, because the decrease in BP was similar for both treatments. In addition, this advantage persisted when the analysis was restricted to patients with BP values within normal range after 12 months of treatment. Dual RAS blockade was well tolerated, as was ACEi plus ß-blocker. Creatinine and potassium levels did not change throughout the study in both groups. However, it should be underlined that we did not enroll patients with significant impairment of renal function, and a deleterious effect of dual RAS blockade can not be excluded in such patients.

The major limitation of this study was that we were unable to demonstrate any advantage from dual therapy in terms of functional improvement. Most patients (95%) were completely asymptomatic at rest in both groups, and exercise tolerability was not evaluated. Whether dual RAS blockade may enhance exercise tolerance remains to be determined. Finally, this study did not address pathophysiologic mechanisms. However, our results are supported by previous experimental studies demonstrating that RAS gene expression is part of the adaptive process of the left ventricle to chronic pressure overload [5].

In conclusion, dual RAS blockade was safe and allowed obtaining complete LV hypertrophy regression in most patients despite the presence of PPM. This effect was partially BP independent. Therefore, this therapy should be recommended for patients with evidence of PPM after AVR for aortic stenosis.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
References
 
DR WALTER MERRILL (Jackson, MS): Let me ask you if there has been any thought given to increasing the intensity of the medical regimen in the postoperataive period, because it seems that at follow-up, the patients still had a pretty high blood pressure.

DR BENEDETTO: Yes, the patients had periodic follow-up to optimize blood pressure control according to a prespecified protocol. At 12-month follow-up, about 20% of patients had no blood pressure control, but they were similar in the two groups.

DR MERRILL: I might also ask if you think with longer-term follow-up there might be a difference in their long-term survival prospects?

DR BENEDETTO: We chose this cutoff at 12 months since a lot of studies show us that the left ventricular hypertrophy regression developed in the first 12 months, and then there was no other change in left ventricular hypertrophy regression, maybe for the irreversible component of hypertrophy. Yes, at long-term follow-up, we have to assess survival benefit and also functional benefit of this therapy, and at this time, we can show a diastolic improvement, but the functional class was not completely assessed.

DR MARTIN CZERNY (Berne, Switzerland): Thank you for this presentation. I have a question regarding the gradients. You didn't tell us about that. Could you comment on the gradients between both groups?

DR BENEDETTO: We have shown on the slides that the mean gradient was 20 to 25 mm, and it was similar in each group. At follow-up, it did not change significantly.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 

  1. Mihaljevic T, Nowicki ER, Rajeswaran J, et al. Survival after valve replacement for aortic stenosis: implications for decision making J Thorac Cardiovasc Surg 2008;135:1270-1278.[Abstract/Free Full Text]
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  3. Weber KT. Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation Circulation 1997;96:4065-4082.[Free Full Text]
  4. Varo N, Etayo J, Zalba G, Monrea LI, Diez J. Losartan inhibits the post-transcriptional synthesis of collagen type I and reverse left ventricular fibrosis in spontaneously hypertensive rats J Hypertens 1997;17:107-114.
  5. Walther T, Schubert A, Falk V, et al. Left ventricular reverse remodeling after surgical therapy for aortic stenosis: correlation to renin-angiotensin system gene expression Circulation 2002;106:I23-I26.[Medline]
  6. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease Circulation 2000;102:1388-1393.[Abstract/Free Full Text]
  7. Mathew J, Sleight P, Lonn E, et al. Heart Outcomes Prevention Evaluation (HOPE) Investigators Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril Circulation 2001;104:1615-1621.[Abstract/Free Full Text]
  8. Grandi AM, Bignotti M, Gaudio G, Zanzi P, Guasti L, Venco A. Ambulatory blood pressure and left ventricular changes during antihypertensive treatment: perindopril versus isradipine J Cardiovasc Pharmacol 1995;26:737-741.[Medline]
  9. Juillerat L, Nussberger J, Ménard J, et al. Determinants of angiotensin II generation during converting enzyme inhibition Hypertension 1990;16:564-572.[Abstract/Free Full Text]
  10. Sato A, Saruta T. Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy Am J Hypertens 2003;16:781-788.[Medline]
  11. Grandi AM, Solbiati F, Laurita E, et al. Effects of dual blockade of renin–angiotensin system on concentric left ventricular hypertrophy in essential hypertension: a randomized, controlled pilot study Am J Hypertens 2008;21:234-240.
  12. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification Eur J Echocardiogr 2006;7:79-108.[Abstract/Free Full Text]
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  15. Imanakaa K, Kohmotob O, Nishimurab S, Yokotea Y, Kyoa S. Impact of postoperative blood pressure control on regression of left ventricular mass following valve replacement for aortic stenosis Eur J Cardiothorac Surg 2005;27:994-999.[Abstract/Free Full Text]




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